IP Library › Granted Patent US 12,410,474
Granted Patent B2
US 12,410,474 · App. 17/526,498 · Granted Sep 9, 2025

Methods, kits, and devices for diagnosing, prognosing, and treating psychiatric disorders in a patient

Inventors: Jiang Li (Chicago, IL); Herbert Y. Meltzer (Chicago, IL)
Assignee: Northwestern University
C12Q1/6883A61K31/454A61K31/519A61K31/551A61K31/5513C12Q2600/106C12Q2600/156
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,410,474
App. No.
17/526,498
Granted
Sep 9, 2025
Kind
B2
Abstract

Disclosed are methods, kits, and devices for diagnosing and treating psychiatric disorders and the symptoms thereof. The methods, kits, and devices relate to identifying genetic markers that may be utilized to diagnose and/or prognose a patient and treat the diagnosed and/or prognosed patient by administering a drug the patient based on the genetic marker having been identified. Genetic markers identified in the methods may include HTR2C polymorphisms such as a polymorphism resulting in a Cys23Ser amino acid substitution, an rs3813929 (-759C/T) polymorphism, and an rs518147 (-697G/C) polymorphism).

Claims (11)

1. A method comprising:

(a) receiving results of a test indicating that a nucleic acid sample from a patient comprises a combination of HTR2C polymorphic alleles comprising a polymorphic allele resulting in a Cys23Ser amino acid substitution, and a C-allele of rs3813929 (-759C/T) polymorphism; and

(b) administering an atypical antipsychotic drug (APD) to the patient after receiving the results of the test;

wherein the patient has exhibited negative symptoms of schizophrenia.

2. The method of claim 1 , wherein the test was performed by amplifying at least a portion of the HTR2C gene from the nucleic acid sample and detecting the HTR2C polymorphisms in the amplified portion.

3. The method of claim 1 , wherein the test was performed by sequencing at least a portion of the HTR2C gene from the nucleic acid sample or from an amplicon obtained by amplifying at least a portion of the HTR2C gene from the nucleic acid sample.

4. The method of claim 1 , wherein the test was performed by contacting the nucleic acid comprising the HTR2C polymorphic alleles with a nucleic acid probe that hybridizes specifically to nucleic acid comprising the HTR2C polymorphic alleles.

5. The method of claim 1 , wherein the test comprises determining whether the nucleic acid sample is homozygous for each of the HTR2C polymorphic alleles.

6. The method of claim 1 , wherein the test comprises determining whether the nucleic acid sample is heterozygous for each of the HTR2C polymorphic alleles.

7. The method of claim 1 , wherein the nucleic acid sample is obtained from blood or a blood product.

8. The method of claim 1 , wherein the atypical APD comprises clozapine, olanzapine, risperidone, or serindole.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 19, 2021
From: MELTZER, HERBERT Y.; LI, JIANG
To: NORTHWESTERN UNIVERSITY
Reel/Frame 058215/0255 →
Continuity (3)
Continuation 14841043 · Aug 31, 2015
Provisional Application 62043937 · Aug 29, 2014
Related Publication 20220177970A1 · Jun 9, 2022
References Cited (74)
US 11174514B2 · Li · 2021 [cited by examiner]
De Luca et al. (Human Psychopharmacology, vol. 22, pp. 463-467, 2007) (Year: 2007). [cited by examiner]
Gunes et al. (Eur. J. Clin Pharmacol, vol. 64, pp. 477-482, 2008). (Year: 2008). [cited by examiner]
Liu et al. (Pharmacogenomics, vol. 11, No. 5, pp. 685-692, 2010). (Year: 2010). [cited by examiner]
Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38: 1083-1152. [cited by applicant]
Berg KA, Clarke WP, Cunningham KA, Spampinato U (2008) Fine-tuning serotonin2c receptor function in the brain: molecular and functional implications. Neuropharmacology 55: 969-976. [cited by applicant]
Boothman L, Raley J, Denk F, Hirani E, Sharp T (2006) In vivo evidence that 5-HT(2C) receptors inhibit 5-HT neuronal activity via a GABAergic mechanism. Br J Pharmacol 149: 861-869. [cited by applicant]
Brummett BH, Babyak MA, Jiang R, Shah SH, Becker RC, et al. (2013) A functional polymorphism in the 5HTR2C gene associated with stress responses also predicts incident cardiovascular events. PLoS One 8: e82781. [cited by applicant]
Buckland PR, Hoogendoorn B, Guy CA, Smith SK, Coleman SL, et al. (2005) Low gene expression conferred by association of an allele of the 5-HT2C receptor gene with antipsychotic-induced weight gain. Am J Psychiatry 162: … [cited by applicant]
Colantuoni C, Lipska BK, Ye T, Hyde TM, Tao R, et al. (2011) Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 478: 519-523. [cited by applicant]
Covell NH, Weissman EM, Essock SM (2004) Weight gain with clozapine compared to first generation antipsychotic medications. Schizophr Bull 30: 229-240. [cited by applicant]
Dunlop J, Watts SW, Barrett JE, Coupet J, Harrison B, et al. (2011) Characterization of vabicaserin (SCA-136), a selective 5-hydroxytryptamine 2C receptor agonist. J Pharmacol Exp Ther 337: 673-680. [cited by applicant]
Fentress HM, Grinde E, Mazurkiewicz JE, Backstrom JR, Herrick-Davis K, et al. (2005) Pharmacological properties of the Cys23Ser single nucleotide polymorphism in human 5-HT2C receptor isoforms. Pharmacogenomics J 5: 244… [cited by applicant]
Gavarini S, Becamel C, Altier C, Lory P, Poncet J, et al. (2006) Opposite effects of PSD-95 and MPP3 Pdz proteins on serotonin 5-hydroxytryptamine2C receptor desensitization and membrane stability. Mol Biol Cell 17: 461… [cited by applicant]
Gurevich I, Tamir H, Arango V, Dwork AJ, Mann JJ, et al. (2002) Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron 34: 349-356. [cited by applicant]
Hernando-Herraez I, Prado-Martinez J, Garg P, Fernandez-Callejo M, Heyn H, et al. (2013) Dynamics of DNA methylation in recent human and great ape evolution. PLoS Genet 9: e1003763. [cited by applicant]
Holmes C, Arranz MJ, Powell JF, Collier DA, Lovestone S (1998) 5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer's disease. Hum Mol Genet 7: 1507-1509. [cited by applicant]
Iwamoto K, Kakiuchi C, Bundo M, Ikeda K, Kato T (2004) Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders. Mol Psychiatry 9: 406-416. [cited by applicant]
Iwamoto K, Bundo M, Kato T (2009) Serotonin receptor 2C and mental disorders: genetic, expression and RNA editing studies. RNA Biol 6: 248-253. [cited by applicant]
Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20: 201-225. [cited by applicant]
Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13: 261-276. [cited by applicant]
Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, et al. (2004) Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 9: 4… [cited by applicant]
Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, et al. (2003) H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28: 519-526. [cited by applicant]
Labasque M, Reiter E, Becamel C, Bockaert J, Marin P (2008) Physical interaction of calmodulin with the 5-hydroxytryptamine2C receptor C-terminus is essential for G protein-independent, arrestin-dependent receptor signa… [cited by applicant]
Lerer B, Macciardi F, Segman RH, Adolfsson R, Blackwood D, et al. (2001) Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder. Mol Psychiatry 6: 579-585. [cited by applicant]
Marquis KL, Sabb AL, Logue SF, Brennan JA, Piesla MJ, et al. (2007) WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7, 1hi ]indole]: A novel 5-hydroxytryptamine 2C receptor-select… [cited by applicant]
Masellis M, Basile V, Meltzer HY, Lieberman JA, Sevy S, et al. (1998) Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology 19: 123-132. [cited by applicant]
Morabito MV, Emeson RB (2009) RNA editing as a therapeutic target for CNS disorders. Neuropsychopharmacology 34: 246. [cited by applicant]
Need AC, Keefe RS, Ge D, Grossman I, Dickson S, et al. (2009) Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis. Eur J Hum Genet 17: 946-957. [cited by applicant]
Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, et al. (2001) RNA editing of the human serotonin 5-HT2C receptor. alterations in suicide and implications for serotonergic pharmacotherapy. Neuropsych… [cited by applicant]
Numata S, Ye T, Hyde TM, Guitart-Navarro X, Tao R, et al. (2012) DNA methylation signatures in development and aging of the human prefrontal cortex. Am J Hum Genet 90: 260-272. [cited by applicant]
Okada M, Northup JK, Ozaki N, Russell JT, Linnoila M, et al. (2004) Modification of human 5-HT(2C) receptor function by Cys23Ser, an abundant, naturally occurring amino-acid substitution. Mol Psychiatry 9: 55-64. [cited by applicant]
Overall JE, Gorham DR (1962) The Brief Psychiatric Rating-Scale. Psychological Reports 10: 799-812. [cited by applicant]
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559-575. [cited by applicant]
Rauser L, Savage JE, Meltzer HY, Roth BL (2001) Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine(2C) receptor. J Pharmacol Exp Ther 299: 83-89. [cited by applicant]
Segman RH, Ebstein RP, Heresco-Levy U, Gorfine M, Avnon M, et al. (1997) Schizophrenia, chronic hospitalization and the 5-HT2C receptor gene. Psychiatr Genet 7: 75-78. [cited by applicant]
Sodhi MS, Burnet PW, Makoff AJ, Kerwin RW, Harrison PJ (2001) RNA editing of the 5-HT(2C) receptor is reduced in schizophrenia. Mol Psychiatry 6: 373-379. [cited by applicant]
Yuan X, Yamada K, Ishiyama-Shigemoto S, Koyama W, Nonaka K (2000) Identification of polymorphic loci in the promoter region of the serotonin 5-HT2C receptor gene and their association with obesity and type II diabetes. … [cited by applicant]
Lieberman, et al., “Effectiveness of Antipsychotic Drigs in Patients with Chromic Schizophrenia”, The New England Journal of Medicine, Sep. 22, 2005; 353:1209-1223. Retrieved from the internet at: https://www.nejm.org/d… [cited by applicant]
Abi-Dargham A, van de Giessen E, Slifstein M, Kegeles LS, Laruelle M (2009) Baseline and amphetamine-stimulated dopamine activity are related in drug-naive schizophrenic subjects. Biol Psychiatry 65: 1091-1093. [cited by applicant]
Arranz MJ, Munro J, Birkett J, Bolonna A, Mancama D, et al. (2000) Pharmacogenetic prediction of clozapine response. Lancet 355: 1615-1616. [cited by applicant]
Assal F, Alarcon M, Solomon EC, Masterman D, Geschwind DH, et al. (2004) Association of the serotonin transporter and receptor gene polymorphisms in neuropsychiatric symptoms in Alzheimer disease. Arch Neurol 61: 1249-1… [cited by applicant]
Bundo M, Iwamoto K, Yamada K, Yoshikawa T, Kato T (2010) Mutation screening and assessment of the effect of genetic variations on expression and RNA editing of serotonin receptor 2C in the human brain. Psychiatry Clin N… [cited by applicant]
Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, et al. (1997) Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387: 303-308. [cited by applicant]
Calcagno E, Carli M, Baviera M, Invernizzi RW (2009) Endogenous serotonin and serotonin2C receptors are involved in the ability of M100907 to suppress cortical glutamate release induced by NMDA receptor blockade. J Neur… [cited by applicant]
Castensson A, Emilsson L, Sundberg R, Jazin E (2003) Decrease of serotonin receptor 2C in schizophrenia brains identified by high-resolution mRNA expression analysis. Biol Psychiatry 54: 1212-1221. [cited by applicant]
Di Giovanni G, De Deurwaerdere P, Di Mascio M, Di Matteo V, Esposito E, et al. (1999) Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electr… [cited by applicant]
Endicott J, Spitzer RL (1978) A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 35: 837-844. [cited by applicant]
Giorgetti M, Tecott LH (2004) Contributions of 5-HT(2C) receptors to multiple actions of central serotonin systems. Eur J Pharmacol 488: 1-9. [cited by applicant]
Gunes A, Dahl ML, Spina E, Scordo MG (2008) Further evidence for the association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients. Eur J Clin Pharmacol 64: 477-48… [cited by applicant]
Gutierrez B, Fananas L, Arranz MJ, Valles V, Guillamat R, et al. (1996) Allelic association analysis of the 5-HT2C receptor gene in bipolar affective disorder. Neurosci Lett 212: 65-67. [cited by applicant]
Guy W (1976) ECDEU Assessment Manual for Psychopharmacology—Revised. DHEW Publ No. ADM 76: 218-222. [cited by applicant]
Hill MJ, Reynolds GP (2011) Functional consequences of two HTR2C polymorphisms associated with antipsychotic-induced weight gain. Pharmacogenomics 12: 727-734. [cited by applicant]
Hsueh YP (2006) The role of the MAGUK protein CASK in neural development and synaptic function. Curr Med Chem 13: 1915-1927. [cited by applicant]
Ju X, Giotakis O, Li T, Karwautz A, Treasure J, et al. (2003) Association of the 5-HT2c gene with susceptibility and minimum body mass index in anorexia nervosa. Neuroreport 14: 781-783. [cited by applicant]
Kusumi M, Araki H, Ijiri T, Kowa H, Adachi Y, et al. (2004) Serotonin 2C receptor gene Cys23Ser polymorphism: a candidate genetic risk factor of migraine with aura in Japanese population. Acta Neurol Scand 109: 407-409. [cited by applicant]
Lappalainen J, Zhang L, Dean M, Oz M, Ozaki N, et al. (1995) Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C). Genomics 27: 274-279. [cited by applicant]
Laruelle M (1998) Imaging dopamine transmission in schizophrenia. A review and meta-analysis. Q J Nucl Med 42: 211-221. [cited by applicant]
Lindenmayer JP, Bernstein-Hyman R, Grochowski S (1994) A new five factor model of schizophrenia. Psychiatr Q 65: 299-322. [cited by applicant]
Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, et al. (2008) Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci 31: 234-242. [cited by applicant]
Liu BC, Zhang J, Wang L, Li XW, Wang Y, et al. (2010) HTR2C promoter polymorphisms are associated with risperidone efficacy in Chinese female patients. Pharmacogenomics 11: 685-692. [cited by applicant]
Malhotra AK, Goldman D, Ozaki N, Rooney W, Clifton A, et al. (1996) Clozapine response and the 5HT2C Cys23Ser polymorphism. Neuroreport 7: 2100-2102. [cited by applicant]
Meltzer HY, Brennan MD, Woodward ND, Jayathilake K (2008) Association of Sult4A1 SNPs with psychopathology and cognition in patients with schizophrenia or schizoaffective disorder. Schizophr Res 106: 258-264. [cited by applicant]
Meltzer HY, Li Z, Kaneda Y, Ichikawa J (2003) Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27: 1159-1172. [cited by applicant]
Meltzer HY, Huang M (2008) In vivo actions of atypical antipsychotic drug on serotonergic and dopaminergic systems. Prog Brain Res 172: 177-197. [cited by applicant]
Mickey BJ, Sanford BJ, Love TM, Shen PH, Hodgkinson CA, et al. (2012) Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans. J Neurosci 32: 9344-9350. [cited by applicant]
Murad I, Kremer I, Dobrusin M, Muhaheed M, Bannoura I, et al. (2001) A family-based study of the Cys23Ser 5HT2C serotonin receptor polymorphism in schizophrenia. Am J Med Genet 105: 236-238. [cited by applicant]
Pritchard AL, Harris J, Pritchard CW, Coates J, Haque S, et al. (2008) Role of 5HT 2A and 5HT 2C polymorphisms in behavioural and psychological symptoms of Alzheimer's disease. Neurobiol Aging 29: 341-347. [cited by applicant]
Reynolds GP, Yao Z, Zhang X, Sun J, Zhang Z (2005) Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response. Eur… [cited by applicant]
Rietschel M, Naber D, Fimmers R, Moller HJ, Propping P, et al. (1997) Efficacy and side-effects of clozapine not associated with variation in the 5-HT2C receptor. Neuroreport 8: 1999-2003. [cited by applicant]
Rushlow WJ, Seah C, Sutton LP, Bjelica A, Rajakumar N (2009) Antipsychotics affect multiple calcium calmodulin dependent proteins. Neuroscience 161: 877-886. [cited by applicant]
Sodhi MS, Arranz MJ, Curtis D, Ball DM, Sham P, et al. (1995) Association between clozapine response and allelic variation in the 5-HT2C receptor gene. Neuroreport 7: 169-172. [cited by applicant]
Vehof J, Burger H, Wilffert B, Al Hadithy A, Alizadeh BZ, et al. (2012) Clinical response to antipsychotic drug treatment: association study of polymorphisms in six candidate genes. Eur Neuropsychopharmacol 22: 625-631. [cited by applicant]
Walstab J, Steinhagen F, Bruss M, Gothert M, Bonisch H (2011) Differences between human wild-type and C23S variant 5-HT2C receptors in inverse agonist-induced resensitization. Pharmacol Rep 63: 45-53. [cited by applicant]