A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression
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Rationale Patients with anxious major depressive disorder (AMDD) have more severe symptoms and poorer treatment response than patients with non-AMDD. Increasing evidence implicates the endogenous opioid system in the pathophysiology of depression. AZD2327 is a selective delta opioid receptor (DOR) agonist with anxiolytic and antidepressant activity in animal models.Objective This double-blind, parallel group design, placebo-controlled pilot study evaluated the safety and efficacy of AZD2327 in a preclinical model and in patients with AMDD.Methods We initially tested the effects of AZD2327 in an animal model of AMDD. Subsequently, 22 subjects with AMDD were randomized to receive AZD2327 (3 mg BID) or placebo for 4 weeks. Primary outcome measures included the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). We also evaluated neurobiological markers implicated in mood and anxiety disorders, including vascular endothelial growth factor (VEGF) and electroencephalogram (EEG).Results Seven (54 %) patients responded to active drug and three (33 %) responded to placebo. No significant main drug effect was found on either the HAM-D (p = 0.39) or the HAM-A (p = 0.15), but the HAM-A had a larger effect size. Levels of AZ12311418, a major metabolite of AZD2327, were higher in patients with an anti-anxiety response to treatment compared to nonresponders (p = 0.03). AZD2327 treatment decreased VEGF levels (p = 0.02). There was a trend (p < 0.06) for those with an anti-anxiety response to have higher EEG gamma power than nonresponders.Conclusion These results suggest that AZD2327 has larger potential anxiolytic than antidepressant efficacy. Additional research with DOR agonists should be considered.
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Two studies examining the efficacy of ziprasidone showed that it was not effective in patients neither with nor without anxious depression.
“Two studies examining the efficacy of ziprasidone showed that this was not effective in patients neither with nor without anxious depression [56,57].”
From Patients with anxious depression: overview of prevalence, pathophysiology and impact on course and treatment outcome (2018) · cites this paper as [57]
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Cites
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,501 · see citing works
Medication Augmentation after the Failure of SSRIs for Depression
Trivedi, M. H., Fava, M., Wisniewski, S. R., Thase, M. E., Quitkin, F., Warden, D., Ritz, L., Nierenberg, A. A., Lebowitz, B. D., Biggs, M. M., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa052964 · Cited by 1,002 · see citing works
Fava, M., Rush, A. J., Alpert, J. E., Balasubramani, G. K., Wisniewski, S. R., Carmin, C. N., Biggs, M. M., Zisook, S., Leuchter, A., Howland, R., et al. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2007.06111868 · Cited by 927 · see citing works
Role of Pharmacokinetics and Metabolism in Drug Discovery and Development
Lin, J. H., & Lu, A. Y. H. (1997) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01340-1 · Cited by 713 · see citing works
Mice deficient for δ- and μ-opioid receptors exhibit opposing alterations of emotional responses
Filliol, D., Ghozland, S., Chluba, J., Martin, M., Matthes, H. W. D., Simonin, F., Befort, K., Gavériaux-Ruff, C., Dierich, A., LeMeur, M., et al. (2000) · Nature Genetics · doi:10.1038/76061 · Cited by 672 · see citing works
Human EEG gamma oscillations in neuropsychiatric disorders
Herrmann, C. S., & Demıralp, T. (2005) · Clinical Neurophysiology · doi:10.1016/j.clinph.2005.07.007 · Cited by 600 · see citing works
Opioid receptors: Distinct roles in mood disorders
Lutz, P.-E., & Kieffer, B. L. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2012.11.002 · Cited by 542 · see citing works
Role of Neurotrophic Factors in the Etiology and Treatment of Mood Disorders
Duman, R. S. (2004) · NeuroMolecular Medicine · doi:10.1385/nmm:5:1:011 · Cited by 537 · see citing works
Differentiation of delta and mu opiate receptor localizations by light microscopic autoradiography.
Goodman, R. R., Snyder, S. H., Kuhar, M. J., & Young, W. S. (1980) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.77.10.6239 · Cited by 467 · see citing works
Serum and plasma BDNF levels in major depression: A replication study and meta-analyses
Bocchio-Chiavetto, L., Bagnardi, V., Zanardini, R., Molteni, R., Gabriela Nielsen, M., Placentino, A., Giovannini, C., Rillosi, L., Ventriglia, M., Riva, M. A., et al. (2010) · The World Journal of Biological Psychiatry · doi:10.3109/15622971003611319 · Cited by 435 · see citing works
Porreca, F., Mosberg, H. I., Hurst, R., et al. (1984) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)21481-1 · Cited by 431 · see citing works
Anxiety disorders in major depression.
Fava, M., Rankin, M. A., Wright, E. C., Alpert, J., Nierenberg, A., Pava, J. A., & Rosenbaum, J. (2000) · Comprehensive Psychiatry · doi:10.1016/s0010-440x(00)90140-8 · Cited by 347 · see citing works
Dysregulation of Endogenous Opioid Emotion Regulation Circuitry in Major Depression in Women
Kennedy, S. E., Koeppe, R. A., Young, E. A., & Zubieta, J. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.11.1199 · Cited by 339 · see citing works
Non-adherence and non-response in the treatment of anxiety disorders
Taylor, S., Abramowitz, J. S., & McKay, D. (2012) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2012.02.010 · Cited by 317 · see citing works
Regionally selective increases in μ opioid receptor density in the brains of suicide victims
Gross‐Isseroff, R., Dillon, K. A., Israeli, M., & Biegon, A. R. (1990) · Brain Research · doi:10.1016/0006-8993(90)91301-v · Cited by 221 · see citing works
Cornwell, B. R., Salvadore, G., Furey, M., Marquardt, C. A., Brutsché, N. E., Grillon, C., & Zarate, C. A. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.03.029 · Cited by 200 · see citing works
Self-citationAndreescu, C., Lenze, E. J., Dew, M. A., Begley, A. E., Mulsant, B. H., Dombrovski, A. Y., Pollock, B. G., STACK, J. A., Miller, M. D., & Reynolds, C. F. (2007) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.106.027169 · Cited by 196 · see citing works
Saitoh, A., Kimura, Y., Suzuki, T., Kawai, K., Nagase, H., & Kamei, J. (2004) · Journal of Pharmacological Sciences · doi:10.1254/jphs.fpj04014x · Cited by 180 · see citing works
Sanderson, W. C., Beck, A. T., & Beck, J. (1990) · American Journal of Psychiatry · doi:10.1176/ajp.147.8.1025 · Cited by 177 · see citing works
Nonpeptidic δ-opioid Receptor Agonists Reduce Immobility in the Forced Swim Assay in Rats
Broom, D. (2002) · Neuropsychopharmacology · doi:10.1016/s0893-133x(01)00413-4 · Cited by 175 · see citing works
Quirion, R., Zajac, J., Morgat, J. L., & Roques, B. P. (1983) · Life Sciences · doi:10.1016/0024-3205(83)90484-8 · Cited by 173 · see citing works
Mansour, A., Thompson, R. C., Akil, H., et al. (1993) · Journal of Chemical Neuroanatomy · doi:10.1016/0891-0618(93)90010-2 · Cited by 143 · see citing works
Knoll, A. T., Muschamp, J. W., Daws, S. E., Ferguson, D., Dietz, D., Meloni, E. G., Carroll, F. I., Nestler, E. J., Konradi, C. L., & Carlezon, W. A. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.03.017 · Cited by 141 · see citing works
Cahill, C. M., McClellan, K. A., Morinville, A., et al. (2001) · The Journal of Comparative Neurology · doi:10.1002/cne.1370 · Cited by 132 · see citing works
Escribá, P. V., Ozaita, A., & Garcı́a-Sevilla, J. A. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300459 · Cited by 125 · see citing works
The Antidepressant -like Effects of Delta-Opioid Receptor Agonists
Jutkiewicz, E. M. (2006) · Molecular Interventions · doi:10.1124/mi.6.3.7 · Cited by 124 · see citing works
Defining anxious depression: a review of the literature
Ionescu, D. F., Niciu, M. J., Henter, I. D., & Zarate, C. A. (2013) · CNS Spectrums · doi:10.1017/s1092852913000114 · Cited by 119 · see citing works
Self-citationKahl, K. G., Bens, S., Ziegler, K. J., Rudolf, S., Kordon, A., DIBBELT, L., & Schweiger, U. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.09.016 · Cited by 112 · see citing works
VEGF and depression: A comprehensive assessment of clinical data
Clark-Raymond, A., & Halaris, A. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.04.008 · Cited by 108 · see citing works
Iga, J., Ueno, S., Yamauchi, K., Numata, S., Shibuya‐Tayoshi, S., Kinouchi, S., Nakataki, M., Song, H., Hokoishi, K., Tanabe, H., et al. (2006) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2006.12.011 · Cited by 105 · see citing works
Tejedor‐Real, P., Micó, J. A., Smadja, C., Maldonado, R. J., Roques, B. P., & Gibert‐Rahola, J. (1998) · European Journal of Pharmacology · doi:10.1016/s0014-2999(98)00423-3 · Cited by 99 · see citing works
Torregrossa, M. M., Jutkiewicz, E. M., Mosberg, H. I., Balboni, G., Watson, S. J., & Woods, J. H. (2005) · Brain Research · doi:10.1016/j.brainres.2005.11.005 · Cited by 98 · see citing works
Increased plasma VEGF levels in major depressive or manic episodes in patients with mood disorders
Lee, B.-H., & Kim, Y. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.07.021 · Cited by 92 · see citing works
VEGF serum levels in depressed patients during SSRI antidepressant treatment
Ventriglia, M., Zanardini, R., Pedrini, L., Placentino, A., Nielsen, M. G., Gennarelli, M., & Bocchio‐Chiavetto, L. (2008) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2008.11.009 · Cited by 69 · see citing works
The δ-Opioid Receptor Agonist (+)BW373U86 Regulates BDNF mRNA Expression in Rats
Torregrossa, M. M., Isgor, C., Folk, J. E., Rice, K. C., Watson, S. J., & Woods, J. H. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300345 · Cited by 67 · see citing works
Rush, A. J., Wisniewski, S. R., Zisook, S., D, M. F. M., Sung, S. C., Haley, C. L., Chan, H. N., Gilmer, W. S., Warden, D., Nierenberg, A. A., et al. (2011) · Psychological Medicine · doi:10.1017/s0033291711002170 · Cited by 65 · see citing works
Activation of N-Methyl-d-Aspartate Receptor Attenuates Acute Responsiveness of δ-Opioid Receptors
Cai, Y.-C., Ma, L., Fan, G.-H., Zhao, J., Jiang, L., & Pei, G. (1997) · Molecular Pharmacology · doi:10.1124/mol.51.4.583 · Cited by 59 · see citing works
Pharmacologic Treatment of Dimensional Anxious Depression: A Review
Ionescu, D. F., Niciu, M. J., Richards, E. M., & Zarate, C. A. (2014) · The Primary Care Companion For CNS Disorders · doi:10.4088/pcc.13r01621 · Cited by 56 · see citing works
Self-citationPreclinical Pharmacology of AZD2327: A Highly Selective Agonist of the δ-Opioid Receptor
Hudzik, T. J., Maciag, C. M., Smith, M. A., CACCESE, R. G., Pietras, M. R., Bui, K., Coupal, M., Adam, L., Payza, K., Griffin, A. M., et al. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.179432 · Cited by 55 · see citing works
Self-citationAutoradiographic localization of delta opiate receptors in rat and human brain
Blackburn, T. P., Cross, A. J., Hille, C. J., & Slater, P. (1988) · Neuroscience · doi:10.1016/0306-4522(88)90283-7 · Cited by 54 · see citing works
Self-citationCognitive therapy for anxious depression in STAR(*) D: what have we learned?
Farabaugh, A., Alpert, J., Wisniewski, S. R., Otto, M. W., Fava, M., Baer, L., Perlis, R., Friedman, E., Nyer, M., Bitran, S., et al. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.04.029 · Cited by 52 · see citing works
Anxious versus non-anxious depression: difference in treatment outcome
Domschke, K., Deckert, J., Arolt, V., & Baune, B. (2010) · Journal of Psychopharmacology · doi:10.1177/0269881108097723 · Cited by 42 · see citing works
Depression and BMI influences the serum vascular endothelial growth factor level
Elfving, B., Buttenschøn, H. N., Foldager, L., Poulsen, P. H. P., Grynderup, M. B., Hansen, Å. M., Kolstad, H. A., Kærlev, L., Mikkelsen, S., Børglum, A. D., et al. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145714000273 · Cited by 40 · see citing works
Naidu, P. S., Lichtman, A. H., Archer, C. C., et al. (2007) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.03.031 · Cited by 40 · see citing works
VEGF plasma level variations in duloxetine-treated patients with major depression
Fornaro, M., Rocchi, G., Escelsior, A., Contini, P., Ghio, M., Colicchio, S., Berardis, D. D., Amore, M., Fornaro, P., & Martino, M. (2013) · Journal of Affective Disorders · doi:10.1016/j.jad.2013.06.055 · Cited by 40 · see citing works
Fusa, K., Takahashi, I., Watanabe, S., et al. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.10.016 · Cited by 39 · see citing works
Antidepressant-Like Effects of the Novel Kappa Opioid Antagonist MCL-144B in the Forced-Swim Test
Reindl, J. D., Rowan, K. M., Carey, A. N., Peng, X., Neumeyer, J. L., & McLaughlin, J. P. (2008) · Pharmacology · doi:10.1159/000112867 · Cited by 38 · see citing works
Torregrossa, M. M., Folk, J. E., Rice, K. C., Watson, S. J., & Woods, J. H. (2005) · Psychopharmacology · doi:10.1007/s00213-005-0113-5 · Cited by 33 · see citing works
Anxiety impairs depression remission in partial responders during extended treatment in late-life
Greenlee, A., Karp, J. F., Dew, M. A., Houck, P. R., Andreescu, C., & Reynolds, C. F. (2010) · Depression and Anxiety · doi:10.1002/da.20672 · Cited by 26 · see citing works
Effects of fluoxetine administration on mu-opoid receptor immunostaining in the rat forebrain
Gandarías, J. M., Echevarrı́a, E., Acebes, I., et al. (1999) · Brain Research · doi:10.1016/s0006-8993(98)01256-6 · Cited by 25 · see citing works
Hudzik, T. J., Pietras, M. R., CACCESE, R. G., et al. (2014) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2014.05.009 · Cited by 20 · see citing works
Self-citationBaker, A. K., Hoffmann, V. L. H., & Meert, T. F. (2002) · PubMed · Cited by 17 · see citing works
Ortega-Álvaro, A., Acebes, I., Sarac�bar, G., et al. (2004) · Psychopharmacology · doi:10.1007/s00213-004-1894-7 · Cited by 16 · see citing works
Bosse, K. E., Jutkiewicz, E. M., Schultz‐Kuszak, K., Mabrouk, O. S., Kennedy, R. T., Gnegy, M. E., & Traynor, J. R. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.08.027 · Cited by 12 · see citing works
Smagin, G. N., Song, D., Medd, A. M., et al. (2008) · European Neuropsychopharmacology · doi:10.1016/s0924-977x(08)70743-0 · Cited by 3 · see citing works
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Research works printed but not linked: 1
- First MB Spitzer RL Gibbon M Williams AR 2001 Structured Clinical Interview for DSM-IV TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P) New York State Psychiatric Institute, Biometrics Research New York
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<p>Management of Treatment-Resistant Depression: Challenges and Strategies</p>
Voineskos, D., Daskalakis, Z. J., & Blumberger, D. M. (2020) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s198774 · Cited by 446 · see citing works
Gaspersz, R., Nawijn, L., Lamers, F., & Penninx, B. W. J. H. (2018) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000376 · Cited by 139 · see citing works
- Authors
- Richards, E. M., Mathews, D. C., Luckenbaugh, D. A., Ionescu, D. F., Machado-Vieira, R., Niciu, M. J., Duncan, W. C., Nolan, N. M., Franco-Chaves, J. A., Hudzik, T., Maciag, C., Li, S., Cross, A., Smith, M. A., & Zarate, C. A.
- Affiliations
- National Institutes of Health (US)
- AbbVie (United States) (US)
- Sage Therapeutics (United States) (US)
- Corresponding author
- Richards, Erica M.
- Venue
- Psychopharmacology
- Published
- 2016-01-04
- Volume
- 233
- Issue
- 6
- Pages
- 1119-1130
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC5103283
- OpenAlex
- W2223515559
- Cited by
- 76
- References
- 55
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 7 · 2019: 9 · 2018: 12 · 2017: 10 · 2016: 5
- FWCI
- 9.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (08-M-0196)
- Brain and Behavior Research Foundation
- NARSAD
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- delta opioid receptor agonists, endogenous opioid system, anxiolytic efficacy, antidepressant efficacy, vascular endothelial growth factor, treatment response, comorbid depression and anxiety
- MeSH terms
- Adolescent, Adult, Aged, Animals, Anxiety, Benzamides, Brain, Major Depressive Disorder, Disease Models, Animal, Double-Blind Method, Electroencephalography, Female, Humans, Male, Middle Aged, Pilot Projects, Piperazines, Anti-Anxiety Agents, Rats, Sprague-Dawley, Receptors, Opioid, delta, Vascular Endothelial Growth Factor A, Young Adult
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