Initial phase 2 trial of a nicotinic agonist in schizophrenia
Open accessAbstract
OBJECTIVE: Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of alpha(7)-nicotinic receptors. Patients' heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial alpha(7)-nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia. METHOD: Thirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers. RESULTS: There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A. CONCLUSION: DMXB-A, a nicotinic agonist that activates alpha(7)-nicotinic receptors, improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs. The clinical utility of this treatment is not yet determined.
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Crossover designs for cognitive outcomes may obscure effects that could be seen in parallel group studies because practice effects and treatment effects may be confounded.
“While crossover designs for cognitive outcomes are appealing due to their capacity to enhance power through within-subjects analyses, these trials may obscure effects that could be seen in parallel group studies because practice effects and treatment effects may be confounded.22”
From Clinical trials of potential cognitive-enhancing drugs in schizophrenia: what have we learned so far? (2013) · cites this paper as [22]
Human studies are mixed, with several but not all showing enhancement of cognition and relief of negative symptoms.
“Human studies are mixed with several but not all showing enhancement of cognition and relief of negative symptoms (39–41).”
From Sensory Processing Dysfunction in the Personal Experience and Neuronal Machinery of Schizophrenia (2015) · cites this paper as [40]
Cites
The Brief Psychiatric Rating Scale.
Overall, J. E., & Gorham, D. R. (1962) · Psychological Reports · doi:10.2466/pr0.1962.10.3.799 · Cited by 11,090 · see citing works
Small sample inference for fixed effects from restricted maximum likelihood
Kenward, M. G., & Roger, J. H. (1997) · Biometrics · doi:10.2307/2533558 · Cited by 4,552 · see citing works
A RATING SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS
Simpson, G. M., B., M., B., G., Angus, J. W. S., P., F. R. C., & M., D. P. (1970) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.1970.tb02066.x · Cited by 3,265 · see citing works
The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity
Nuechterlein, K. H., Green, M. F., Kern, R. S., Baade, L. E., Barch, D. M., Cohen, J. D., Essock, S., Fenton, W. S., Frese, F. J., Gold, J. M., et al. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2007.07010042 · Cited by 2,342 · see citing works
Self-citationNegative Symptoms in Schizophrenia: Definition and Reliability
Andreasen, N. C. (1982) · Archives of General Psychiatry · doi:10.1001/archpsyc.1982.04290070020005 · Cited by 2,247 · see citing works
Progress in Experimental Personality Research
Roth, D. L. (1986) · The Journal of Nervous and Mental Disease · doi:10.1097/00005053-198609000-00013 · Cited by 1,546 · see citing works
Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus
Freedman, R., Coon, H., Myles-Worsley, M., Orr-Urtreger, A., Olincy, A., Davis, A., Polymeropoulos, M., Holik, J., Hopkins, J., Hoff, M., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.2.587 · Cited by 1,141 · see citing works
Self-citation15 Design and Analysis of Cross-Over Trials
Kenward, M. G., & Jones, B. C. (2007) · Handbook of statistics · doi:10.1016/s0169-7161(07)27015-4 · Cited by 873 · see citing works
The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization
Kern, R. S., Nuechterlein, K. H., Green, M. F., Baade, L. E., Fenton, W. S., Gold, J. M., Keefe, R. S. E., Mesholam-Gately, R., Mintz, J., Seidman, L. J., et al. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2007.07010043 · Cited by 744 · see citing works
Self-citationFreedman, R., Hall, M., Adler, L. E., & Leonard, S. (1995) · Biological Psychiatry · doi:10.1016/0006-3223(94)00252-x · Cited by 678 · see citing works
Self-citationProof-of-Concept Trial of an α7 Nicotinic Agonist in Schizophrenia
D, A. O. M., Harris, J. G., Johnson, L. L., Pender, V., Kongs, S., Allensworth, D., Ellis, J., Zerbe, G. O., Leonard, S. S., Stevens, K. E., et al. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.6.630 · Cited by 530 · see citing works
Self-citationDesign and Analysis of Cross-Over Trials
Jones, B. C., & Kenward, M. G. (2003) · Chapman & Hall/CRC eBooks · doi:10.1201/9781420036091 · Cited by 483 · see citing works
INPUT DYSFUNCTION IN SCHIZOPHRENIA.
Ph, V. (1964) · PubMed · Cited by 473 · see citing works
Leonard, S. S., Gault, J., Hopkins, J., Logel, J., Vianzon, R., Short, M., Drebing, C. J., Berger, R., Venn, D., Sirota, P., et al. (2002) · Archives of General Psychiatry · doi:10.1001/archpsyc.59.12.1085 · Cited by 443 · see citing works
Self-citationGoldberg, T. E., GOLDMAN, R. S., Burdick, K. E., Malhotra, A. K., Lencz, T., Patel, R. C., Woerner, M. G., Schooler, N. R., Kane, J. M., & Robinson, D. G. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.10.1115 · Cited by 396 · see citing works
Nicotine-Haloperidol Interactions and Cognitive Performance in Schizophrenics
Levin, E. D. (1996) · Neuropsychopharmacology · doi:10.1016/s0893-133x(96)00018-8 · Cited by 342 · see citing works
Effects of Cigarette Smoking on Spatial Working Memory and Attentional Deficits in Schizophrenia
Sacco, K. A., Termine, A., Seyal, A. A., Dudas, M. M., Vessicchio, J. C., Krishnan‐Sarin, S., Jatlow, P. I., Wexler, B. E., & George, T. P. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.6.649 · Cited by 330 · see citing works
Gold, J. M., Queern, C. A., Iannone, V. N., & Buchanan, R. W. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.12.1944 · Cited by 327 · see citing works
Self-citationSelective α 7 -nicotinic agonists normalize inhibition of auditory response in DBA mice
Stevens, K. E., Kem, W. R., Mahnir, V. M., & Freedman, R. (1998) · Psychopharmacology · doi:10.1007/s002130050573 · Cited by 269 · see citing works
Self-citationBuchanan, R. W., Breier, A. F., Kirkpatrick, B. W., Ball, P. M., & Carpenter, W. T. (1998) · American Journal of Psychiatry · doi:10.1176/ajp.155.6.751 · Cited by 263 · see citing works
Self-citationNeuronal Nicotinic Receptors in Dementia with Lewy Bodies and Schizophrenia
COURT, J. A., Spurden, D., Lloyd, S. R., McKeith, I. G., Ballard, C. G., Cairns, N. J., Kerwin, R. W., Perry, R., & Perry, E. K. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0731590.x · Cited by 254 · see citing works
D, A. O. M., Young, D. A., & Freedman, R. (1997) · Biological Psychiatry · doi:10.1016/s0006-3223(96)00302-2 · Cited by 252 · see citing works
Self-citationBarr, R. S., Maravić, M. C., Jubelt, L. E., Mufti, R. S., Dyer, M. A., Weiss, A. P., Deckersbach, T., Kelly, J. F., Freudenreich, O., GOFF, D. C., et al. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301423 · Cited by 238 · see citing works
KITAGAWA, H., TAKENOUCHI, T., Azuma, R., Wesnes, K. A., Kramer, W. G., Clody, D. E., & Burnett, A. L. (2002) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300028 · Cited by 238 · see citing works
Effects of Nicotine on Cognitive Deficits in Schizophrenia
Harris, J. G., Kongs, S., Allensworth, D., Martín, L., Tregellas, J. R., Sullivan, B. F., Zerbe, G. O., & Freedman, R. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300450 · Cited by 237 · see citing works
Self-citationNicotine effects on brain function and functional connectivity in schizophrenia
Jacobsen, L. K., D’Souza, D. C., Mencl, W. E., Pugh, K. R., Skudlarski, P., & Krystal, J. H. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2003.12.023 · Cited by 232 · see citing works
Varied Effects of Atypical Neuroleptics on P50 Auditory Gating in Schizophrenia Patients
Adler, L. E., D, A. O. M., Cawthra, E. M., McRae, K. A., Harris, J. G., Nagamoto, H. T., Waldo, M. C., Hall, M., Bowles, A., Woodward, L., et al. (2004) · American Journal of Psychiatry · doi:10.1176/ajp.161.10.1822 · Cited by 197 · see citing works
Self-citationEffects of Nicotine Nasal Spray on Cognitive Function in Schizophrenia
Smith, R. C., Warner‐Cohen, J., Matute, M., Butler, E., Kelly, E., Vaidhyanathaswamy, S., & Khan, A. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300881 · Cited by 182 · see citing works
Effects of clozapine on smoking in chronic schizophrenic outpatients.
George, T. P., Sernyak, M. J., Ziedonis, D. M., & Woods, S. W. (1995) · PubMed · Cited by 179 · see citing works
Dépatie, L. (2002) · Neuropsychopharmacology · doi:10.1016/s0893-133x(02)00372-x · Cited by 175 · see citing works
Smoking and therapeutic response to clozapine in patients with schizophrenia
McEvoy, J. P., Freudenreich, O., & Wilson, W. H. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00377-1 · Cited by 172 · see citing works
Galantamine for the treatment of cognitive impairments in people with schizophrenia
Buchanan, R. W., Conley, R. R., Dickinson, D., Ball, M. P., Feldman, S., Gold, J. M., & McMahon, R. P. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2007.07050724 · Cited by 170 · see citing works
Self-citationSimosky, J. K., Stevens, K. E., Adler, L. E., & Freedman, R. (2003) · Psychopharmacology · doi:10.1007/s00213-002-1285-x · Cited by 121 · see citing works
Self-citationKem, W. R., Mahnir, V. M., Papke, R. L., & Lingle, C. J. (1997) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37134-4 · Cited by 119 · see citing works
Self-citationClozapine's effect on negative symptoms in treatment-refractory schizophrenics
Miller, D. D., Perry, P. J., Cadoret, R. J., & Andreasen, N. C. (1994) · Comprehensive Psychiatry · doi:10.1016/0010-440x(94)90164-3 · Cited by 110 · see citing works
Kem, W. R., Mahnir, V. M., Prókai, L., Papke, R. L., Cao, X., LeFrancois, S., Wildeboer, K. M., Prókai-Tátrai, K., Porter-Papke, J., & Soti, F. S. (2004) · Molecular Pharmacology · doi:10.1124/mol.65.1.56 · Cited by 100 · see citing works
Self-citationHuman α 7 nicotinic acetylcholine receptor responses to novel ligands
Briggs, C. A., McKenna, D. G., & Piattina-kaplan, M. (1995) · Neuropharmacology · doi:10.1016/0028-3908(95)00028-5 · Cited by 88 · see citing works
Nicotine improves delayed recognition in schizophrenic patients
Myers, C. S., Robles, O., Kakoyannis, A. N., Sherr, J. D., Avila, M. T., Blaxton, T. A., & Thaker, G. K. (2004) · Psychopharmacology · doi:10.1007/s00213-003-1764-8 · Cited by 87 · see citing works
SHARMA, T., REED, C., Aasen, I., & Kumari, V. (2006) · Schizophrenia Research · doi:10.1016/j.schres.2006.03.037 · Cited by 79 · see citing works
Pharmacokinetics and urinary excretion of DMXBA (GTS-21), a compound enhancing cognition
Mahnir, V. M., Lin, B., Prókai-Tátrai, K., et al. (1998) · Biopharmaceutics & Drug Disposition · doi:10.1002/(sici)1099-081x(199804)19:3 · Cited by 40 · see citing works
Nicotinic Agonist Modulation of Neurotransmitter Levels in the Rat Frontoparietal Cortex
Summers, K. L., Kem, W. R., & Giacobini, E. (1997) · The Japanese Journal of Pharmacology · doi:10.1254/jjp.74.139 · Cited by 40 · see citing works
Self-citation
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Modes and models of forebrain cholinergic neuromodulation of cognition
Hasselmo, M. E., & Sarter, M. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2010.104 · Cited by 733 · see citing works
Sensory Processing Dysfunction in the Personal Experience and Neuronal Machinery of Schizophrenia
Javitt, D. C., & Freedman, R. (2015) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2014.13121691 · Cited by 403 · see citing works
Self-citationRethinking inflammation: neural circuits in the regulation of immunity
Olofsson, P. S., Rosas‐Ballina, M., Levine, Y. A., & Tracey, K. J. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01138.x · Cited by 393 · see citing works
Keefe, R. S. E., Fox, K. H., Harvey, P. D., Cucchiaro, J., Siu, C., & Loebel, A. (2011) · Schizophrenia Research · doi:10.1016/j.schres.2010.09.015 · Cited by 237 · see citing works
Buchanan, R. W., Keefe, R. S. E., Umbricht, D., Green, M. F., Laughren, T., & Marder, S. R. (2011) · Schizophrenia Bulletin · doi:10.1093/schbul/sbq038 · Cited by 154 · see citing works
Self-citationKeefe, R. S. E., Buchanan, R. W., Marder, S. R., Schooler, N. R., Dugar, A., Zivkov, M., & Stewart, M. (2013) · Schizophrenia Bulletin · doi:10.1093/schbul/sbr153 · Cited by 138 · see citing works
Self-citationImportance of the nicotinic acetylcholine receptor system in the prefrontal cortex
Wallace, T. L., & Bertrand, D. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.04.001 · Cited by 133 · see citing works
Drug targets for cognitive enhancement in neuropsychiatric disorders.
Wallace, T. L., Ballard, T. M., Pouzet, B., Riedel, W. J., & Wettstein, J. G. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.03.022 · Cited by 127 · see citing works
Galvin, V. C., Yang, S. T., Paspalas, C. D., Yang, Y., Jin, L. E., Datta, D., Morozov, Y. M., Lightbourne, T. C., Lowet, A. S., Rakic, P., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.02.030 · Cited by 79 · see citing works
Leveraging the cortical cholinergic system to enhance attention
Demeter, E., & Sarter, M. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.06.060 · Cited by 75 · see citing works
Konradsson‐Geuken, Å., Gash, C. R., Alexander, K., Pomerleau, F., Huettl, P., Gerhardt, G. A., & Bruno, J. P. (2009) · Synapse · doi:10.1002/syn.20693 · Cited by 71 · see citing works
Young, J. W., Meves, J. M., & Geyer, M. A. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.11.028 · Cited by 69 · see citing works
Lee, C.-H., & Hung, S.-Y. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics15010031 · Cited by 50 · see citing works
Burns, L. H., Pei, Z., & Wang, H. (2023) · Drug Development Research · doi:10.1002/ddr.22085 · Cited by 35 · see citing works
Acheson, D. T., Twamley, E. W., & Young, J. W. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00103 · Cited by 26 · see citing works
Galvin, V. C., Arnsten, A. F. T., & Wang, M. (2018) · Frontiers in Neural Circuits · doi:10.3389/fncir.2018.00067 · Cited by 25 · see citing works
Othman, A. A., Lenz, R. A., Zhang, J., Li, J., Awni, W. M., & Dutta, S. (2011) · The Journal of Clinical Pharmacology · doi:10.1177/0091270010370460 · Cited by 24 · see citing works
Marder, S. R. (2011) · Schizophrenia Bulletin · doi:10.1093/schbul/sbq166 · Cited by 14 · see citing works
Pharmacological Treatment of Cognitive Dysfunction in Neuropsychiatric Disorders
Venero, C. (2015) · Cognitive Enhancement · doi:10.1016/b978-0-12-417042-1.00010-3 · Cited by 4 · see citing works
- Authors
- Freedman, R., Olincy, A., Buchanan, R. W., Harris, J. G., Gold, J. M., Johnson, L., Allensworth, D., Guzman-Bonilla, A., Clement, B., Ball, M. P., Kutnick, J., Pender, V., Martin, L. F., Stevens, K. E., Wagner, B. D., Zerbe, G. O., Soti, F., & Kem, W. R.
- Affiliations
- Denver VA Medical Center (US)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2008-08
- Volume
- 165
- Issue
- 8
- Pages
- 1040-1047
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC3746983
- OpenAlex
- W2120431726
- Cited by
- 426
- References
- 41
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 5 · 2023: 6 · 2022: 9 · 2021: 5 · 2020: 12 · 2019: 14 · 2018: 19 · 2017: 21 · 2016: 21 · 2015: 41 · 2014: 35 · 2013: 41 · 2012: 41
- FWCI
- 19.45
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH061412, MH-068582, MH-061412, P50MH068582)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Keywords
- schizophrenia, α7 nicotinic acetylcholine receptor agonist, negative symptoms, anhedonia, alogia, cognitive enhancement, working memory, attention, antipsychotic augmentation, tremor, nausea
- MeSH terms
- Adult, Attention, Benzylidene Compounds, Cognition Disorders, Drug Administration Schedule, Female, Humans, Male, Memory, Short-Term, Middle Aged, Neuropsychological Tests, Brief Psychiatric Rating Scale, Pyridines, Receptors, Cholinergic, Receptors, Nicotinic, Schizophrenia, Severity of Illness Index, Nicotinic Agonists
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