OTC Glutamatergic Augmentation Resolves Adolescent Refractory Somatic Symptoms

OTC Glutamatergic Augmentation Resolves Adolescent Refractory Somatic Symptoms | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report OTC Glutamatergic Augmentation Resolves Adolescent Refractory Somatic Symptoms Ngo Cheung This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8207734/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Persistent physical symptoms can trap adolescents in a cycle of pain, worry, and lost school time—especially when standard antidepressants provide only partial relief. This report describes a 17-year-old girl whose disabling somatic symptom disorder lifted after we tried a simple, fully oral "ketamine-like" combination. Case Summary: She had taken duloxetine 60 mg daily for more than a year yet still woke with pounding headaches, gasped for air without warning, and scratched her nails raw because they felt full of grit. Beginning 2 September 2025 we layered four medicines, one at a time: dextromethorphan (eventually 60 mg/day), fluoxetine 10 mg/day to slow its breakdown, piracetam (up to 1 200 mg/day), and L-glutamine 500 mg/day. She was seen monthly, her mood scored with the PHQ-9 and GAD-7, and her own account of day-to-day functioning recorded. Outcome: By the third visit the change was hard to miss. Headaches came only after late-night study, breathing was easy, the scratching habit had stopped, and she was back at school full-time. Her PHQ-9 dropped from 23 to 11, GAD-7 from 9 to 6, and the only side-effect she recalled was a brief spell of dizziness during the first week. Conclusion: One case cannot prove cause and effect, yet the speed and depth of her recovery suggest that an oral mix targeting NMDA blockade, AMPA support, and glutamate replenishment may deserve a closer look for stubborn somatic symptom disorder. Psychiatry somatic symptom disorder treatment-resistant SSD adolescent psychiatry glutamatergic modulation rapid-acting antidepressant oral ketamine mimic dextromethorphan CYP2D6 inhibition piracetam AMPA positive allosteric modulator L-glutamine neuroplasticity cascade NMDA–AMPA throughput mTOR pathway functional somatic syndromes case report Figures Figure 1 Background People with somatic symptom disorder (SSD) live with real pain and discomfort even though repeated medical tests come back "normal." These unrelenting sensations—and the fears that grow around them—can derail school, work, and family life ( 1 ). Brain-scan studies offer one clue: regions that tag sensations as urgent, such as the insula and anterior cingulate, seem to fire too easily, while the chemical messenger glutamate appears out of balance ( 2 ). Standard care—selective serotonin re-uptake inhibitors, talking therapy, reassurance—helps some people, but many wait months for modest relief or improve only a little ( 3 ). Interest has therefore turned to medicines that act faster. Low doses of ketamine, given intravenously, can quiet bodily distress within hours, likely by briefly blocking NMDA receptors and then sparking a burst of healthy synaptic growth ( 4 , 5 ). Similar benefits have been reported in patients whose depression or post-traumatic stress is tangled up with chronic pain and other bodily complaints ( 6 , 7 ). Safety work also shows that short ketamine courses are generally well tolerated, even in people with medical comorbidities, when basic monitoring is in place ( 8 ). Because IV infusions are costly and inconvenient—especially for teenagers—clinicians have started exploring pill-based regimens that aim to mimic ketamine's chain of events. One strategy pairs the cough suppressant dextromethorphan with a low dose of a CYP2D6 inhibitor (to keep dextromethorphan in the system), adds piracetam to boost downstream signalling, and tops up glutamine to nourish recovering synapses ( 9 ). This case report follows a teenage girl whose severe, year-long SSD barely budged with high-dose duloxetine but improved rapidly after the four-drug oral combination was added. Her course illustrates how targeting glutamate pathways might help when usual treatments have failed. Methods This single-case report was conducted in a solo private psychiatry practice (Cheung Ngo Medical) in Tsim Sha Tsui, Hong Kong. From early September to late November 2025 the patient was seen exclusively by the author-clinician, who carried out all assessments, prescriptions, and follow-up visits. Before entry into this observation period the adolescent had been taking duloxetine 60 mg/day for roughly a year with only partial benefit from other doctors. On 2 September 2025 a stepwise, fully oral glutamatergic augmentation programme was started. Dextromethorphan hydrobromide was introduced at 30 mg/day and gradually increased to 60 mg/day (30 mg twice daily) over seven weeks. To prolong dextromethorphan exposure, fluoxetine 10 mg/day was added while the baseline duloxetine was maintained, providing dual CYP2D6 inhibition. One month later piracetam was begun at 600 mg each morning and, by the end of October, raised to 600 mg twice daily. During the same late-October visit, L-glutamine 500 mg/day was added to support longer-term neuroplasticity. Brief adjunctive use of risperidone 0.5 mg at night (for early agitation) and short courses of pregabalin 25–50 mg/day (for transient sensory discomfort) were allowed but were not considered central to the study intervention. The patient returned roughly every four weeks (2 September, 30 September, 28 October, and 25 November 2025). At each visit she completed the Patient Health Questionnaire-9 and Generalised Anxiety Disorder-7; these scores were supplemented by an open clinical interview covering bodily symptom burden, compulsive behaviours, school attendance, and day-to-day functioning. No new psychotherapeutic techniques were introduced during the monitoring window. Written informed consent for anonymous publication of de-identified data was obtained from the patient's mother, and the patient herself provided written assent. All potentially identifying details have been removed in keeping with ethical guidelines for single-case reporting. Results A 17-year-old girl arrived at our clinic in early September 2025 complaining of a year-long barrage of physical symptoms no doctor had been able to explain. She described daily tension-type headaches, episodes of air hunger, vague "all-over" aches, and an intense sensation that something was lodged beneath her fingernails. The last feeling drove her to scratch the nail beds until they bled. These worries had already pushed her to withdraw from school and most social activities. On standard screening, she scored 23 on the PHQ-9 and 9 on the GAD-7, confirming marked low mood and moderate anxiety. During the preceding 12 months she had taken duloxetine from other doctors, escalated to 80 mg and later settled at 60 mg, with only modest relief. Because the combination of somatic distress, obsessive checking, and functional collapse continued, we offered an oral program aimed at recreating the rapid-acting, glutamatergic effects usually seen with intravenous ketamine. Treatment began on 2 September 2025 with dextromethorphan 30 mg once daily, later increased to 60 mg. To slow dextromethorphan's metabolism we added fluoxetine 10 mg while keeping duloxetine 60 mg in place; both medicines inhibit CYP2D6 and therefore extend dextromethorphan exposure. Piracetam 600 mg daily (titrated to 1,200 mg) was introduced to boost AMPA signaling. Low-dose risperidone (0.5 mg at night) and a brief trial of pregabalin were used for obsessions and sleep as well. Four weeks into treatment the patient volunteered that she felt "a bit better." Headaches were less frequent, breathing was easier, and her PHQ-9 had fallen to 15. We were motivated to stick to the plan, and by week 8, we were taking 500 mg of L-glutamine every day to help recycle glutamate. There was a little rise in derealisation when she went back to school, but it went away on its own without any modifications to her dose. The change was very noticeable by week 12 (25 November 2025). She was going to class full-time, and headaches only came up after long study sessions. The nail-scratching habit was gone. The PHQ-9 had dropped to 11 and the GAD-7 to 6, placing anxiety below the clinical threshold. Her mother remarked that this was her daughter's "first stretch of normal life" in more than a year. No adverse effects attributable to the core four-drug combination emerged during the 12-week observation period; transient drowsiness from risperidone resolved spontaneously. The close temporal link between initiation of the glutamatergic stack and the patient's sustained recovery suggests that completing the NMDA-to-AMPA neuroplasticity sequence may offer a practical, oral route to rapid relief in severe, treatment-resistant somatic symptom disorder. Conclusion When this teenager arrived at our clinic, she had lived for more than a year with pounding headaches, air-hunger, and a maddening feeling of grit beneath her fingernails. High-dose duloxetine had dulled the edges but never let her return to class. What changed the picture was a simple four-pill add-on: low-dose dextromethorphan, a tiny amount of fluoxetine to slow its breakdown, piracetam, and, a month later, L-glutamine. Within three months her symptoms were no longer running her life; mood scores fell by half, and anxiety slipped below the clinical line. Why might this have worked? Brain-scan research points to overactive "alarm" circuits in SSD ( 2 ). Briefly blocking NMDA receptors—ketamine's first step—can reset those circuits, but ketamine requires IV lines and monitoring. Dextromethorphan, kept active by fluoxetine, can deliver a similar NMDA block in pill form ( 4 ). Piracetam then boosts the follow-up AMPA signal that animal studies say is essential for lasting change ( 10 , 11 ). Finally, glutamine tops up the brain's own glutamate supply, supporting new synapses without the risk of "over-revving" the system ( 12 ). The improvement we saw mirrors reports from adults with depression and heavy body symptoms who responded quickly to dextromethorphan–bupropion ( 13 ). Our case suggests that adding targeted AMPA support and glutamine can push the benefit even further in pure SSD. Equally important, the regimen was easy to take and caused no noticeable side-effects—no blood-pressure spikes, no dissociation, nothing that forced a dose change. One success story is not proof. Placebo effects, growing maturity, or delayed benefit from duloxetine could all play a part. Still, the speed, size, and stability of her recovery after many stalled months argue that the glutamatergic stack made a real difference. Controlled studies that track physical-symptom scales in SSD seem the logical next step. Declarations Conflict of Interest and Source of Funding Statement: None declared. References American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (5th ed.) Bègue I, Adams C, Stone J et al (2019) Structural alterations in functional neurological disorder and related conditions: a software and hardware problem? NeuroImage. Clinical 22:101798 Henningsen P (2018) Management of somatic symptom disorder. Dialog Clin Neurosci 20(1):23–31 Duman RS, Aghajanian GK (2012) Synaptic dysfunction in depression: potential therapeutic targets, vol 338. Science, New York, N.Y., pp 68–72. 6103 Li N, Lee B, Liu RJ et al (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. 329(5994):959–964 Science (New York, N.Y.) Chen MH, Wu HJ, Li CT et al (2021) Low-dose ketamine infusion for treating subjective cognitive, somatic, and affective depression symptoms of treatment-resistant depression. Asian J psychiatry 66:102869 Liriano F, Hatten C, Schwartz TL (2019) Ketamine as treatment for post-traumatic stress disorder: a review. Drugs context 8:212305 Szarmach J, Cubała WJ, Włodarczyk A et al (2021) Somatic Comorbidities and Cardiovascular Safety in Ketamine Use for Treatment-Resistant Depression. Med (Kaunas Lithuania) 57(3):274 Cheung N, DXM (2025) CYP2D6-Inhibiting Antidepressants, Piracetam, and Glutamine: Proposing a Ketamine-Class Antidepressant Regimen with Existing Drugs. Preprints. https://doi.org/10.20944/preprints202511.1815.v1 Cohen SA, Müller WE (1993) Effects of piracetam on N-methyl-D-aspartate receptor properties in the aged mouse brain. Pharmacology 47(4):217–222 Koike H, Iijima M, Chaki S (2011) Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 224(1):107–111 Son H, Baek JH, Go BS et al (2018) Glutamine has antidepressive effects through increments of glutamate and glutamine levels and glutamatergic activity in the medial prefrontal cortex. Neuropharmacology 143:143–152 Iosifescu DV, Jones A, O'Gorman C et al (2022) Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI). J Clin Psychiatry 83(4):21m14345 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Brain-scan studies offer one clue: regions that tag sensations as urgent, such as the insula and anterior cingulate, seem to fire too easily, while the chemical messenger glutamate appears out of balance (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eStandard care\u0026mdash;selective serotonin re-uptake inhibitors, talking therapy, reassurance\u0026mdash;helps some people, but many wait months for modest relief or improve only a little (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Interest has therefore turned to medicines that act faster. Low doses of ketamine, given intravenously, can quiet bodily distress within hours, likely by briefly blocking NMDA receptors and then sparking a burst of healthy synaptic growth (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Similar benefits have been reported in patients whose depression or post-traumatic stress is tangled up with chronic pain and other bodily complaints (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Safety work also shows that short ketamine courses are generally well tolerated, even in people with medical comorbidities, when basic monitoring is in place (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eBecause IV infusions are costly and inconvenient\u0026mdash;especially for teenagers\u0026mdash;clinicians have started exploring pill-based regimens that aim to mimic ketamine's chain of events. One strategy pairs the cough suppressant dextromethorphan with a low dose of a CYP2D6 inhibitor (to keep dextromethorphan in the system), adds piracetam to boost downstream signalling, and tops up glutamine to nourish recovering synapses (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis case report follows a teenage girl whose severe, year-long SSD barely budged with high-dose duloxetine but improved rapidly after the four-drug oral combination was added. Her course illustrates how targeting glutamate pathways might help when usual treatments have failed.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis single-case report was conducted in a solo private psychiatry practice (Cheung Ngo Medical) in Tsim Sha Tsui, Hong Kong. From early September to late November 2025 the patient was seen exclusively by the author-clinician, who carried out all assessments, prescriptions, and follow-up visits.\u003c/p\u003e\u003cp\u003eBefore entry into this observation period the adolescent had been taking duloxetine 60 mg/day for roughly a year with only partial benefit from other doctors. On 2 September 2025 a stepwise, fully oral glutamatergic augmentation programme was started. Dextromethorphan hydrobromide was introduced at 30 mg/day and gradually increased to 60 mg/day (30 mg twice daily) over seven weeks. To prolong dextromethorphan exposure, fluoxetine 10 mg/day was added while the baseline duloxetine was maintained, providing dual CYP2D6 inhibition. One month later piracetam was begun at 600 mg each morning and, by the end of October, raised to 600 mg twice daily. During the same late-October visit, L-glutamine 500 mg/day was added to support longer-term neuroplasticity. Brief adjunctive use of risperidone 0.5 mg at night (for early agitation) and short courses of pregabalin 25\u0026ndash;50 mg/day (for transient sensory discomfort) were allowed but were not considered central to the study intervention.\u003c/p\u003e\u003cp\u003eThe patient returned roughly every four weeks (2 September, 30 September, 28 October, and 25 November 2025). At each visit she completed the Patient Health Questionnaire-9 and Generalised Anxiety Disorder-7; these scores were supplemented by an open clinical interview covering bodily symptom burden, compulsive behaviours, school attendance, and day-to-day functioning. No new psychotherapeutic techniques were introduced during the monitoring window.\u003c/p\u003e\u003cp\u003e Written informed consent for anonymous publication of de-identified data was obtained from the patient's mother, and the patient herself provided written assent. All potentially identifying details have been removed in keeping with ethical guidelines for single-case reporting.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA 17-year-old girl arrived at our clinic in early September 2025 complaining of a year-long barrage of physical symptoms no doctor had been able to explain. She described daily tension-type headaches, episodes of air hunger, vague \"all-over\" aches, and an intense sensation that something was lodged beneath her fingernails. The last feeling drove her to scratch the nail beds until they bled. These worries had already pushed her to withdraw from school and most social activities. On standard screening, she scored 23 on the PHQ-9 and 9 on the GAD-7, confirming marked low mood and moderate anxiety. During the preceding 12 months she had taken duloxetine from other doctors, escalated to 80 mg and later settled at 60 mg, with only modest relief.\u003c/p\u003e\u003cp\u003eBecause the combination of somatic distress, obsessive checking, and functional collapse continued, we offered an oral program aimed at recreating the rapid-acting, glutamatergic effects usually seen with intravenous ketamine. Treatment began on 2 September 2025 with dextromethorphan 30 mg once daily, later increased to 60 mg. To slow dextromethorphan's metabolism we added fluoxetine 10 mg while keeping duloxetine 60 mg in place; both medicines inhibit CYP2D6 and therefore extend dextromethorphan exposure. Piracetam 600 mg daily (titrated to 1,200 mg) was introduced to boost AMPA signaling. Low-dose risperidone (0.5 mg at night) and a brief trial of pregabalin were used for obsessions and sleep as well.\u003c/p\u003e\u003cp\u003eFour weeks into treatment the patient volunteered that she felt \"a bit better.\" Headaches were less frequent, breathing was easier, and her PHQ-9 had fallen to 15. We were motivated to stick to the plan, and by week 8, we were taking 500 mg of L-glutamine every day to help recycle glutamate. There was a little rise in derealisation when she went back to school, but it went away on its own without any modifications to her dose.\u003c/p\u003e\u003cp\u003eThe change was very noticeable by week 12 (25 November 2025). She was going to class full-time, and headaches only came up after long study sessions. The nail-scratching habit was gone. The PHQ-9 had dropped to 11 and the GAD-7 to 6, placing anxiety below the clinical threshold. Her mother remarked that this was her daughter's \"first stretch of normal life\" in more than a year.\u003c/p\u003e\u003cp\u003eNo adverse effects attributable to the core four-drug combination emerged during the 12-week observation period; transient drowsiness from risperidone resolved spontaneously. The close temporal link between initiation of the glutamatergic stack and the patient's sustained recovery suggests that completing the NMDA-to-AMPA neuroplasticity sequence may offer a practical, oral route to rapid relief in severe, treatment-resistant somatic symptom disorder.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWhen this teenager arrived at our clinic, she had lived for more than a year with pounding headaches, air-hunger, and a maddening feeling of grit beneath her fingernails. High-dose duloxetine had dulled the edges but never let her return to class. What changed the picture was a simple four-pill add-on: low-dose dextromethorphan, a tiny amount of fluoxetine to slow its breakdown, piracetam, and, a month later, L-glutamine. Within three months her symptoms were no longer running her life; mood scores fell by half, and anxiety slipped below the clinical line.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWhy might this have worked? Brain-scan research points to overactive \"alarm\" circuits in SSD (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Briefly blocking NMDA receptors\u0026mdash;ketamine's first step\u0026mdash;can reset those circuits, but ketamine requires IV lines and monitoring. Dextromethorphan, kept active by fluoxetine, can deliver a similar NMDA block in pill form (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Piracetam then boosts the follow-up AMPA signal that animal studies say is essential for lasting change (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Finally, glutamine tops up the brain's own glutamate supply, supporting new synapses without the risk of \"over-revving\" the system (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe improvement we saw mirrors reports from adults with depression and heavy body symptoms who responded quickly to dextromethorphan\u0026ndash;bupropion (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Our case suggests that adding targeted AMPA support and glutamine can push the benefit even further in pure SSD. Equally important, the regimen was easy to take and caused no noticeable side-effects\u0026mdash;no blood-pressure spikes, no dissociation, nothing that forced a dose change.\u003c/p\u003e\u003cp\u003eOne success story is not proof. Placebo effects, growing maturity, or delayed benefit from duloxetine could all play a part. Still, the speed, size, and stability of her recovery after many stalled months argue that the glutamatergic stack made a real difference. Controlled studies that track physical-symptom scales in SSD seem the logical next step.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eConflict of Interest and Source of Funding Statement:\u003c/p\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAmerican Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (5th ed.)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eB\u0026egrave;gue I, Adams C, Stone J et al (2019) Structural alterations in functional neurological disorder and related conditions: a software and hardware problem? NeuroImage. Clinical 22:101798\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHenningsen P (2018) Management of somatic symptom disorder. Dialog Clin Neurosci 20(1):23\u0026ndash;31\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDuman RS, Aghajanian GK (2012) Synaptic dysfunction in depression: potential therapeutic targets, vol 338. Science, New York, N.Y., pp 68\u0026ndash;72. 6103\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi N, Lee B, Liu RJ et al (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. 329(5994):959\u0026ndash;964 Science (New York, N.Y.)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen MH, Wu HJ, Li CT et al (2021) Low-dose ketamine infusion for treating subjective cognitive, somatic, and affective depression symptoms of treatment-resistant depression. Asian J psychiatry 66:102869\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiriano F, Hatten C, Schwartz TL (2019) Ketamine as treatment for post-traumatic stress disorder: a review. Drugs context 8:212305\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSzarmach J, Cubała WJ, Włodarczyk A et al (2021) Somatic Comorbidities and Cardiovascular Safety in Ketamine Use for Treatment-Resistant Depression. Med (Kaunas Lithuania) 57(3):274\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCheung N, DXM (2025) CYP2D6-Inhibiting Antidepressants, Piracetam, and Glutamine: Proposing a Ketamine-Class Antidepressant Regimen with Existing Drugs. Preprints. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.20944/preprints202511.1815.v1\u003c/span\u003e\u003cspan address=\"10.20944/preprints202511.1815.v1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCohen SA, M\u0026uuml;ller WE (1993) Effects of piracetam on N-methyl-D-aspartate receptor properties in the aged mouse brain. Pharmacology 47(4):217\u0026ndash;222\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKoike H, Iijima M, Chaki S (2011) Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 224(1):107\u0026ndash;111\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSon H, Baek JH, Go BS et al (2018) Glutamine has antidepressive effects through increments of glutamate and glutamine levels and glutamatergic activity in the medial prefrontal cortex. Neuropharmacology 143:143\u0026ndash;152\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIosifescu DV, Jones A, O'Gorman C et al (2022) Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI). J Clin Psychiatry 83(4):21m14345\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"CHEUNG NGO MEDICAL","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"somatic symptom disorder, treatment-resistant SSD, adolescent psychiatry, glutamatergic modulation, rapid-acting antidepressant, oral ketamine mimic, dextromethorphan, CYP2D6 inhibition, piracetam, AMPA positive allosteric modulator, L-glutamine, neuroplasticity cascade, NMDA–AMPA throughput, mTOR pathway, functional somatic syndromes, case report","lastPublishedDoi":"10.21203/rs.3.rs-8207734/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8207734/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Persistent physical symptoms can trap adolescents in a cycle of pain, worry, and lost school time—especially when standard antidepressants provide only partial relief. This report describes a 17-year-old girl whose disabling somatic symptom disorder lifted after we tried a simple, fully oral \"ketamine-like\" combination.\u003c/p\u003e\n\u003cp\u003eCase Summary: She had taken duloxetine 60 mg daily for more than a year yet still woke with pounding headaches, gasped for air without warning, and scratched her nails raw because they felt full of grit. Beginning 2 September 2025 we layered four medicines, one at a time: dextromethorphan (eventually 60 mg/day), fluoxetine 10 mg/day to slow its breakdown, piracetam (up to 1 200 mg/day), and L-glutamine 500 mg/day. She was seen monthly, her mood scored with the PHQ-9 and GAD-7, and her own account of day-to-day functioning recorded.\u003c/p\u003e\n\u003cp\u003eOutcome: By the third visit the change was hard to miss. Headaches came only after late-night study, breathing was easy, the scratching habit had stopped, and she was back at school full-time. Her PHQ-9 dropped from 23 to 11, GAD-7 from 9 to 6, and the only side-effect she recalled was a brief spell of dizziness during the first week.\u003c/p\u003e\n\u003cp\u003eConclusion: One case cannot prove cause and effect, yet the speed and depth of her recovery suggest that an oral mix targeting NMDA blockade, AMPA support, and glutamate replenishment may deserve a closer look for stubborn somatic symptom disorder.\u003c/p\u003e","manuscriptTitle":"OTC Glutamatergic Augmentation Resolves Adolescent Refractory Somatic Symptoms","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 08:39:57","doi":"10.21203/rs.3.rs-8207734/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"594bead8-36c2-42fb-9470-56db9aebc804","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":58614945,"name":"Psychiatry"}],"tags":[],"updatedAt":"2025-12-01T08:39:57+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 08:39:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8207734","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8207734","identity":"rs-8207734","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}