Clozapine and the Voice Within: A Case of New-Onset Vocalizations and Obsessive Compulsive Symptoms

Clozapine and the Voice Within: A Case of New-Onset Vocalizations and Obsessive Compulsive 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 Clozapine and the Voice Within: A Case of New-Onset Vocalizations and Obsessive Compulsive Symptoms Suchitha Kolloju, Jean Pierre Lindenmayer, Jose Jeletta, Anzalee Khan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7436319/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: Treatment-resistant schizophrenia is the occurrence of delusions or hallucinations despite two antipsychotic drug attempts. Clozapine, an FDA-approved atypical antipsychotic, is reserved for such a case due to its efficacy but is handicapped by a wide array of side effects like sedation, agranulocytosis, seizures, metabolic syndrome, and neuroleptic malignant syndrome. Interestingly, clozapine has also been associated with the development or worsening of obsessive-compulsive symptoms (OCS) in up to 38.2% of patients, purportedly a byproduct of its serotonin 5-HT2A and 5-HT2C receptor antagonism. By comparison, tic-like vocalizations on clozapine are utterly rare and maybe underreported. Case presentation: We report the case of a 39-year-old man with treatment-resistant schizophrenia and psychogenic polydipsia who exhibited tic-like vocalizations and compulsive behavior upon clozapine initiation and dose escalation. Despite initial therapeutic response, the patient evolved with chronic OCS and vocalization, necessitating adjunctive antipsychotic therapy (Aripiprazole) and close behavioral monitoring. Comprehensive assessment excluded organic causes. Unfortunately, treatment with aripiprazole showed no improvement, and he is being monitored on Clozapine. Conclusion: This report underscores the importance of early detection and tailored treatment of rare neuropsychiatric side effects such as clozapine-induced vocal tics. Clinicians must remain vigilant for such signs to optimize therapeutic benefits in treatment-resistant schizophrenia. Regular screening with rating scales is recommended. Treatments like aripiprazole have shown significant OCS improvement, while adjuncts such as valproic acid, often combined with dose reduction, have also been explored. Treatment resistant schizophrenia Clozapine OCS Vocalizations Vocal tics Clozapine side effects Background The definition of treatment-resistant schizophrenia is persistent or moderate delusions or hallucinations after failing two trials of antipsychotic medicines. Clozapine is an FDA-approved atypical antipsychotic medication for treatment-resistant schizophrenia. Clozapine is not the first-line drug of choice due to its range of adverse effects, making compliance an issue for many patients. Clozapine is also approved for schizophrenia-associated suicide prevention. According to the FDA, clozapine's maximum recommended dosage is up to 900 mg daily. The average dose is 300 mg for women and 400 mg daily for men. Slow titration is vital for reducing many side effects associated with clozapine. Clozapine is typically associated with sedation, hypersalivation, agranulocytosis, seizures, Metabolic syndrome, Pulmonary embolism, Constipation and Neuroleptic Malignant Syndrome. While other concerning but rare drug adverse effects may include orthostatic hypotension, tachycardia, sexual dysfunction, and urinary retention. The emergence or worsening of obsessive-compulsive symptoms (OCS) is a reported adverse effect of clozapine treatment, occurring in up to 20–38.2% of patients. (Mahendran et al., 2007 ) As selective serotonin reuptake inhibitors (SSRIs) are used to treat OCD and OCS, clozapine’s antiserotonergic effects, ie., antagonism of 5-HT 2A and 5-HT 2C receptors are potential causative factors for emergence of OCS on Clozapine. (Besnard et al., 2012 ) The incidence of de novo OCS while on clozapine is reported to be between 3.5% and 28.4% (Bleakley et al., 2011a ) a range which includes in it the naturally occurring incidence of comorbid schizophrenia and OCS described above. Higher plasma concentrations of clozapine and its metabolite, norclozapine, have been linked to the emergence of OCS (Villari et al., 2011 ). Emergence of tics is extremely rare. It has been shown to occur in the presence of one or more factors such as abnormal electrophysiological findings and seizures, extrapyramidal symptoms, brain pathology, and a family history of tics. A case report revealed that clozapine-induced obsessions were misdiagnosed as psychosis, resulting in inadequate treatment for OCD, thereby underscoring that clozapine can exacerbate OCS (Leung & Palmer, 2016 ). Few case reports have documented the occurrence of clozapine-induced stuttering in the absence of risk factors. This case report examines a patient who developed recurrent vocalizations and OCS following clozapine treatment, and it details the management strategies employed for these symptoms. Case Presentation History of presenting illness: The patient is a 39-year-old man with a complicated psychiatric background that includes schizophrenia, polysubstance abuse, and several previous hospital stays for psychiatric care, including extended and forensic admissions. He also has a history of significant violence and was transferred to our facility in December 2024. His medical history is marked by intravenous drug use (IVDU), chronic hepatitis C virus (HCV) infection, psychogenic polydipsia, and Wolff-Parkinson-White Syndrome, for which he underwent an ablation. He was admitted after being observed displaying erratic behavior and sleeping near subway tracks. When he arrived, he was actively responding to internal stimuli, which was evident when he spat at people passing by. During his admission, he reported grandiose delusions about being extremely wealthy and exhibited paranoid thoughts, refusing to get out of bed because he believed both of his feet were broken. A review of his symptoms showed some inconsistencies; he denied feeling depressed, experiencing anhedonia, or having any thoughts of suicide or homicide, as well as any auditory or other psychotic hallucinations. He had previously experienced suicidal thoughts related to self-harm during relationship issues, but there was no record of actual suicide attempts or non-suicidal self-injury (NSSIB). His family history included cases of schizophrenia among second-degree relatives. Before being transferred to our facility, he was started on Haloperidol to help manage his psychosis and divalproex for mood stabilization. Upon his admission to the Manhattan Psychiatric Center in December 2024, the patient was noted to be irritable, intense, and unpredictable in his behavior. In the early days of his hospitalization, he physically assaulted a staff member, which required immediate intramuscular medication intervention. He was later stabilized on haloperidol and divalproex. Given his past issues with psychogenic polydipsia, he engaged in excessive fluid-seeking behavior. Investigations and Hospital Course: The repeated fluid seeking behaviours resulted in the development of hyponatremia, documented on January 9, 2025. His blood counts, comprehensive metabolic panel, RPR, HIV, liver and renal function tests were monitored regularly and remained within normal limits. His serum electrolytes, particularly serum sodium, were closely monitored in the context of psychogenic polydipsia versus diabetes insipidus. The patient was monitored for psychogenic polydipsia and mild hyponatremia on CPO. Despite ongoing treatment, the patient exhibited persistent psychotic symptoms, notably kissing inanimate objects such as windows and floors. Due to inadequate symptom control with the existing regimen, a cross-titration from haloperidol to clozapine was initiated on January 9, 2025, starting at 25 mg daily, in an effort to achieve greater antipsychotic efficacy. On January 17, 2025, the patient's clozapine dosage was increased to 50 mg due to significant behavioral and thought disorganization, psychosis, and delusionality.​ The patient's fluid-seeking behaviors and serum sodium levels (135 mEq/L) improved during the first week after clozapine initiation. By January 23, 2025, haloperidol was discontinued, and the clozapine dosage was raised to 100 mg. The patient became more engaged, organized, and less internally preoccupied with improved insight, leading to the maintenance of the 100 mg clozapine dosage for one week. However, over the following month there was regression of his symptoms. He exhibited persistent bizarre and grandiose beliefs, such as believing he was a dog or owned a supportive residence in Brooklyn, though he endorsed these ideas less spontaneously. Intermittent disorganized behaviors were observed, including kissing a window on the unit at times. To enhance the antipsychotic effect, the clozapine dosage was increased to 150 mg on February 28, 2025. The patient was also receiving Divalproex 1000mg up to that point. Throughout March 2025, the patient's clinical condition regressed, characterized by increased disorganization, disinhibition, and interaction with hallucinatory stimuli.​ Notably, he became more resistant to unit rules and treatment expectations. A reduction in serum psychotropic blood levels suggested the patient was cheeking his medication, leading to the implementation of strict mouth checks. To address these issues, the clozapine dosage was increased to 350 mg and Divalproex ER to 2000 mg as of March 31, 2025. In the subsequent month, the patient experienced multiple episodes of nocturia and bedwetting, even with evening fluid restrictions and bedwetting protocols. A 24-hour urine collection from April 8–9, 2025, measured 4000mL. To differentiate between psychogenic polydipsia and diabetes insipidus, further tests were conducted, revealing a high serum osmolality of 317 mOsm/kg and a 24-hour urine osmolality of 133 mOsm/kg. A nephrology consultation was recommended in August 2025. There was no evidence of medication cheeking, as the patient's valproic acid level was 84.1 on April 1, 2025, and weekly serum clozapine levels consistently exceeded 350 over the past month. On April 30, 2025, the clozapine dosage was increased to 475 mg orally once daily at bedtime. While on the established medication regimen, the patient developed compulsive behaviors and tic-like vocalizations during May 2025​. On May 16, 2025, he was again placed on a Continuous Psychiatric Observation (CPO) 1:1 protocol due to compulsive fluid consumption and disorganized behaviors, with fluid intake restricted to less than 1.5 liters per day. It was discovered that he was spending an excessive amount of time in the bathroom engaging in incessant hand and face washing, which resulted in small superficial abrasions to his forehead. He was also observed repeating words and sounds uncontrollably, and compulsively consuming water. The patient had no prior personal or family history of tics or vocalizations. However, the CPO was discontinued on May 20, 2025, due to an initial improvement in compulsive fluid-seeking and disorganized behaviors. On June 5, 2025, Aripiprazole 20 mg was added to his psychotropic regimen as an adjunctive treatment. Over the subsequent month, no clinical improvement was observed with the addition of aripiprazole; instead, the patient became more restless. Consequently, the decision was made to discontinue aripiprazole. In the following month, the patient's psychosis remained persistent, possibly increasing. He continued to exhibit grandiose and bizarre delusions, which interfered with his understanding of his community needs. Clozapine titration was ongoing during this period. His psychiatric medications at this point were, Clozapine 575 mg po qhs and Divalproex ER 1,000 mg po bid. Duration/Timeline Pharmacological treatment/ Daily dose Symptomatology December 2024 Haloperidol 15 mg po bid Divalproex ER 1,000 mg po bid, necessitated IM STAT medications Irritable, intense, and unpredictable behavior (he physically assaulted a staff member) January 9th 2025 Clozapine 25 mg daily Haloperidol 10 mg po bid Divalproex ER 1,000 mg po bid Psychotic symptoms, notably kissing inanimate objects such as windows and floors January 17, 2025 Clozapine 50 mg po bid Haloperidol 5 mg po bid Divalproex ER 1,000 mg po bid Behavioral and thought disorganization, psychosis, and delusionality.​ January 23, 2025 Clozapine 100 mg po bid Divalproex ER 1,000 mg po bid More engaged, organized, and less internally preoccupied February 28, 2025 Clozapine 150 mg po bid Divalproex ER 1,000 mg po bid Intermittent disorganized behaviors were observed, including kissing a window on the unit at times. March 31, 2025 Clozapine 350 mg po qhs Divalproex ER 2,000 mg po qhs More resistant, reduction in serum psychotropic levels suggesting cheeking of medication April 30, 2025 Clozapine 475 mg po qhsDivalproex ER 2,000 mg po qhs Multiple episodes of nocturia in addition to persistent psychosis May 16, 2025 Clozapine 475 mg and Divalproex 2000mg Incessant hand and face washing , leading to superficial abrasions on his forehead, uncontrolled repetition of words and sounds, along with compulsive water consumption. June 5, 2025 Aripiprazole 25 mg, Clozapine 475 mg and Divalproex 2000 mg No clinical improvement, patient became more restless July 2025 Clozapine 575 mg and Divalproex 1000 mg (Aripiprazole was discontinued) Patient under observation for improvement of symptoms Discussion Clozapine is an atypical antipsychotic. It acts as an antagonist to dopamine and serotonin receptors. Clozapine binds to the dopamine D4 receptor with a higher affinity than the dopamine D2 receptor, contributing to decreased adverse events and extrapyramidal symptoms. Clozapine targets several serotonin receptors, with its antagonism of the 5-HT2A and 5-HT2C receptors being specifically implicated in the emergence of OCS (Marek et al., 2003 ). Clozapine is a partial 5-HT1A agonist that reduces adverse and extrapyramidal symptoms and a muscarinic M1, M2, M3, M5, histamine, and alpha-1 adrenergic-receptor antagonist. Norclozapine, the metabolite of clozapine, actively works on the M1 and M4 receptors. Clozapine causes fewer extrapyramidal symptoms at clinically effective doses due to its potent 5-HT2A and weak D2 receptor blocking properties which makes it a desirable option (Meltzer, 1990 ). One key thing to keep in mind is how to tell apart vocalizations caused by clozapine from other potential reasons. Clozapine-induced OCS might be misinterpreted as worsening psychosis, leading to inappropriate dose escalation of clozapine, which can worsen OCS. The main differentials to consider include Tourette Syndrome, Obsessive-Compulsive Syndrome (OCS), functional tics, and Myoclonus. Tourette Syndrome (TS) is a hereditary neurological condition marked by persistent motor and vocal tics that usually kick off in childhood and can carry on into adulthood. OCS involves having obsessive thoughts and engaging in compulsive behaviors, which often occur alongside Tourette Syndrome. It's worth noting that while tics in TS often affect the head, functional tics are less likely to involve the head and are more commonly seen in the limbs (Arbuckle et al., 2023 ). While tics can have a jerky quality, they are not as brief as myoclonus and are typically associated with a premonitory urge and suppressibility, which are absent in myoclonus. While some research points out that tic-like symptoms can emerge during treatment with atypical antipsychotics such as clozapine, quetiapine, atomoxetine, olanzapine, and aripiprazole, other findings suggest that high doses of clozapine may trigger these symptoms, which tend to fade away when the dosage is lowered. Interestingly, there are instances where clozapine, sometimes combined with other antipsychotics like risperidone, has effectively managed severe adult-onset vocal tics in patients with schizophrenia who haven't responded to other atypical antipsychotics (Begum et al., 2021 ). Certain psychotropic medications, like psychostimulants such as methylphenidate used for ADHD, can sometimes trigger secondary tics by boosting dopamine release. Additionally, antiepileptic drugs like carbamazepine and lamotrigine have been associated with the onset of tics, likely due to their effect on increasing dopaminergic transmission (Madruga-Garrido & Mir, 2013 ) It's really important to understand the intricate relationship between clozapine and vocalizations, as it can both trigger and ease these symptoms depending on the person and the clinical situation. When it comes to clozapine-related obsessive-compulsive symptoms (OCS), which might show up alongside tic-like behaviors, some common management approaches include introducing selective serotonin reuptake inhibitors (SSRIs), clomipramine, or aripiprazole, often while reducing the clozapine dosage. If antidepressants don’t do the trick, adding aripiprazole either with or without lowering the clozapine dose can be a solid alternative (Kim et al., 2020 ). In some cases where treatment has been successful, lower doses of clozapine (around 100–150 mg per day) have been effective. On the other hand, reports of worsening symptoms often come from higher doses (between 150–500 mg per day). This variation in dosage, along with the length of treatment, might help clarify the different outcomes observed. Additionally, there have been instances where obsessive-compulsive symptoms (OCS) and tics appeared during clozapine withdrawal but disappeared once clozapine was reintroduced. This suggests that an imbalance between the dopamine and serotonin systems could be behind these complications. Conclusion Recognizing vocalizations and obsessive-compulsive symptoms (OCS) early in patients taking clozapine is crucial. This involves keeping an eye out for any new or worsening behaviors and speech patterns that are characteristic of these issues. Key signs to look for in vocalizations include repetitive sounds, changes in how fluently someone speaks (known as speech dysfluency), involuntary movements that may accompany the vocalizations, and patterns that worsen under stress but improve when the dosage is adjusted. For OCS, early signs might include the emergence or intensification of compulsive behaviors, a possible imbalance between dopamine and serotonin levels, and the presence of taboo thoughts. Clinicians need to stay alert to the potential side effects of clozapine and provide the necessary treatments. This should involve regular screenings for OCS using formal rating scales as part of routine health checks for patients on clozapine (Bleakley et al., 2011b ). Some clinical reports indicated that aripiprazole significantly reduced OCS, showing marked improvement. Other Adjunctive Therapies such as valproic acid, have been explored, often in combination with clozapine dose reduction (Zink et al., 2007 ) Declarations Conflict of interest disclosure: The authors have disclosed no conflicts of interest. Patient Consent Statement The patient has provided informed consent for the case study and the potential publication of any identifying patient information. Author Contribution Author 1: Manuscript text writing and editingAuthor 2: Conception and Resources Author 3: Conception, Case presentation, Resources and Manuscript editingAuthor 4: Editing and Reviewing the Manuscript Text References Arbuckle AL, Bihun EC, Schlaggar BL, Black KJ. (2023). Functional tic-like presentations differ strikingly from Provisional Tic Disorder. F1000Research , 11 , 1566. https://doi.org/10.12688/f1000research.129252.2 Begum G, Nkemjika S, Olayinka O, Olupona T, Jolayemi A. Clozapine Response for Vocal Tics in Schizophrenic Patients: A Case Report With Literature Review. Cureus. 2021. https://doi.org/10.7759/cureus.14111 . Besnard J, Ruda GF, Setola V, Abecassis K, Rodriguiz RM, Huang X-P, Norval S, Sassano MF, Shin AI, Webster LA, Simeons FRC, Stojanovski L, Prat A, Seidah NG, Constam DB, Bickerton GR, Read KD, Wetsel WC, Gilbert IH, Hopkins AL. Automated design of ligands to polypharmacological profiles. Nature. 2012;492(7428):215–20. https://doi.org/10.1038/nature11691 . Bleakley S, Brown D, Taylor D. Does clozapine cause or worsen obsessive compulsive symptoms? An analysis and literature review. Therapeutic Adv Psychopharmacol. 2011a;1(6):181–8. https://doi.org/10.1177/2045125311425971 . Bleakley S, Brown D, Taylor D. Does clozapine cause or worsen obsessive compulsive symptoms? An analysis and literature review. Therapeutic Adv Psychopharmacol. 2011b;1(6):181–8. https://doi.org/10.1177/2045125311425971 . Kim DD, Barr AM, Lu C, Stewart SE, White RF, Honer WG, Procyshyn RM. Clozapine-Associated Obsessive-Compulsive Symptoms and Their Management: A Systematic Review and Analysis of 107 Reported Cases. Psychother Psychosom. 2020;89(3):151–60. https://doi.org/10.1159/000505876 . Leung JG, Palmer BA. (2016). Psychosis or Obsessions? Clozapine Associated with Worsening Obsessive-Compulsive Symptoms. Case Reports in Psychiatry , 2016 , 1–5. https://doi.org/10.1155/2016/2180748 Madruga-Garrido M, Mir P. (2013). Tics and Other Stereotyped Movements as Side Effects of Pharmacological Treatment. In International Review of Neurobiology (Vol. 112, pp. 481–494). Elsevier. https://doi.org/10.1016/B978-0-12–411546–0.00016–0 Mahendran R, Liew E, Subramaniam M. De Novo Emergence of Obsessive-Compulsive Symptoms With Atypical Antipsychotics in Asian Patients With Schizophrenia or Schizoaffective Disorder: A Retrospective, Cross-Sectional Study. J Clin Psychiatry. 2007;68(04):542–5. https://doi.org/10.4088/JCP.v68n0408 . Marek GJ, Carpenter LL, McDougle CJ, Price LH. Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders. Neuropsychopharmacology. 2003;28(2):402–12. https://doi.org/10.1038/sj.npp.1300057 . Meltzer HY. The Role of Serotonin in the Action of Atypical Antipsychotic Drugs. Psychiatric Annals. 1990;20(10):571–9. https://doi.org/10.3928/0048-5713-19901001–08 . Villari V, Frieri T, Fagiolini A. Aripiprazole Augmentation in Clozapine-Associated Obsessive-Compulsive Symptoms. J Clin Psychopharmacol. 2011;31(3):375–6. https://doi.org/10.1097/JCP.0b013e31821927d8 . Zink M, Englisch S, Knopf U, Kuwilsky A, Dressing H. Augmentation of Clozapine with Valproic Acid for Clozapine-Induced Obsessive-Compulsive Symptoms. Pharmacopsychiatry. 2007;40(5):202–3. https://doi.org/10.1055/s–2007–985885 . Additional Declarations No competing interests reported. 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. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7436319","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":505085984,"identity":"bc72b341-ac0a-4c67-a115-819ad7c9de8b","order_by":0,"name":"Suchitha Kolloju","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABB0lEQVRIie3PsWrDMBCA4TOBTH4AhRTrCQIygXRom75F5jMGa3EhY0aFDln8AC6C9hVaCpllNGTJAwTSwVk8u5vHWk5bKNROxkL1j8d9HAdgs/3N+oCggEBvqcAFz4xUfpKgIY4wZNwQPEXgmwAEwsy6CE3DIj9Ub3SwWgpVXmj+NNOH+srUG4nfCdtFlwyx8KWbiSx19d3LPmI1CccT1UJI3CeI2nkkgdCuIRINUcG6hdD0SG6/CPclLzsJ7I4kkJ8E6TDuvsK2xYRgpMOHpPmF+8/DeK6Qtf9CV2ExqK71Tbq5z/L35IpSyV/LcjH12sjPnKS+22yyc9abqvquOHvbZrPZ/kkfAuFrEkLc7ToAAAAASUVORK5CYII=","orcid":"","institution":"Manhattan Psychiatric Center","correspondingAuthor":true,"prefix":"","firstName":"Suchitha","middleName":"","lastName":"Kolloju","suffix":""},{"id":505085985,"identity":"ba669269-820d-4d6e-b875-1e0ac0cc3f88","order_by":1,"name":"Jean Pierre Lindenmayer","email":"","orcid":"","institution":"Nathan Kline Institute for Psychiatric Research","correspondingAuthor":false,"prefix":"","firstName":"Jean","middleName":"Pierre","lastName":"Lindenmayer","suffix":""},{"id":505085989,"identity":"2c45bdc8-49bd-46cc-b0be-b3f7c234043b","order_by":2,"name":"Jose Jeletta","email":"","orcid":"","institution":"Manhattan Psychiatric Center","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"","lastName":"Jeletta","suffix":""},{"id":505085991,"identity":"75bc0366-1fa5-4919-ad22-0d21ba22ad21","order_by":3,"name":"Anzalee Khan","email":"","orcid":"","institution":"Nathan Kline Institute for Psychiatric Research","correspondingAuthor":false,"prefix":"","firstName":"Anzalee","middleName":"","lastName":"Khan","suffix":""}],"badges":[],"createdAt":"2025-08-22 16:38:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7436319/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7436319/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106393068,"identity":"c141b483-859f-4b0c-97ab-4633330e70f0","added_by":"auto","created_at":"2026-04-08 07:30:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":442936,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7436319/v1/47711f5e-ac2c-43f1-9424-aa18aae7ca19.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clozapine and the Voice Within: A Case of New-Onset Vocalizations and Obsessive Compulsive Symptoms","fulltext":[{"header":"Background","content":"\u003cp\u003eThe definition of treatment-resistant schizophrenia is persistent or moderate delusions or hallucinations after failing two trials of antipsychotic medicines. Clozapine is an FDA-approved atypical antipsychotic medication for treatment-resistant schizophrenia. Clozapine is not the first-line drug of choice due to its range of adverse effects, making compliance an issue for many patients. Clozapine is also approved for schizophrenia-associated suicide prevention. According to the FDA, clozapine's maximum recommended dosage is up to 900 mg daily. The average dose is 300 mg for women and 400 mg daily for men. Slow titration is vital for reducing many side effects associated with clozapine. Clozapine is typically associated with sedation, hypersalivation, agranulocytosis, seizures, Metabolic syndrome, Pulmonary embolism, Constipation and Neuroleptic Malignant Syndrome. While other concerning but rare drug adverse effects may include orthostatic hypotension, tachycardia, sexual dysfunction, and urinary retention.\u003c/p\u003e\u003cp\u003eThe emergence or worsening of obsessive-compulsive symptoms (OCS) is a reported adverse effect of clozapine treatment, occurring in up to 20\u0026ndash;38.2% of patients. (Mahendran et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2007\u003c/span\u003e) As selective serotonin reuptake inhibitors (SSRIs) are used to treat OCD and OCS, clozapine\u0026rsquo;s antiserotonergic effects, ie., antagonism of 5-HT 2A and 5-HT 2C receptors are potential causative factors for emergence of OCS on Clozapine. (Besnard et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2012\u003c/span\u003e) The incidence of de novo OCS while on clozapine is reported to be between 3.5% and 28.4% (Bleakley et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2011a\u003c/span\u003e) \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003ea\u003c/span\u003e range which includes in it the naturally occurring incidence of comorbid schizophrenia and OCS described above. Higher plasma concentrations of clozapine and its metabolite, norclozapine, have been linked to the emergence of OCS (Villari et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2011\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eEmergence of tics is extremely rare. It has been shown to occur in the presence of one or more factors such as abnormal electrophysiological findings and seizures, extrapyramidal symptoms, brain pathology, and a family history of tics. A case report revealed that clozapine-induced obsessions were misdiagnosed as psychosis, resulting in inadequate treatment for OCD, thereby underscoring that clozapine can exacerbate OCS (Leung \u0026amp; Palmer, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Few case reports have documented the occurrence of clozapine-induced stuttering in the absence of risk factors. This case report examines a patient who developed recurrent vocalizations and OCS following clozapine treatment, and it details the management strategies employed for these symptoms.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eHistory of presenting illness:\u003c/h2\u003e\u003cp\u003eThe patient is a 39-year-old man with a complicated psychiatric background that includes schizophrenia, polysubstance abuse, and several previous hospital stays for psychiatric care, including extended and forensic admissions. He also has a history of significant violence and was transferred to our facility in December 2024. His medical history is marked by intravenous drug use (IVDU), chronic hepatitis C virus (HCV) infection, psychogenic polydipsia, and Wolff-Parkinson-White Syndrome, for which he underwent an ablation. He was admitted after being observed displaying erratic behavior and sleeping near subway tracks. When he arrived, he was actively responding to internal stimuli, which was evident when he spat at people passing by. During his admission, he reported grandiose delusions about being extremely wealthy and exhibited paranoid thoughts, refusing to get out of bed because he believed both of his feet were broken. A review of his symptoms showed some inconsistencies; he denied feeling depressed, experiencing anhedonia, or having any thoughts of suicide or homicide, as well as any auditory or other psychotic hallucinations.\u003c/p\u003e\u003cp\u003eHe had previously experienced suicidal thoughts related to self-harm during relationship issues, but there was no record of actual suicide attempts or non-suicidal self-injury (NSSIB). His family history included cases of schizophrenia among second-degree relatives. Before being transferred to our facility, he was started on Haloperidol to help manage his psychosis and divalproex for mood stabilization.\u003c/p\u003e\u003cp\u003eUpon his admission to the Manhattan Psychiatric Center in December 2024, the patient was noted to be irritable, intense, and unpredictable in his behavior. In the early days of his hospitalization, he physically assaulted a staff member, which required immediate intramuscular medication intervention. He was later stabilized on haloperidol and divalproex. Given his past issues with psychogenic polydipsia, he engaged in excessive fluid-seeking behavior.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eInvestigations and Hospital Course:\u003c/h3\u003e\n\u003cp\u003eThe repeated fluid seeking behaviours resulted in the development of hyponatremia, documented on January 9, 2025. His blood counts, comprehensive metabolic panel, RPR, HIV, liver and renal function tests were monitored regularly and remained within normal limits. His serum electrolytes, particularly serum sodium, were closely monitored in the context of psychogenic polydipsia versus diabetes insipidus. The patient was monitored for psychogenic polydipsia and mild hyponatremia on CPO. Despite ongoing treatment, the patient exhibited persistent psychotic symptoms, notably kissing inanimate objects such as windows and floors. Due to inadequate symptom control with the existing regimen, a cross-titration from haloperidol to clozapine was initiated on January 9, 2025, starting at 25 mg daily, in an effort to achieve greater antipsychotic efficacy.\u003c/p\u003e\u003cp\u003eOn January 17, 2025, the patient's clozapine dosage was increased to 50 mg due to significant behavioral and thought disorganization, psychosis, and delusionality.​ The patient's fluid-seeking behaviors and serum sodium levels (135 mEq/L) improved during the first week after clozapine initiation. By January 23, 2025, haloperidol was discontinued, and the clozapine dosage was raised to 100 mg. The patient became more engaged, organized, and less internally preoccupied with improved insight, leading to the maintenance of the 100 mg clozapine dosage for one week. However, over the following month there was regression of his symptoms. He exhibited persistent bizarre and grandiose beliefs, such as believing he was a dog or owned a supportive residence in Brooklyn, though he endorsed these ideas less spontaneously. Intermittent disorganized behaviors were observed, including kissing a window on the unit at times. To enhance the antipsychotic effect, the clozapine dosage was increased to 150 mg on February 28, 2025. The patient was also receiving Divalproex 1000mg up to that point.\u003c/p\u003e\u003cp\u003eThroughout March 2025, the patient's clinical condition regressed, characterized by increased disorganization, disinhibition, and interaction with hallucinatory stimuli.​ Notably, he became more resistant to unit rules and treatment expectations. A reduction in serum psychotropic blood levels suggested the patient was cheeking his medication, leading to the implementation of strict mouth checks. To address these issues, the clozapine dosage was increased to 350 mg and Divalproex ER to 2000 mg as of March 31, 2025.\u003c/p\u003e\u003cp\u003eIn the subsequent month, the patient experienced multiple episodes of nocturia and bedwetting, even with evening fluid restrictions and bedwetting protocols. A 24-hour urine collection from April 8\u0026ndash;9, 2025, measured 4000mL. To differentiate between psychogenic polydipsia and diabetes insipidus, further tests were conducted, revealing a high serum osmolality of 317 mOsm/kg and a 24-hour urine osmolality of 133 mOsm/kg. A nephrology consultation was recommended in August 2025. There was no evidence of medication cheeking, as the patient's valproic acid level was 84.1 on April 1, 2025, and weekly serum clozapine levels consistently exceeded 350 over the past month. On April 30, 2025, the clozapine dosage was increased to 475 mg orally once daily at bedtime.\u003c/p\u003e\u003cp\u003eWhile on the established medication regimen, the patient developed \u003cb\u003ecompulsive behaviors\u003c/b\u003e and \u003cb\u003etic-like vocalizations\u003c/b\u003e during May 2025​. On May 16, 2025, he was again placed on a Continuous Psychiatric Observation (CPO) 1:1 protocol due to compulsive fluid consumption and disorganized behaviors, with fluid intake restricted to less than 1.5 liters per day. It was discovered that he was spending an excessive amount of time in the bathroom engaging in incessant hand and face washing, which resulted in small superficial abrasions to his forehead. He was also observed repeating words and sounds uncontrollably, and compulsively consuming water. The patient had no prior personal or family history of tics or vocalizations. However, the CPO was discontinued on May 20, 2025, due to an initial improvement in compulsive fluid-seeking and disorganized behaviors. On June 5, 2025, Aripiprazole 20 mg was added to his psychotropic regimen as an adjunctive treatment. Over the subsequent month, no clinical improvement was observed with the addition of aripiprazole; instead, the patient became more restless. Consequently, the decision was made to discontinue aripiprazole. In the following month, the patient's psychosis remained persistent, possibly increasing. He continued to exhibit grandiose and bizarre delusions, which interfered with his understanding of his community needs. Clozapine titration was ongoing during this period. His psychiatric medications at this point were, Clozapine 575 mg po qhs and Divalproex ER 1,000 mg po bid.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration/Timeline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePharmacological treatment/ Daily dose\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSymptomatology\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDecember 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHaloperidol 15 mg po bid\u003c/p\u003e\u003cp\u003eDivalproex ER 1,000 mg po bid, necessitated IM STAT medications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIrritable, intense, and unpredictable behavior (he physically assaulted a staff member)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJanuary 9th 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClozapine 25 mg daily\u003c/p\u003e\u003cp\u003eHaloperidol 10 mg po bid\u003c/p\u003e\u003cp\u003eDivalproex ER 1,000 mg po bid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePsychotic symptoms, notably kissing inanimate objects such as windows and floors\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJanuary 17, 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClozapine 50 mg po bid\u003c/p\u003e\u003cp\u003eHaloperidol 5 mg po bid\u003c/p\u003e\u003cp\u003eDivalproex ER 1,000 mg po bid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBehavioral and thought disorganization, psychosis, and delusionality.​\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJanuary 23, 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClozapine 100 mg po bid\u003c/p\u003e\u003cp\u003eDivalproex ER 1,000 mg po bid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMore engaged, organized, and less internally preoccupied\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFebruary 28, 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClozapine 150 mg po bid\u003c/p\u003e\u003cp\u003eDivalproex ER 1,000 mg po bid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIntermittent disorganized behaviors were observed, including kissing a window on the unit at times.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMarch 31, 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClozapine 350 mg po qhs\u003c/p\u003e\u003cp\u003eDivalproex ER 2,000 mg po qhs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMore resistant, reduction in serum psychotropic levels suggesting cheeking of medication\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApril 30, 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClozapine 475 mg po qhsDivalproex ER 2,000 mg po qhs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMultiple episodes of nocturia in addition to persistent psychosis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMay 16, 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClozapine 475 mg and Divalproex 2000mg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eIncessant hand and face washing\u003c/b\u003e, leading to superficial abrasions on his forehead, \u003cb\u003euncontrolled repetition of words\u003c/b\u003e and sounds, along with compulsive water consumption.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJune 5, 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAripiprazole 25 mg, Clozapine 475 mg and Divalproex 2000 mg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo clinical improvement, patient became more restless\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJuly 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClozapine 575 mg and Divalproex 1000 mg (Aripiprazole was discontinued)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePatient under observation for improvement of symptoms\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eClozapine is an atypical antipsychotic. It acts as an antagonist to dopamine and serotonin receptors. Clozapine binds to the dopamine D4 receptor with a higher affinity than the dopamine D2 receptor, contributing to decreased adverse events and extrapyramidal symptoms. Clozapine targets several serotonin receptors, with its antagonism of the 5-HT2A and 5-HT2C receptors being specifically implicated in the emergence of OCS (Marek et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). Clozapine is a partial 5-HT1A agonist that reduces adverse and extrapyramidal symptoms and a muscarinic M1, M2, M3, M5, histamine, and alpha-1 adrenergic-receptor antagonist. Norclozapine, the metabolite of clozapine, actively works on the M1 and M4 receptors. Clozapine causes fewer extrapyramidal symptoms at clinically effective doses due to its potent 5-HT2A and weak D2 receptor blocking properties which makes it a desirable option (Meltzer, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e1990\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOne key thing to keep in mind is how to tell apart vocalizations caused by clozapine from other potential reasons. Clozapine-induced OCS might be misinterpreted as worsening psychosis, leading to inappropriate dose escalation of clozapine, which can worsen OCS. The main differentials to consider include Tourette Syndrome, Obsessive-Compulsive Syndrome (OCS), functional tics, and Myoclonus. Tourette Syndrome (TS) is a hereditary neurological condition marked by persistent motor and vocal tics that usually kick off in childhood and can carry on into adulthood. OCS involves having obsessive thoughts and engaging in compulsive behaviors, which often occur alongside Tourette Syndrome. It's worth noting that while tics in TS often affect the head, functional tics are less likely to involve the head and are more commonly seen in the limbs (Arbuckle et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). While tics can have a jerky quality, they are not as brief as myoclonus and are typically associated with a premonitory urge and suppressibility, which are absent in myoclonus.\u003c/p\u003e\u003cp\u003eWhile some research points out that tic-like symptoms can emerge during treatment with atypical antipsychotics such as clozapine, quetiapine, atomoxetine, olanzapine, and aripiprazole, other findings suggest that high doses of clozapine may trigger these symptoms, which tend to fade away when the dosage is lowered. Interestingly, there are instances where clozapine, sometimes combined with other antipsychotics like risperidone, has effectively managed severe adult-onset vocal tics in patients with schizophrenia who haven't responded to other atypical antipsychotics (Begum et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eCertain psychotropic medications, like psychostimulants such as methylphenidate used for ADHD, can sometimes trigger secondary tics by boosting dopamine release. Additionally, antiepileptic drugs like carbamazepine and lamotrigine have been associated with the onset of tics, likely due to their effect on increasing dopaminergic transmission (Madruga-Garrido \u0026amp; Mir, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2013\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eIt's really important to understand the intricate relationship between clozapine and vocalizations, as it can both trigger and ease these symptoms depending on the person and the clinical situation. When it comes to clozapine-related obsessive-compulsive symptoms (OCS), which might show up alongside tic-like behaviors, some common management approaches include introducing selective serotonin reuptake inhibitors (SSRIs), clomipramine, or aripiprazole, often while reducing the clozapine dosage. If antidepressants don\u0026rsquo;t do the trick, adding aripiprazole either with or without lowering the clozapine dose can be a solid alternative (Kim et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn some cases where treatment has been successful, lower doses of clozapine (around 100\u0026ndash;150 mg per day) have been effective. On the other hand, reports of worsening symptoms often come from higher doses (between 150\u0026ndash;500 mg per day). This variation in dosage, along with the length of treatment, might help clarify the different outcomes observed. Additionally, there have been instances where obsessive-compulsive symptoms (OCS) and tics appeared during clozapine withdrawal but disappeared once clozapine was reintroduced. This suggests that an imbalance between the dopamine and serotonin systems could be behind these complications.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eRecognizing vocalizations and obsessive-compulsive symptoms (OCS) early in patients taking clozapine is crucial. This involves keeping an eye out for any new or worsening behaviors and speech patterns that are characteristic of these issues. Key signs to look for in vocalizations include repetitive sounds, changes in how fluently someone speaks (known as speech dysfluency), involuntary movements that may accompany the vocalizations, and patterns that worsen under stress but improve when the dosage is adjusted. For OCS, early signs might include the emergence or intensification of compulsive behaviors, a possible imbalance between dopamine and serotonin levels, and the presence of taboo thoughts. Clinicians need to stay alert to the potential side effects of clozapine and provide the necessary treatments. This should involve regular screenings for OCS using formal rating scales as part of routine health checks for patients on clozapine (Bleakley et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2011b\u003c/span\u003e). Some clinical reports indicated that aripiprazole significantly reduced OCS, showing marked improvement. Other Adjunctive Therapies such as valproic acid, have been explored, often in combination with clozapine dose reduction (Zink et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2007\u003c/span\u003e)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest disclosure:\u003c/strong\u003e\u003cp\u003eThe authors have disclosed no conflicts of interest.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003ePatient Consent Statement\u003c/strong\u003e\u003cp\u003e The patient has provided informed consent for the case study and the potential publication of any identifying patient information.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor 1: Manuscript text writing and editingAuthor 2: Conception and Resources Author 3: Conception, Case presentation, Resources and Manuscript editingAuthor 4: Editing and Reviewing the Manuscript Text\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eArbuckle AL, Bihun EC, Schlaggar BL, Black KJ. (2023). Functional tic-like presentations differ strikingly from Provisional Tic Disorder. \u003cem\u003eF1000Research\u003c/em\u003e, \u003cem\u003e11\u003c/em\u003e, 1566. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.12688/f1000research.129252.2\u003c/span\u003e\u003cspan address=\"10.12688/f1000research.129252.2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBegum G, Nkemjika S, Olayinka O, Olupona T, Jolayemi A. Clozapine Response for Vocal Tics in Schizophrenic Patients: A Case Report With Literature Review. Cureus. 2021. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.7759/cureus.14111\u003c/span\u003e\u003cspan address=\"10.7759/cureus.14111\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBesnard J, Ruda GF, Setola V, Abecassis K, Rodriguiz RM, Huang X-P, Norval S, Sassano MF, Shin AI, Webster LA, Simeons FRC, Stojanovski L, Prat A, Seidah NG, Constam DB, Bickerton GR, Read KD, Wetsel WC, Gilbert IH, Hopkins AL. Automated design of ligands to polypharmacological profiles. Nature. 2012;492(7428):215\u0026ndash;20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/nature11691\u003c/span\u003e\u003cspan address=\"10.1038/nature11691\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBleakley S, Brown D, Taylor D. Does clozapine cause or worsen obsessive compulsive symptoms? An analysis and literature review. Therapeutic Adv Psychopharmacol. 2011a;1(6):181\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/2045125311425971\u003c/span\u003e\u003cspan address=\"10.1177/2045125311425971\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBleakley S, Brown D, Taylor D. Does clozapine cause or worsen obsessive compulsive symptoms? An analysis and literature review. Therapeutic Adv Psychopharmacol. 2011b;1(6):181\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/2045125311425971\u003c/span\u003e\u003cspan address=\"10.1177/2045125311425971\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim DD, Barr AM, Lu C, Stewart SE, White RF, Honer WG, Procyshyn RM. Clozapine-Associated Obsessive-Compulsive Symptoms and Their Management: A Systematic Review and Analysis of 107 Reported Cases. Psychother Psychosom. 2020;89(3):151\u0026ndash;60. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1159/000505876\u003c/span\u003e\u003cspan address=\"10.1159/000505876\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLeung JG, Palmer BA. (2016). Psychosis or Obsessions? Clozapine Associated with Worsening Obsessive-Compulsive Symptoms. \u003cem\u003eCase Reports in Psychiatry\u003c/em\u003e, \u003cem\u003e2016\u003c/em\u003e, 1\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1155/2016/2180748\u003c/span\u003e\u003cspan address=\"10.1155/2016/2180748\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMadruga-Garrido M, Mir P. (2013). Tics and Other Stereotyped Movements as Side Effects of Pharmacological Treatment. In \u003cem\u003eInternational Review of Neurobiology\u003c/em\u003e (Vol. 112, pp. 481\u0026ndash;494). Elsevier. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/B978-0-12\u0026ndash;411546\u0026ndash;0.00016\u0026ndash;0\u003c/span\u003e\u003cspan address=\"10.1016/B978-0-12\u0026ndash;411546\u0026ndash;0.00016\u0026ndash;0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMahendran R, Liew E, Subramaniam M. De Novo Emergence of Obsessive-Compulsive Symptoms With Atypical Antipsychotics in Asian Patients With Schizophrenia or Schizoaffective Disorder: A Retrospective, Cross-Sectional Study. J Clin Psychiatry. 2007;68(04):542\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4088/JCP.v68n0408\u003c/span\u003e\u003cspan address=\"10.4088/JCP.v68n0408\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMarek GJ, Carpenter LL, McDougle CJ, Price LH. Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders. Neuropsychopharmacology. 2003;28(2):402\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/sj.npp.1300057\u003c/span\u003e\u003cspan address=\"10.1038/sj.npp.1300057\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeltzer HY. The Role of Serotonin in the Action of Atypical Antipsychotic Drugs. Psychiatric Annals. 1990;20(10):571\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3928/0048-5713-19901001\u0026ndash;08\u003c/span\u003e\u003cspan address=\"10.3928/0048-5713-19901001\u0026ndash;08\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVillari V, Frieri T, Fagiolini A. Aripiprazole Augmentation in Clozapine-Associated Obsessive-Compulsive Symptoms. J Clin Psychopharmacol. 2011;31(3):375\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/JCP.0b013e31821927d8\u003c/span\u003e\u003cspan address=\"10.1097/JCP.0b013e31821927d8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZink M, Englisch S, Knopf U, Kuwilsky A, Dressing H. Augmentation of Clozapine with Valproic Acid for Clozapine-Induced Obsessive-Compulsive Symptoms. Pharmacopsychiatry. 2007;40(5):202\u0026ndash;3. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1055/s\u0026ndash;2007\u0026ndash;985885\u003c/span\u003e\u003cspan address=\"10.1055/s\u0026ndash;2007\u0026ndash;985885\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\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":"","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":"Treatment resistant schizophrenia, Clozapine, OCS, Vocalizations, Vocal tics, Clozapine side effects","lastPublishedDoi":"10.21203/rs.3.rs-7436319/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7436319/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Treatment-resistant schizophrenia is the occurrence of delusions or hallucinations despite two antipsychotic drug attempts. Clozapine, an FDA-approved atypical antipsychotic, is reserved for such a case due to its efficacy but is handicapped by a wide array of side effects like sedation, agranulocytosis, seizures, metabolic syndrome, and neuroleptic malignant syndrome. Interestingly, clozapine has also been associated with the development or worsening of obsessive-compulsive symptoms (OCS) in up to 38.2% of patients, purportedly a byproduct of its serotonin 5-HT2A and 5-HT2C receptor antagonism. By comparison, tic-like vocalizations on clozapine are utterly rare and maybe underreported.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e We report the case of a 39-year-old man with treatment-resistant schizophrenia and psychogenic polydipsia who exhibited tic-like vocalizations and compulsive behavior upon clozapine initiation and dose escalation. Despite initial therapeutic response, the patient evolved with chronic OCS and vocalization, necessitating adjunctive antipsychotic therapy (Aripiprazole) and close behavioral monitoring. Comprehensive assessment excluded organic causes. Unfortunately, treatment with aripiprazole showed no improvement, and he is being monitored on Clozapine.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e This report underscores the importance of early detection and tailored treatment of rare neuropsychiatric side effects such as clozapine-induced vocal tics. Clinicians must remain vigilant for such signs to optimize therapeutic benefits in treatment-resistant schizophrenia. Regular screening with rating scales is recommended. Treatments like aripiprazole have shown significant OCS improvement, while adjuncts such as valproic acid, often combined with dose reduction, have also been explored.\u003c/p\u003e","manuscriptTitle":"Clozapine and the Voice Within: A Case of New-Onset Vocalizations and Obsessive Compulsive Symptoms","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-26 07:51:36","doi":"10.21203/rs.3.rs-7436319/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":"e324087d-d43c-4936-aa78-a5c43e57c794","owner":[],"postedDate":"August 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-08T07:27:26+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-26 07:51:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7436319","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7436319","identity":"rs-7436319","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}