Key Points
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The search for novel drugs for psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies.
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The rapid advances in understanding the structure and regulation of genes encoding neuropeptides, the characterization of their receptors, the synthesis of non-peptide receptor ligands and the wealth of animal data have made neuropeptide receptors attractive therapeutic targets for the treatment of psychiatric disorders.
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However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by animal studies.
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In this Review, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs.
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Although drugs targeting neuropeptide receptors have not met their expectations, we do not believe that the whole concept should be considered a failure.
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Among the most commonly noted reasons for the failure to successfully develop neuropeptide receptor ligands for psychiatric disorders is the poor predictivity of the animal models that have been used to screen these molecules. Drug selection based on data from animal models must be much more stringent and use a variety of models assessing different aspects of the disease.
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The future development of drugs targeting neuropeptide receptors also has to bear in mind the specificity of their mechanism of action. Genetic tests and biomarkers are needed to identify subgroups of patients in whom a specific neuropeptidergic mechanism accounts for the clinical condition and who would thus be anticipated to benefit from a specific drug intervention.
Abstract
The search for novel drugs for treating psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies. Given the wealth of preclinical data supporting the role of neuropeptides in modulating behaviour, pharmaceutical companies have been attempting to target neuropeptide receptors for over two decades. However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by studies in animal models. Here, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs.
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References
Kramer, M. S. et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281, 1640–1645 (1998).
Belzung, C., Yalcin, I., Griebel, G., Surget, A. & Leman, S. Neuropeptides in psychiatric diseases: an overview with a particular focus on depression and anxiety disorders. CNS Neurol. Disord. Drug Targets 5, 135–145 (2006).
Griebel, G. Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders? Pharmacol. Ther. 82, 1–61 (1999).
Steckler, T. Developing small molecule nonpeptidergic drugs for the treatment of anxiety disorders: is the challenge still ahead? Curr. Top. Behav. Neurosci. 2, 415–428 (2010).
Herranz, R. Cholecystokinin antagonists: pharmacological and therapeutic potential. Med. Res. Rev. 23, 559–605 (2003).
Turiault, M., Cohen, C. & Griebel, G. in Encyclopedia of Psychopharmacology (ed. Stolerman, I. P.) 1301–1303 (Springer-Verlag 2010).
Regoli, D., Boudon, A. & Fauchere, J. L. Receptors and antagonists for substance P and related peptides. Pharmacol. Rev. 46, 551–599 (1994).
Rigby, M., O'Donnell, R. & Rupniak, N. M. Species differences in tachykinin receptor distribution: further evidence that the substance P (NK1) receptor predominates in human brain. J. Comp. Neurol. 490, 335–353 (2005).
Beaujouan, J. C., Torrens, Y., Saffroy, M., Kemel, M. L. & Glowinski, J. A 25 year adventure in the field of tachykinins. Peptides 25, 339–357 (2004).
Varty, G. B. et al. The gerbil elevated plus-maze II: anxiolytic-like effects of selective neurokinin NK1 receptor antagonists. Neuropsychopharmacology 27, 371–379 (2002).
Varty, G. B., Morgan, C. A., Cohen-Williams, M. E., Coffin, V. L. & Carey, G. J. The gerbil elevated plus-maze I: behavioral characterization and pharmacological validation. Neuropsychopharmacology 27, 357–370 (2002).
Marco, N. et al. Activation of dopaminergic and cholinergic neurotransmission by tachykinin NK3 receptor stimulation: an in vivo microdialysis approach in guinea pig. Neuropeptides 32, 481–488 (1998).
Snider, R. M. et al. A potent nonpeptide antagonist of the substance P (NK1) receptor. Science 251, 435–437 (1991).
Herpfer, I. & Lieb, K. Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential. CNS Drugs 19, 275–293 (2005).
Ebner, K. & Singewald, N. The role of substance P in stress and anxiety responses. Amino Acids 31, 251–272 (2006).
Gobbi, G. & Blier, P. Effect of neurokinin-1 receptor antagonists on serotoninergic, noradrenergic and hippocampal neurons: comparison with antidepressant drugs. Peptides 26, 1383–1393 (2005).
Kramer, M. S. et al. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 29, 385–392 (2004).
Chappell, P. Effect of CP-122,721, a selective NK-1 receptor antagonist, in patients with MDD. In: Proceedings of the 42nd Annual Meeting of the New Clinical Drug Evaluation Unit (Boca Raton, Florida, 2002).
Ratti, E. et al. Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder. J. Clin. Psychopharmacol. 31, 727–733 (2011).
Keller, M. et al. Lack of efficacy of the substance P (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol. Psychiatry 59, 216–223 (2006).
Liu, K. S. et al. Is bigger better for depression trials? J. Psychiatr. Res. 42, 622–630 (2008).
Ratti, E. et al. Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder. J. Clin. Psychopharmacol. 31, 727–733 (2011).
Liebowitz, M., Sheehan, D., Melia, L. A. & Siffert, J. Safety and efficacy of AV608 in subjects with social anxiety disorder. In: Proceedings of the 47th Annual Meeting of the New Clinical Drug Evaluation Unit (Boca Raton, Florida, 2007).
Tauscher, J. et al. Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder. Eur. Neuropsychopharmacol. 20, 80–87 (2010).
Mathew, S. J. et al. A selective neurokinin-1 receptor antagonist in chronic PTSD: a randomized, double-blind, placebo-controlled, proof-of-concept trial. Eur. Neuropsychopharmacol. 21, 221–229 (2011).
Rupniak, N. M. & Kramer, M. S. Discovery of the antidepressant and anti-emetic efficacy of substance P receptor (NK1) antagonists. Trends Pharmacol. Sci. 20, 485–490 (1999).
Ebner, K., Sartori, S. B. & Singewald, N. Tachykinin receptors as therapeutic targets in stress-related disorders. Curr. Pharm. Des. 15, 1647–1674 (2009).
Pringle, A. et al. Short-term NK1 receptor antagonism and emotional processing in healthy volunteers. Psychopharmacology (Berl.) 215, 239–246 (2011).
Chandra, P. et al. NK1 receptor antagonism and emotional processing in healthy volunteers. J. Psychopharmacol. 24, 481–487 (2010).
McCabe, C., Cowen, P. J. & Harmer, C. J. NK1 receptor antagonism and the neural processing of emotional information in healthy volunteers. Int. J. Neuropsychopharmacol. 12, 1261–1274 (2009).
Emonds-Alt, X. et al. A potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor. Life Sci. 50, PL101–PL106 (1992).
Steinberg, R. et al. Selective blockade of neurokinin-2 receptors produces antidepressant-like effects associated with reduced corticotropin-releasing factor function. J. Pharmacol. Exp. Ther. 299, 449–458 (2001).
Louis, C. et al. Additional evidence for anxiolytic- and antidepressant-like activities of saredutant (SR48968), an antagonist at the neurokinin-2 receptor in various rodent-models. Pharmacol. Biochem. Behav. 89, 36–45 (2008).
Overstreet, D. H., Naimoli, V. M. & Griebel, G. Saredutant, an NK2 receptor antagonist, has both antidepressant-like effects and synergizes with desipramine in an animal model of depression. Pharmacol. Biochem. Behav. 96, 206–210 (2010).
Griebel, G., Perrault, G. & Soubrie, P. Effects of SR48968, a selective non-peptide NK2 receptor antagonist on emotional processes in rodents. Psychopharmacology 158, 241–251 (2001).
Emonds-Alt, X. et al. SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor. Life Sci. 56, L27–L32 (1995).
Dawson, L. A. & Smith, P. W. Therapeutic utility of NK3 receptor antagonists for the treatment of schizophrenia. Curr. Pharm. Des. 16, 344–357 (2010).
Juhl, K. et al. Identification of a new series of non-peptidic NK3 receptor antagonists. Bioorg. Med.Chem. Lett. 21, 1498–1501 (2011).
Simonsen, K. B., Juhl, K., Steiniger-Brach, B. & Nielsen, S. M. Novel NK3 receptor antagonists for the treatment of schizophrenia and other CNS indications. Curr. Opin. Drug Discov. Devel. 13, 379–388 (2010).
Malherbe, P., Ballard, T. M. & Ratni, H. Tachykinin neurokinin 3 receptor antagonists: a patent review (2005–2010). Expert. Opin. Ther. Pat. 21, 637–655 (2011).
Griebel, G. & Beeske, S. Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases? Pharmacol. Ther. 133, 116–123 (2011).
Spooren, W., Riemer, C. & Meltzer, H. NK3 receptor antagonists: the next generation of antipsychotics? Nature Rev. Drug Discov. 4, 967–975 (2005).
Meltzer, H. Y., Arvanitis, L., Bauer, D. & Rein, W. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am. J. Psychiatry 161, 975–984 (2004).
Evangelista, S. Talnetant GlaxoSmithKline. Curr. Opin. Investig. Drugs 6, 717–721 (2005).
Liem-Moolenaar, M. et al. Psychomotor and cognitive effects of a single oral dose of talnetant (SB223412) in healthy volunteers compared with placebo or haloperidol. J. Psychopharmacol. 24, 73–82 (2010).
Vale, W. W., Spiess, J., Rivier, C. & Rivier, J. Characterization of a 41 residue ovine hypothalamic peptide that stimulates the secretion of corticotropin and β-endorphin. Science 213, 1394–1397 (1981).
Hauger, R. L. et al. International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands. Pharmacol. Rev. 55, 21–26 (2003).
Chalmers, D. T., Lovenberg, T. W. & De Souza, E. B. Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J. Neurosci. 15, 6340–6350 (1995).
Gehlert, D. R. et al. Stress and central urocortin increase anxiety-like behavior in the social interaction test via the CRF1 receptor. Eur. J. Pharmacol. 509, 145–153 (2005).
De Souza, E. B. Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinology 20, 789–819 (1995).
Reul, J. M. & Holsboer, F. Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr. Opin. Pharmacol. 2, 23–33 (2002).
Behan, D. P. et al. Neurobiology of corticotropin releasing factor (CRF) receptors and CRF-binding protein: implications for the treatment of CNS disorders. Mol. Psychiatr. 1, 265–277 (1996).
Hauger, R. L., Risbrough, V., Brauns, O. & Dautzenberg, F. M. Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS Neurol. Disord. Drug Targets 5, 453–479 (2006).
Refojo, D. et al. Corticotropin-releasing hormone activates ERK1/2 MAPK in specific brain areas. Proc. Natl Acad. Sci. USA 102, 6183–6188 (2005).
Zobel, A. W. et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatr. Res. 34, 171–181 (2000).
Nestler, E. J. & Hyman, S. E. Animal models of neuropsychiatric disorders. Nature Neurosci. 13, 1161–1169 (2010).
Paykel, E. S. Contribution of life events to causation of psychiatric illness. Psychol. Med. 8, 245–253 (1978).
Kendler, K. S., Karkowski, L. M. & Prescott, C. A. Causal relationship between stressful life events and the onset of major depression. Am. J. Psychiatr. 156, 837–841 (1999).
Hammen, C. Stress and depression. Annu. Rev. Clin. Psychol. 1, 293–319 (2005).
Kimura, M. et al. Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep. Mol. Psychiatry 15, 154–165 (2010).
Lu, A. et al. Conditional CRH overexpressing mice: an animal model for stress-elicited pathologies and treatments that target the central CRH system. Mol. Psychiatry 13, 989 (2008).
Lauer, C. J., Schreiber, W., Holsboer, F. & Krieg, J. C. In quest of identifying vulnerability markers for psychiatric disorders by all-night polysomnography. Arch. Gen. Psychiatry 52, 145–153 (1995).
Held, K. et al. Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression. J. Psychiatr. Res. 38, 129–136 (2004).
Holsboer, F. & Ising, M. Stress hormone regulation: biological role and translation into therapy. Annu. Rev. Psychol. 61, 81–109 (2010).
Keck, M. E. et al. Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 1196–1204 (2008).
Landgraf, R. The involvement of the vasopressin system in stress-related disorders. CNS Neurol. Disord. Drug Targets 5, 167–179 (2006).
Keck, M. E. Corticotropin-releasing factor, vasopressin and receptor systems in depression and anxiety. Amino Acids 31, 241–250 (2006).
Licinio, J. et al. Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans. Mol. Psychiatry 9, 1075–1082 (2004).
Liu, Z. et al. Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression. Neurosci. Lett. 404, 358–362 (2006).
Binder, E. B. et al. Association of polymorphisms in genes regulating the corticotropin-releasing factor system with antidepressant treatment response. Arch. Gen. Psychiatry 67, 369–379 (2010).
Dong, C., Wong, M. L. & Licinio, J. Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans. Mol. Psychiatry 14, 1105–1118 (2009).
Bradley, R. G. et al. Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch. Gen. Psychiatry 65, 190–200 (2008).
Polanczyk, G. et al. Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment: replication and extension. Arch. Gen. Psychiatry 66, 978–985 (2009).
Grabe, H. J. et al. Childhood maltreatment, the corticotropin-releasing hormone receptor gene and adult depression in the general population. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B, 1483–1493 (2010).
Tyrka, A. R. et al. Interaction of childhood maltreatment with the corticotropin-releasing hormone receptor gene: effects on hypothalamic–pituitary–adrenal axis reactivity. Biol. Psychiatry 66, 681–685 (2009).
Murgatroyd, C. et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nature Neurosci. 12, 1559–1566 (2009).
Elliott, E., Ezra-Nevo, G., Regev, L., Neufeld-Cohen, A. & Chen, A. Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice. Nature Neurosci. 13, 1351–1353 (2010).
Spengler, D., Rupprecht, R., Van, L. P. & Holsboer, F. Identification and characterization of a 3′,5′-cyclic adenosine monophosphate-responsive element in the human corticotropin-releasing hormone gene promoter. Mol. Endocrinol. 6, 1931–1941 (1992).
Grunder, G., Hiemke, C., Paulzen, M., Veselinovic, T. & Vernaleken, I. Therapeutic plasma concentrations of antidepressants and antipsychotics: lessons from PET imaging. Pharmacopsychiatry 44, 236–248 (2011).
Sullivan, G. M. et al. PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density? Nucl. Med. Biol. 34, 353–361 (2007).
Uhr, M. et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron 57, 203–209 (2008).
Ising, M. et al. High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response. Neuropsychopharmacology 32, 1941–1949 (2007).
McCann, S. M. & Brobeck, J. R. Evidence for a role of the supraopticohypophyseal system in the regulation of adrenocorticotropin secretion. Proc. Natl Acad. Sci. USA 87, 318–324 (1954).
Antoni, F. A. Vasopressinergic control of pituitary adrenocorticotropin secretion comes of age. Front. Neuroendocrinol. 14, 76–122 (1993).
Aguilera, G. Regulation of pituitary ACTH secretion during chronic stress. Front. Neuroendocrinol. 15, 321–350 (1994).
Engelmann, M., Wotjak, C. T., Neumann, I., Ludwig, M. & Landgraf, R. Behavioral consequences of intracerebral vasopressin and oxytocin: focus on learning and memory. Neurosci. Biobehav. Rev. 20, 341–358 (1996).
Caffé, A. R., van Leeuwen, F. W. & Luiten, P. G. M. Vasopressin cells in the medial amygdala of the rat project to the lateral septum and ventral hippocampus. J. Comp. Neurol. 261, 237–252 (1987).
De Vries, G. J. & Buijs, R. M. The origin of the vasopressinergic and oxytocinergic innervation of the rat brain with special reference to the lateral septum. Brain Res. 273, 307–317 (1983).
van Leeuwen, F. W. & Caffé, A. R. Vasopressin-immunoreactive cell bodies in the bed nucleus of the stria terminalis of the rat. Cell Tissue Res. 28, 525–534 (1983).
Lolait, S. J. et al. Extrapituitary expression of the rat V1b vasopressin receptor gene. Proc. Natl Acad. Sci. USA 92, 6783–6787 (1995).
Young, L. J., Toloczko, D. & Insel, T. R. Localization of vasopressin (V1a) receptor binding and mRNA in the rhesus monkey brain. J. Neuroendocrinol. 11, 291–297 (1999).
Vaccari, C., Lolait, S. J. & Ostrowski, N. L. Comparative distribution of vasopressin V1b and oxytocin receptor messenger ribonucleic acids in brain. Endocrinology 139, 5015–5033 (1998).
Morel, A., O'Carroll, A. M., Brownstein, M. J. & Lolait, S. J. Molecular cloning and expression of a rat V1a arginine vasopressin receptor. Nature 356, 523–526 (1992).
Tribollet, E., Raufaste, D., Maffrand, J. & Serradeil-Le Gal, C. Binding of the non-peptide vasopressin V1a receptor antagonist SR-49059 in the rat brain: an in vitro and in vivo autoradiographic study. Neuroendocrinology 69, 113–120 (1999).
Stemmelin, J., Lukovic, L., Salome, N. & Griebel, G. Evidence that the lateral septum is involved in the antidepressant-like effects of the vasopressin V1b receptor antagonist, SSR149415. Neuropsychopharmacology 30, 35–42 (2005).
Aguilera, G. & Rabadan-Diehl, C. Vasopressinergic regulation of the hypothalamic–pituitary–adrenal axis: implications for stress adaptation. Regul. Pept. 96, 23–29 (2000).
Abelson, J. L., Le Mellédo, J. M. & Bichet, D. G. Dose response of arginine vasopressin to the CCK-B agonist pentagastrin. Neuropsychopharmacology 24, 161–169 (2001).
Purba, J. S., Hoogendijk, W. J. G., Hofman, M. A. & Swaab, D. F. Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch. Gen. Psychiatry 53, 137–143 (1996).
Zhou, J. N. et al. Alterations in arginine vasopressin neurons in the suprachiasmatic nucleus in depression. Arch. Gen. Psychiatry 58, 655–662 (2001).
van Londen, L. et al. Plasma levels of arginine vasopressin elevated in patients with major depression. Neuropsychopharmacology 17, 284–292 (1997).
Gjerris, A., Hammer, M., Vendsborg, P., Christensen, N. J. & Rafaelsen, O. J. Cerebrospinal fluid vasopressin — changes in depression. Br. J. Psychiatry 147, 696–701 (1985).
Altemus, M. et al. Abnormalities in the regulation of vasopressin and corticotropin releasing factor secretion in obsessive-compulsive disorder. Arch. Gen. Psychiatry 49, 9–20 (1992).
Holsboer, F. & Barden, N. Antidepressants and hypothalamic–pituitary–adrenocortical regulation. Endocrine Rev. 17, 187–205 (1996).
Dinan, T. G. et al. Desmopressin normalizes the blunted adrenocorticotropin response to corticotropin-releasing hormone in melancholic depression: evidence of enhanced vasopressinergic responsivity. J. Clin. Endocrinol. Metab. 84, 2238–2240 (1999).
Griebel, G. et al. Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders. Proc. Natl Acad. Sci. USA 99, 6370–6375 (2002).
Gillies, G. E., Linton, E. A. & Lowry, P. J. Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature 299, 355–357 (1982).
von Bardeleben, U., Holsboer, F., Stalla, G. K. & Muller, O. A. Combined administration of human corticotropin-releasing factor and lysine vasopressin induces cortisol escape from dexamethasone suppression in healthy subjects. Life Sci. 37, 1613–1618 (1985).
De Kloet, E. R., Joels, M. & Holsboer, F. Stress and the brain: from adaptation to disease. Nature Rev. Neurosci. 6, 463–475 (2005).
Ising, M. et al. Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression — a potential biomarker? Biol. Psychiatry 62, 47–54 (2007).
Schule, S. et al. Restriction of HIV-1 replication in monocytes is abolished by Vpx of SIVsmmPBj. PLoS ONE 4, e7098 (2009).
Hennings, J. M. et al. Clinical characteristics and treatment outcome in a representative sample of depressed inpatients — findings from the Munich Antidepressant Response Signature (MARS) project. J. Psychiatr. Res. 43, 215–229 (2009).
Paslakis, G. et al. Venlafaxine and mirtazapine treatment lowers serum concentrations of dehydroepiandrosterone-sulfate in depressed patients remitting during the course of treatment. J. Psychiatr. Res. 44, 556–560 (2010).
Serradeil-Le Gal, C. et al. Characterization of (2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide (SSR149415), a selective and orally active vasopressin V1b receptor antagonist. J. Pharmacol. Exp. Ther. 300, 1122–1130 (2002).
Griebel, G., Stemmelin, J., Serradeil-Le Gal, C. & Soubrié, P. Non-peptide vasopressin V1b receptor antagonists as potential drugs for the treatment of stress-related disorders. Curr. Pharm. Des. 11, 1549–1559 (2005).
Roper, J., O'Carroll, A. M., Young, W. & Lolait, S. The vasopressin Avpr1b receptor: molecular and pharmacological studies. Stress 14, 98–115 (2011).
Craighead, M. et al. Characterization of a novel and selective V1B receptor antagonist. Prog. Brain Res. 170, 527–535 (2008).
Wernet, W. et al. In vitro characterization of the selective vasopressin V1b receptor antagonists ABT-436 and ABT-558. Program No. 560.16. 2008 Neuroscience Meeting Planner (Washington DC; Society for Neuroscience; 2008).
Carraway, R. & Leeman, S. E. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J. Biol. Chem. 248, 6854–6861 (1973).
St Pierre, S. et al. Neurotensin, a multi-action peptide hormone. Union Med. Can. 109, 1447–1455 (1980).
Caceda, R., Kinkead, B. & Nemeroff, C. B. Neurotensin: role in psychiatric and neurological diseases. Peptides 27, 2385–2404 (2006).
Kinkead, B. & Nemeroff, C. B. Novel treatments of schizophrenia: targeting the neurotensin system. CNS Neurol. Disord. Drug Targets 5, 205–218 (2006).
Boules, M., Shaw, A., Fredrickson, P. & Richelson, E. Neurotensin agonists: potential in the treatment of schizophrenia. CNS Drugs 21, 13–23 (2007).
Tanaka, K., Masu, M. & Nakanishi, S. Structure and functional expression of the cloned rat neurotensin receptor. Neuron 4, 847–854 (1990).
Chalon, P. et al. Molecular cloning of a levocabastine-sensitive neurotensin binding site. FEBS Lett. 386, 91–94 (1996).
Mazella, J. et al. The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. J. Biol. Chem. 273, 26273–26276 (1998).
Pettibone, D. J. et al. The effects of deleting the mouse neurotensin receptor NTR1 on central and peripheral responses to neurotensin. J. Pharmacol. Exp. Ther. 300, 305–313 (2002).
Boudin, H., Pelaprat, D., Rostene, W. & Beaudet, A. Cellular distribution of neurotensin receptors in rat brain: immunohistochemical study using an antipeptide antibody against the cloned high affinity receptor. J. Comp. Neurol. 373, 76–89 (1996).
Elde, R., Schalling, M., Ceccatelli, S., Nakanishi, S. & Hokfelt, T. Localization of neuropeptide receptor mRNA in rat brain: initial observations using probes for neurotensin and substance P receptors. Neurosci. Lett. 120, 134–138 (1990).
Fassio, A. et al. Distribution of the neurotensin receptor NTS1 in the rat CNS studied using an amino-terminal directed antibody. Neuropharmacology 39, 1430–1442 (2000).
Alexander, M. J. & Leeman, S. E. Widespread expression in adult rat forebrain of mRNA encoding high-affinity neurotensin receptor. J. Comp. Neurol. 402, 475–500 (1998).
Boules, M. et al. Neurotensin analog selective for hypothermia over antinociception and exhibiting atypical neuroleptic-like properties. Brain Res. 919, 1–11 (2001).
Tyler, B. M. et al. In vitro binding and CNS effects of novel neurotensin agonists that cross the blood–brain barrier. Neuropharmacology 38, 1027–1034 (1999).
Tyler-McMahon, B. M., Stewart, J. A., Farinas, F., McCormick, D. J. & Richelson, E. Highly potent neurotensin analog that causes hypothermia and antinociception. Eur. J. Pharmacol. 390, 107–111 (2000).
Machida, R., Tokumura, T., Tsuchiya, Y., Sasaki, A. & Abe, K. Pharmacokinetics of novel hexapeptides with neurotensin activity in rats. Biol. Pharm. Bull. 16, 43–47 (1993).
Tokumura, T. et al. Stability of a novel hexapeptide, (Me)Arg-Lys-Pro-Trp-tert-Leu-Leu-OEt, with neurotensin activity, in aqueous solution and in the solid state. Chem. Pharm. Bull. (Tokyo) 38, 3094–3098 (1990).
Michaud, J. C., Gueudet, C. & Soubrie, P. Effects of neurotensin receptor antagonists on the firing rate of rat ventral pallidum neurons. Neuroreport 11, 1437–1441 (2000).
Richelson, E. NT69L: a neurotensin receptor agonist for treatment of neuropsychiatric diseases. Neuropsychopharmacology 30, S50 (2005).
Smith, K. Trillion-dollar brain drain. Nature 478, 15 (2011).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). (American Psychiatric Association, Washington DC, 2000).
Holsboer, F. How can we realize the promise of personalized antidepressant medicines? Nature Rev. Neurosci. 9, 638–646 (2008).
Kirsch, I. The Emperor's New Drugs: Exploring the Antidepressant Myth (Bodley Head, 2010).
Leucht, S., Heres, S. & Davis, J. M. Considerations about the efficacy of psychopharmacological drugs. Nervenarzt 82, 1425–1430 (2011).
Hokfelt, T., Bartfai, T. & Bloom, F. Neuropeptides: opportunities for drug discovery. Lancet Neurol. 2, 463–472 (2003).
Hokfelt, T., Johansson, O., Ljungdahl, A., Lundberg, J. M. & Schultzberg, M. Peptidergic neurones. Nature 284, 515–521 (1980).
Refojo, D. et al. Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 333, 1903–1907 (2011).
Edwards, T. C., Patrick, D. L. & Topolski, T. D. Quality of life of adolescents with perceived disabilities. J. Pediatr. Psychol. 28, 233–241 (2003).
Heim, C., Newport, D. J., Mletzko, T., Miller, A. H. & Nemeroff, C. B. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 33, 693–710 (2008).
McCauley, J. et al. Clinical characteristics of women with a history of childhood abuse: unhealed wounds. JAMA 277, 1362–1368 (1997).
Molnar, B. E., Buka, S. L. & Kessler, R. C. Child sexual abuse and subsequent psychopathology: results from the National Comorbidity Survey. Am. J. Public Health 91, 753–760 (2001).
Holsboer, F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 477–501 (2000).
Ising, M. et al. The combined dexamethasone/CRH test as a potential surrogate marker in depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 1085–1093 (2005).
Raison, C. L. & Miller, A. H. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am. J. Psychiatry 160, 1554–1565 (2003).
Nemeroff, C. B. The role of corticotropin-releasing factor in the pathogenesis of major depression. Pharmacopsychiatry 21, 76–82 (1988).
Papiol, S. et al. Genetic variability at HPA axis in major depression and clinical response to antidepressant treatment. J. Affect. Disord. 104, 83–90 (2007).
Holsboer, F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J. Psychiatr. Res. 33, 181–214 (1999).
Chen, Y. et al. Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling. Proc. Natl Acad. Sci. USA 107, 13123–13128 (2010).
Coplan, J. D. et al. Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders. Proc. Natl Acad. Sci. USA 93, 1619–1623 (1996).
Wang, X. D. et al. Forebrain CRF modulates early-life stress-programmed cognitive deficits. J. Neurosci. 31, 13625–13634 (2011).
Brunson, K. L., Eghbal-Ahmadi, M., Bender, R., Chen, Y. & Baram, T. Z. Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress. Proc. Natl Acad. Sci. USA 98, 8856–8861 (2001).
Ivy, A. S. et al. Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J. Neurosci. 30, 13005–13015 (2010).
Muller, M. B. et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nature Neurosci. 6, 1100–1107 (2003).
Kolber, B. J. et al. Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice. J. Neurosci. 30, 2571–2581 (2010).
Griebel, G., Perrault, G. & Sanger, D. J. Characterization of the behavioral profile of the non-peptide CRF receptor antagonist CP-154,526 in anxiety models in rodents. Comparison with diazepam and buspirone. Psychopharmacology 138, 55–66 (1998).
Habib, K. E. et al. Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proc. Natl Acad. Sci. USA 97, 6079–6084 (2000).
Brothers, S. P. & Wahlestedt, C. Therapeutic potential of neuropeptide Y (NPY) receptor ligands. EMBO Mol. Med. 2, 429–439 (2010).
Civelli, O. The orphanin FQ/nociceptin (OFQ/N) system. Results Probl. Cell Differ. 46, 1–25 (2008).
Shimazaki, T., Yoshimizu, T. & Chaki, S. Melanin-concentrating hormone MCH1 receptor antagonists: a potential new approach to the treatment of depression and anxiety disorders. CNS Drugs 20, 801–811 (2006).
Chung, S. et al. The melanin-concentrating hormone (MCH) system modulates behaviors associated with psychiatric disorders. PLoS. ONE 6, e19286 (2011).
Holmes, A., Heilig, M., Rupniak, N. M., Steckler, T. & Griebel, G. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol. Sci. 24, 580–588 (2003).
Lang, R., Gundlach, A. L. & Kofler, B. The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease. Pharmacol. Ther. 115, 177–207 (2007).
Striepens, N., Kendrick, K. M., Maier, W. & Hurlemann, R. Prosocial effects of oxytocin and clinical evidence for its therapeutic potential. Front. Neuroendocrinol. 32, 426–450 (2011).
Xu, Y. L. et al. Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 43, 487–497 (2004).
Ionescu, I. et al. Intranasally administered neuropeptide S (NPS) exerts anxiolytic effects following internalization into NPS receptor-expressing neurons. Neuropsychopharmacology 37, 1323–1337 (2012).
Binneman, B. et al. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am. J. Psychiatry 165, 617–620 (2008).
Kirchhoff, V. D., Nguyen, H. T., Soczynska, J. K., Woldeyohannes, H. & McIntyre, R. S. Discontinued psychiatric drugs in 2008. Expert. Opin. Investig. Drugs 18, 1431–1443 (2009).
Coric, V. et al. Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress. Anxiety 27, 417–425 (2010).
Griebel, G., Stahl, S. & Arvanitis, L. The V1b receptor antagonist SSR149415 in the treatment of major depressive and generalized anxiety disorders: results from three double-blind, placebo-controlled studies. Neuropsychopharmacology 36, S351 (2011).
Furmark, T. et al. Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo. Biol. Psychiatry 58, 132–142 (2005).
Kronenberg, G. et al. Randomized, double-blind study of SR142801 (osanetant). A novel neurokinin-3 (NK3) receptor antagonist in panic disorder with pre- and posttreatment cholecystokinin tetrapeptide (CCK-4) challenges. Pharmacopsychiatry 38, 24–29 (2005).
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We thank S. Beeské and H. Junkert for their editorial assistance.
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Florian Holsboer is cofounder of HMNC (HolsboerMaschmeyer NeuroChemie) GmbH, a biotechnology company aiming to develop new personalized treatments for treating depression.
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Supplementary Information, Table 1
Drugs in clinical development for the treatment of schizophrenia, anxiety and major depressive disorders as of November 2011 (PDF 150 kb)
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FURTHER INFORMATION
Glossary
- Hypothalamic–pituitary–adrenal axis
-
A tightly linked, interdependent endocrine structure that comprises a major peripheral part of the stress system, the main function of which is to maintain basal and stress-related homeostasis.
- Neurogenesis
-
The growth and development of nerve tissues.
- Cyclic AMP response element-binding protein
-
A cellular transcription factor that binds to certain DNA sequences called cyclic AMP response elements, thereby increasing or decreasing the transcription of downstream genes.
- Forced swim test
-
A screening model of depression in rodents that measures immobility in a beaker half-filled with water as a measure of despair behaviour. This test has been widely used in the discovery of monoamine-based drugs because of its high predictive validity.
- Limbic structures
-
Set of areas of the brain including the amygdala, anterior thalamic nuclei, fornix, hippocampus, limbic cortex and septum, which have a modulatory role in various functions including emotion, memory and olfaction.
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Griebel, G., Holsboer, F. Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?. Nat Rev Drug Discov 11, 462–478 (2012). https://doi.org/10.1038/nrd3702
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DOI: https://doi.org/10.1038/nrd3702
