For decades, scientists at Zucker Hillside Hospital have been exploring every possible avenue to figure out what causes schizophrenia and test ways to treat the symptoms that alter the lives of one in every 100 people and their families.
 
Dr. Anil Malhotra works on identifying the biological underpinnings of schizophrenia and is trying to determine how anti-psychotic drugs work to quell the symptoms of the disease. Dr. Malhotra has studied a number of genes associated with increased risk for the disorder andis interested in how they trigger hallucinations, delusions and cognitive impairment.
 
Now, with risk genes in hand, they can begin to examine the role these genetic factors play in predicting the disease course and individual responses to pharmacological treatment. His group conducted the first whole-genome-association study of schizophrenia, and is collaborating with colleagues at Cold Spring Harbor Laboratory on a study on the genetics of early-onset psychiatric disorders.

Scientific Investigators/Collaborators:

 

• Todd Lencz, PhD
• Katherine Burdick, PhD
• Philip Szeszko, PhD
• Pamela DeRosse, PhD

 

For more information on genetics in psychiatry at The Zucker Hillside Hospital: www.pharmacogeneticsinpsychiatry.com.

Select Publications:

Malhotra AK, Pinals DA, Weingartner H, et al.  NMDA receptor function and human cognition: The effects of ketamine in healthy volunteers. Neuropsychopharmacology 1996; 14:301-307.

Malhotra AK, Goldman D, Buchanan R, Breier A, Pickar D. 5HT2A receptor T102C polymorphism and schizophrenia. Lancet 1996; 347:1830-1831.

Malhotra AK, Goldman D, Ozaki N, et al.  Lack of association between polymorphisms in the 5HT2A receptor gene and the antipsychotic response to clozapine. Am J Psychiatry 1996; 153:1092-1094.

Malhotra AK, Virkkunen M, Rooney W, et al.  The association between the dopamine D4 receptor (D4DR) 16 amino acid repeat polymorphism and novelty seeking. Mol Psychiatry 1996; 1:388-391. Malhotra AK, Goldman D, Ozaki N, et al. Clozapine response and the 5HT2C Cys23Ser polymorphism. NeuroReport 1996; 7:2100-2102.

Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method. Proc Natl Acad Sci 1997; 94:2569-2574.

Breier A, Malhotra AK, Pinals DA, et al. Ketamine-induced psychosis is associated with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 1997; 154:805-811.

Malhotra AK, Pinals DA, Adler CM, et al. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 1997; 17:141-150. 

Malhotra AK, Adler CM, Kennison SD, et al. Clozapine blunts NMDA antagonist-induced psychosis: A study with ketamine. Biol Psychiatry 1997; 42:664-668.

Pickar D, Malhotra AK, Rooney W, et al. Apolipoprotein E E4 allele and clinical phenotype in schizophrenia. Lancet 1997; 350:930-931.
Malhotra AK, Goldman D, Buchanan RW, et al. The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: A haplotype relative risk study and association with clozapine response. Mol Psychiatry 1998; 3:72-75

Adler CM, Goldberg T, Malhotra AK, Pickar D, Breier A. Effects of ketamine on thought disorder, working memory and semantic memory in healthy volunteers. Biol  Psychiatry 1998; 43:811-816.
Malhotra AK, Breier A, Goldman D, Picken L, Pickar D. The apolipoprotein E E4 allele is associated with blunting of ketamine-induced psychosis in schizophrenia. Neuropsychopharmacology 1998; 19:445-448.

Malhotra AK, Goldman D, Mazzanti C, et al.  A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics. Mol Psychiatry 1998; 3:328-32.
Breier A, Malhotra AK, Su TP, et al.  Clozapine and risperidone in chronic schizophrenia: Effects on symptomatology, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 1999; 56:294-8.

Malhotra AK, Goldman D.  Benefits and pitfalls encountered in psychiatric genetic association studies. Biol Psychiatry 1999; 45:544-550.

Cornblatt B, Malhotra AK. Impaired attention as an endophenotype for molecular genetic studies of schizophrenia. Neuropsychiatric Gen 2001; 105:11-15.

Malhotra AK, Kestler LJ, Mazzanti C, et al. A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry 2002; 159:652-654.
Bilder RM, Volavka J, Czobor P, Malhotra AK, et al.  Neurocognitive correlates of the COMT Val158Met polymorphism in chronic schizophrenia.  Biol Psychiatry 2002; 52:701-707.

Correll CU, Malhotra AK, Saurabh K, McMeniman M, Kane JM: Early prediction of antipsychotic response in schizophrenia.  Am J Psychiatry 2003; 160:2063-2065.

Malhotra AK, Murphy GM, Kennedy JL. Pharmacogenetics of psychotropic drug response. Am J Psychiatry 2004; 161(5):780-796.
Correll CU, Malhotra AK.  Pharmacogenetics of antipsychotic-induced weight gain.  Psychopharmacology 2004; 174:477-489. 

Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, Malhotra AK.  Disrupted in schizophrenia 1 (DISC1): Association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J  Hum Genet 2004; 75:862-872.  

Funke B, Finn CT, Plocik AM, Lake S, DeRosse P, Kane JM, Kucherlapati R, Malhotra AK.  Association of the DTNBP1 locus with schizophrenia in a U.S. population.  Am J Hum Genet 2004; 75:891-898. 

Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK.  DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16:1399-1402.

Szeszko PR, Lipsky R, Mentschel C, Robinson D, Gunduz-Bruce H, Sevy S, Ashtari M, Napolitano B, Bilder RM, Kane JM, Goldman D, Malhotra AK. Brain-derived neurotrophic factor Val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry 2005; 10:631-636.

Burdick KE, Goldberg JF, Harrow M, Faull RN, Malhotra AK.  Neurocognition as a stable endophenotype in bipolar disorder and schizophrenia. J Nerv Ment Dis 2006; 194:255-260.

DeRosse P, Funke B, Burdick KE, Lencz T, Ekholm JM, Kane JM, Malhotra AK. Dysbindin (DTNBP1) genotype and negative symptoms in schizophrenia. Am J Psychiatry 2006; 163:532-534. 

Lencz T, Robinson DG, Xu K, Ekholm J, Sevy S, Gunduz-Bruce H, Woerner MG, Kane  JM, Goldman D, Malhotra AK. DRD2 promoter region variation predicts sustained response to antipsychotic medication in first episode schizophrenia. Am J Psychiatry 2006;163: 529-531.

Burdick KE, Lencz T, Funke B, Finn CT, Szeszko PR, Kane JM, Kucherlapati R, Malhotra AK. Genetic variation in DTNBP1 influences general cognitive ability.  Hum Mol Genet 2006; 15(10):1563-8.

Sevy S, Hassoun Y, Bechara A, Yechiam E, Napolitano B, Burdick KE, Delman H, Malhotra AK. Emotion-based decision making in healthy individuals: short term effects of reducing dopamine levels. Psychopharmacology 2006;188:228-35.

Malhotra AK, Burdick KE, Razi K, Bates JA, Sanders M, Kane JM. Ziprasidone-induced cognitive enhancement in schizophrenia: Specificity or pseudospecificity? Schizophr Res 2006; 87:181-184
DeRosse P, Funke B, Burdick KE, Lencz T, Goldberg TE, Kane JM, Kucherlapati R, Malhotra AK. COMT genotype and manic symptoms in schizophrenia. Schizophr Res 2006; 87:28-31.

Burdick KE, Goldberg TE, Funke B, Bates, JA, Lencz T, Kucherlapati R, Malhotra AK.  DTNBP1 genotype influences cognitive decline in schizophrenia. Schizophr Res 2007; 89:169-172

Lencz T, Morgan TV, Athanasiou M, Dain B, Reed CR, Kane JM, Kucherlapati R, Malhotra AK. Converging evidence for a psuedoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry 2007; 12:572-580.

DeRosse P, Hodgkinson CA, Lencz T, Burdick KE, Kane JM, Goldman D, Malhotra AK. Disrupted in schizophrenia 1 (DISC1) genotype and positive symptoms in  schizophrenia. Biol Psychiatry 2007; 61:1208-1210.

Burdick, KE, Funke B, Goldberg JF, Bates JA, Jaeger J, Kucherlapati R, Malhotra AK. COMT genotype increases risk for bipolar I disorder and influences neurocognitive performance. Bipolar Disor. 2007;9:370-6.

Keefe RSE, Malhotra AK, Meltzer H, Kane JM, Buchanan RW, Murthy A, Sovel M, Li C, Goldman R. Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder: Significant placebo /practice effects in a 12-week, randomized, double-blind, placebo-controlled trial. Neuropsychopharmacology 2008; 33:1217-1228.

Goldberg TE, Goldman RS, Burdick KE, Malhotra AK, et al. Cognitive improvements after treatment with second generation antipsychotic medications in first episode schizophrenia: Is it a practice effect. Arch Gen Psychiatry 2007; 64:1115-1122.

Lencz T, Lambert C, DeRosse P, Burdick, KE, Moran TV, Kane JM, Kucherlapati R, Malhotra AK. Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia. PNAS 2007; 104:19942-19947. PMCID: PMC2148402

Loftus ST, Garno JL, Jaeger J, Malhotra AK. Temperament and character dimensions in bipolar I disorder: A comparison to healthy controls. J Psychiatr Res 2008; 42:1131-1136.

Szeszko PR, Hodgkinson CA, Robinson DG, DeRosse P, Bilder RM, Lencz T, Burdick KE, Napolitano B, Betensky JD, Kane JM, Goldman D, Malhotra AK. DISC1 is  associated with prefrontal cortical gray matter and positive symptoms in  schizophrenia. Biol Psychol, 79:103-10, 2008. PMCID: PMC2623247

DeRosse P, Lencz T, Burdick KE, Siris SG, Kane JM, Malhotra AK. The genetics of symptom-based phenotypes: Toward a molecular classification of schizophrenia. Schizophr Bull 2008; 34:1047-53. PMCID: PMC2632513

Opgen-Rhein C, Lencz T, Burdick KE, Neuhaus AH, Derosse P, Goldberg TE, Malhotra AK. Genetic variation in the DAOA gene complex: Impact on susceptibility for schizophrenia and on cognitive performance. Schizophr Res 2008; 103:169-77. PMCID: PMC2605318

Burdick KE, Kamiya A, Hodgkinson CA, Lencz T, Derosse P, Ishizuka K, Elashvili S, Arai H, Godlman D, Sawa A, Malhotra AK. Elucidating the relationship between DISC1, NDEL1, and NDE1 and the risk for schizophrenia: Evidence of epistasis and competitive binding. Hum Mol Genet 2008; 17:2462-73. PMCID: PMC2486442

Burdick KE, Gunawardane N, Goldberg JF, Halperin J, Garno JL, Malhotra AK. Attention and psychomotor functioning in bipolar depression. Psychiatry Res 2009; 166:192-200.

Neuhaus AH, Goldberg TE, Hassoun Y, Bates JA, Nassauer KW, Sevy S, Opgen-Rhein C, Malhotra AK. Acute dopamine depletion with branched chain amino acids decreases auditory top-down event-related potentials in healthy subjects Schizophr Res 2009; 111:167-73.NIHMSID#114466

Volpi S, Potkin SG, Malhotra AK, Licamele L, Lavedan C. Applicability of a genetic signature for enhances iloperidone efficacy in the treatment of schizophrenia. J Clin Psychiatry 2009; 6:801-809. 

Burdick KE, Gunawardane N, Woodberry K, Malhotra AK. The role of general intelligence as an intermediate phenotype for neuropsychiatric disorders. Cogn Neuropsychiatry 2009; 4:299-311. NIHMSID# 137256

Goldberg TE, Kotov R, Lee AT, Gregersen PK, Lencz T, Bromet E, Malhotra AK. The serotonin transporter gene and disease modification in psychosis: evidence for systematic differences in allelic directionality at the 5-HTTLPR locus. Schizophrenia Research 2009; 111:103-8. NIHMSID#104148

Narr KL, Szeszko PR, Lencz T, Woods RP, Hamilton LS, Phillips O, Robinson D, Burdick KE, Derosse P, Kucherlapati R, Thompson PM, Toga AW, Malhotra AK, Bilder RM. DTNBP1 is associated with imaging phenotypes in schizophrenia. Hum Brain Mapp 2009 [Epub ahead of print] PMCID Journal - In Process