Distinct mechanism for antidepressant activity by blockade of central substance P receptors

Science

Volumn 281, Issue 5383, 1998, Pages 1640-1645

  Kramer, Mark S ^a   Cutler, Neal ^a   Feighner, John ^a   Shrivastava, Ram ^a   Carman, John ^a   Sramek, John J ^a   Reines, Scott A ^a   Liu, Guanghan ^a   Snavely, Duane ^a   Wyatt Knowles, Edwina ^a   Hale, Jeffrey J ^a   Mills, Sander G ^a   MacCoss, Malcolm ^a   Swain, Christopher J ^a   Harrison, Timothy ^a   Hill, Raymond G ^a   Hefti, Franz ^a   Scolnick, Edward M ^a   Cascieri, Margaret A ^a   Chicchi, Gary G ^a   Sadowski, Sharon ^a   Williams, Angela R ^a   Hewson, Louise ^a   Smith, David ^a   Carlson, Emma J ^a   Hargreaves, Richard J ^a   Rupniak, Nadia M J ^a   more..

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

2 BENZHYDRYL 3 (2 METHOXYBENZYLAMINO) 1 AZABICYCLO[2.2.2]OCTANE; ANTIDEPRESSANT AGENT; APREPITANT; PAROXETINE; SUBSTANCE P; SUBSTANCE P ANTAGONIST; SUBSTANCE P RECEPTOR; UNCLASSIFIED DRUG;

ARTICLE; BRAIN REGION; CLINICAL TRIAL; CONTROLLED STUDY; DEPRESSION; DOUBLE BLIND PROCEDURE; DRUG EFFECT; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; GASTROINTESTINAL SYMPTOM; HUMAN; MAJOR CLINICAL STUDY; MONOAMINERGIC SYSTEM; NEUROTOXICITY; ORAL DRUG ADMINISTRATION; PRIORITY JOURNAL; PROTEIN LOCALIZATION; RANDOMIZED CONTROLLED TRIAL; RECEPTOR BLOCKING; RESPIRATORY TRACT INFECTION; SEXUAL DYSFUNCTION; STRESS; VOCALIZATION;

ADOLESCENT; ADULT; AGED; AMYGDALA; ANIMALS; ANTIDEPRESSIVE AGENTS, SECOND-GENERATION; BEHAVIOR, ANIMAL; BRAIN; DEPRESSIVE DISORDER; FEMALE; GERBILLINAE; GUINEA PIGS; HUMANS; MALE; MIDDLE AGED; MORPHOLINES; NOREPINEPHRINE; PAROXETINE; RECEPTORS, NEUROKININ-1; SEROTONIN; STRESS, PSYCHOLOGICAL; SUBSTANCE P; VOCALIZATION, ANIMAL;

EID: 0032508514     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.281.5383.1640     Document Type: Article

References (83)

1. MIMS Annual (Tien Wah Press, Singapore, ed. 20, 1996), pp. 3.250-3.268; Martindale the Extra Pharmacopoeia (Royal Pharmaceutical Society, London, ed. 21, 1996), pp. 299-340; Physicians' Desk Reference (Medical Economics Company, Montvale, NJ, ed. 51, 1997), pp. 2494-2509.
2. MIMS Annual (Tien Wah Press, Singapore, ed. 20, 1996), pp. 3.250-3.268; Martindale the Extra Pharmacopoeia (Royal Pharmaceutical Society, London, ed. 21, 1996), pp. 299-340; Physicians' Desk Reference (Medical Economics Company, Montvale, NJ, ed. 51, 1997), pp. 2494-2509.
3. MIMS Annual (Tien Wah Press, Singapore, ed. 20, 1996), pp. 3.250-3.268; Martindale the Extra Pharmacopoeia (Royal Pharmaceutical Society, London, ed. 21, 1996), pp. 299-340; Physicians' Desk Reference (Medical Economics Company, Montvale, NJ, ed. 51, 1997), pp. 2494-2509.
4. P. W. Mantyh, S. P. Hunt, J. E. Maggio, Brain Res. 307, 147 (1984); T. Hokfelt et al., in Psychopharmacology: The Third Generation of Progress, H. Y. Meltzer, Ed. (Raven, New York, 1987), pp. 401-416; E. P. Pioro, J. M. Mai, A. C. Cuello, in The Human Nervous System, G. Paxinos, Ed. (Academic Press, New York, 1990), pp. 1051-1094.
5. P. W. Mantyh, S. P. Hunt, J. E. Maggio, Brain Res. 307, 147 (1984); T. Hokfelt et al., in Psychopharmacology: The Third Generation of Progress, H. Y. Meltzer, Ed. (Raven, New York, 1987), pp. 401-416; E. P. Pioro, J. M. Mai, A. C. Cuello, in The Human Nervous System, G. Paxinos, Ed. (Academic Press, New York, 1990), pp. 1051-1094.
6. P. W. Mantyh, S. P. Hunt, J. E. Maggio, Brain Res. 307, 147 (1984); T. Hokfelt et al., in Psychopharmacology: The Third Generation of Progress, H. Y. Meltzer, Ed. (Raven, New York, 1987), pp. 401-416; E. P. Pioro, J. M. Mai, A. C. Cuello, in The Human Nervous System, G. Paxinos, Ed. (Academic Press, New York, 1990), pp. 1051-1094.
7. N. Barden et al., J. Neurochem. 41, 834 (1983); E. Brodin, S. O. Ogren, E. Theodorsson-Norheim, Neuropharmacology 26, 581 (1987); L. A. Riley, R. P. Hart, G. M. Jonakait, Mol. Cell. Neurosci. 2, 139 (1991); Y. Shirayama et al., Brain Res. 739, 70 (1996).
8. N. Barden et al., J. Neurochem. 41, 834 (1983); E. Brodin, S. O. Ogren, E. Theodorsson-Norheim, Neuropharmacology 26, 581 (1987); L. A. Riley, R. P. Hart, G. M. Jonakait, Mol. Cell. Neurosci. 2, 139 (1991); Y. Shirayama et al., Brain Res. 739, 70 (1996).
9. N. Barden et al., J. Neurochem. 41, 834 (1983); E. Brodin, S. O. Ogren, E. Theodorsson-Norheim, Neuropharmacology 26, 581 (1987); L. A. Riley, R. P. Hart, G. M. Jonakait, Mol. Cell. Neurosci. 2, 139 (1991); Y. Shirayama et al., Brain Res. 739, 70 (1996).
10. N. Barden et al., J. Neurochem. 41, 834 (1983); E. Brodin, S. O. Ogren, E. Theodorsson-Norheim, Neuropharmacology 26, 581 (1987); L. A. Riley, R. P. Hart, G. M. Jonakait, Mol. Cell. Neurosci. 2, 139 (1991); Y. Shirayama et al., Brain Res. 739, 70 (1996).
11. A. Lisoprawski, G. Blanc, J. Glowinski, Neurosci. lett. 25, 47 (1981); R. A. Siegel et al., Neurochem. Int. 6, 783 (1984); M. J. Bannon et al., Brain Res. 381, 393 (1986); A. Rosen et al., Acta Physiol. Scand. 146, 341 (1992); E. Brodin et al., Neuropeptides 26, 253 (1994).
12. A. Lisoprawski, G. Blanc, J. Glowinski, Neurosci. lett. 25, 47 (1981); R. A. Siegel et al., Neurochem. Int. 6, 783 (1984); M. J. Bannon et al., Brain Res. 381, 393 (1986); A. Rosen et al., Acta Physiol. Scand. 146, 341 (1992); E. Brodin et al., Neuropeptides 26, 253 (1994).
13. A. Lisoprawski, G. Blanc, J. Glowinski, Neurosci. lett. 25, 47 (1981); R. A. Siegel et al., Neurochem. Int. 6, 783 (1984); M. J. Bannon et al., Brain Res. 381, 393 (1986); A. Rosen et al., Acta Physiol. Scand. 146, 341 (1992); E. Brodin et al., Neuropeptides 26, 253 (1994).
14. A. Lisoprawski, G. Blanc, J. Glowinski, Neurosci. lett. 25, 47 (1981); R. A. Siegel et al., Neurochem. Int. 6, 783 (1984); M. J. Bannon et al., Brain Res. 381, 393 (1986); A. Rosen et al., Acta Physiol. Scand. 146, 341 (1992); E. Brodin et al., Neuropeptides 26, 253 (1994).
15. A. Lisoprawski, G. Blanc, J. Glowinski, Neurosci. lett. 25, 47 (1981); R. A. Siegel et al., Neurochem. Int. 6, 783 (1984); M. J. Bannon et al., Brain Res. 381, 393 (1986); A. Rosen et al., Acta Physiol. Scand. 146, 341 (1992); E. Brodin et al., Neuropeptides 26, 253 (1994).
16. P. J. Elliott, Exp. Brain. Res. 73, 345 (1988); R. M. Teixeira et al., Fur. J. Pharmacol. 311, 7 (1996); M. S. Aguiar and M. L. Brandao, Physiol. Behav. 60, 1183 (1996).
17. P. J. Elliott, Exp. Brain. Res. 73, 345 (1988); R. M. Teixeira et al., Fur. J. Pharmacol. 311, 7 (1996); M. S. Aguiar and M. L. Brandao, Physiol. Behav. 60, 1183 (1996).
18. P. J. Elliott, Exp. Brain. Res. 73, 345 (1988); R. M. Teixeira et al., Fur. J. Pharmacol. 311, 7 (1996); M. S. Aguiar and M. L. Brandao, Physiol. Behav. 60, 1183 (1996).
19. R. Rimon et al., Biol. Psychiatry 19, 509 (1983).
20. W. H. Berrettini et al., ibid. 20, 965 (1985).
21. R. M. Snider et al., Science 251, 435 (1991).
22. This was complicated by interspecies variants in neurokinin receptor distribution [M. M. Dietl and J. M. Palacios, Brain Res. 593, 211 (1991)] and pharmacology [B. D. Gitter et al., Eur. J. Pharmacol. 197, 237 (1991); I. J. M. Beresford et al., Br. J. Pharmacol. 104, 292 (1991)], by nonspecific pharmacological effects of antagonists [A. Nagahisa et al., ibid. 107, 273 (1992); N. M. J. Rupniak et al., ibid. 110, 1607 (1993)], and by the poor CNS penetration of many compounds [see (14)].
23. This was complicated by interspecies variants in neurokinin receptor distribution [M. M. Dietl and J. M. Palacios, Brain Res. 593, 211 (1991)] and pharmacology [B. D. Gitter et al., Eur. J. Pharmacol. 197, 237 (1991); I. J. M. Beresford et al., Br. J. Pharmacol. 104, 292 (1991)], by nonspecific pharmacological effects of antagonists [A. Nagahisa et al., ibid. 107, 273 (1992); N. M. J. Rupniak et al., ibid. 110, 1607 (1993)], and by the poor CNS penetration of many compounds [see (14)].
24. This was complicated by interspecies variants in neurokinin receptor distribution [M. M. Dietl and J. M. Palacios, Brain Res. 593, 211 (1991)] and pharmacology [B. D. Gitter et al., Eur. J. Pharmacol. 197, 237 (1991); I. J. M. Beresford et al., Br. J. Pharmacol. 104, 292 (1991)], by nonspecific pharmacological effects of antagonists [A. Nagahisa et al., ibid. 107, 273 (1992); N. M. J. Rupniak et al., ibid. 110, 1607 (1993)], and by the poor CNS penetration of many compounds [see (14)].
25. This was complicated by interspecies variants in neurokinin receptor distribution [M. M. Dietl and J. M. Palacios, Brain Res. 593, 211 (1991)] and pharmacology [B. D. Gitter et al., Eur. J. Pharmacol. 197, 237 (1991); I. J. M. Beresford et al., Br. J. Pharmacol. 104, 292 (1991)], by nonspecific pharmacological effects of antagonists [A. Nagahisa et al., ibid. 107, 273 (1992); N. M. J. Rupniak et al., ibid. 110, 1607 (1993)], and by the poor CNS penetration of many compounds [see (14)].
26. This was complicated by interspecies variants in neurokinin receptor distribution [M. M. Dietl and J. M. Palacios, Brain Res. 593, 211 (1991)] and pharmacology [B. D. Gitter et al., Eur. J. Pharmacol. 197, 237 (1991); I. J. M. Beresford et al., Br. J. Pharmacol. 104, 292 (1991)], by nonspecific pharmacological effects of antagonists [A. Nagahisa et al., ibid. 107, 273 (1992); N. M. J. Rupniak et al., ibid. 110, 1607 (1993)], and by the poor CNS penetration of many compounds [see (14)].
27. J. J. Hale et al., J. Med. Chem., in press.
28. L-760,735 and L-770,765 were synthesized as described in International (PCT) Publication WO 95/18124 (1995).
29. T. Harrison et al., Bioorg. Med. Chem. Lett. 4, 2545 (1994); N. M. J. Rupniak et al., Pain 67, 189 (1996).
30. T. Harrison et al., Bioorg. Med. Chem. Lett. 4, 2545 (1994); N. M. J. Rupniak et al., Pain 67, 189 (1996).
31. 3 receptors was determined after expression in CHO cells as described [S. Sadowski et al., Neuropeptides 24, 317 (1993)]. Affinity for more than 90 other neurotransmitter receptors and ion channels was determined by Panlabs DiscoveryScreen; assays for monoamine transporters were based on P. Berger et al., Eur. J. Pharmacol. 177, 91 (1990); A. M. Cesura et al., ibid. 186, 95 (1990); S. M. Tejani-Butt et al., ibid. 191, 239 (1990); J. W. Boja et al., Synapse 12, 27 (1992).
32. 3 receptors was determined after expression in CHO cells as described [S. Sadowski et al., Neuropeptides 24, 317 (1993)]. Affinity for more than 90 other neurotransmitter receptors and ion channels was determined by Panlabs DiscoveryScreen; assays for monoamine transporters were based on P. Berger et al., Eur. J. Pharmacol. 177, 91 (1990); A. M. Cesura et al., ibid. 186, 95 (1990); S. M. Tejani-Butt et al., ibid. 191, 239 (1990); J. W. Boja et al., Synapse 12, 27 (1992).
33. 3 receptors was determined after expression in CHO cells as described [S. Sadowski et al., Neuropeptides 24, 317 (1993)]. Affinity for more than 90 other neurotransmitter receptors and ion channels was determined by Panlabs DiscoveryScreen; assays for monoamine transporters were based on P. Berger et al., Eur. J. Pharmacol. 177, 91 (1990); A. M. Cesura et al., ibid. 186, 95 (1990); S. M. Tejani-Butt et al., ibid. 191, 239 (1990); J. W. Boja et al., Synapse 12, 27 (1992).
34. 3 receptors was determined after expression in CHO cells as described [S. Sadowski et al., Neuropeptides 24, 317 (1993)]. Affinity for more than 90 other neurotransmitter receptors and ion channels was determined by Panlabs DiscoveryScreen; assays for monoamine transporters were based on P. Berger et al., Eur. J. Pharmacol. 177, 91 (1990); A. M. Cesura et al., ibid. 186, 95 (1990); S. M. Tejani-Butt et al., ibid. 191, 239 (1990); J. W. Boja et al., Synapse 12, 27 (1992).
35. 3 receptors was determined after expression in CHO cells as described [S. Sadowski et al., Neuropeptides 24, 317 (1993)]. Affinity for more than 90 other neurotransmitter receptors and ion channels was determined by Panlabs DiscoveryScreen; assays for monoamine transporters were based on P. Berger et al., Eur. J. Pharmacol. 177, 91 (1990); A. M. Cesura et al., ibid. 186, 95 (1990); S. M. Tejani-Butt et al., ibid. 191, 239 (1990); J. W. Boja et al., Synapse 12, 27 (1992).
36. 3 receptors was determined after expression in CHO cells as described [S. Sadowski et al., Neuropeptides 24, 317 (1993)]. Affinity for more than 90 other neurotransmitter receptors and ion channels was determined by Panlabs DiscoveryScreen; assays for monoamine transporters were based on P. Berger et al., Eur. J. Pharmacol. 177, 91 (1990); A. M. Cesura et al., ibid. 186, 95 (1990); S. M. Tejani-Butt et al., ibid. 191, 239 (1990); J. W. Boja et al., Synapse 12, 27 (1992).
37. 3 receptors was determined after expression in CHO cells as described [S. Sadowski et al., Neuropeptides 24, 317 (1993)]. Affinity for more than 90 other neurotransmitter receptors and ion channels was determined by Panlabs DiscoveryScreen; assays for monoamine transporters were based on P. Berger et al., Eur. J. Pharmacol. 177, 91 (1990); A. M. Cesura et al., ibid. 186, 95 (1990); S. M. Tejani-Butt et al., ibid. 191, 239 (1990); J. W. Boja et al., Synapse 12, 27 (1992).
38. N. M. J. Rupniak and A. R. Williams, Eur. J. Pharmacol. 265, 179 (1994); L. J. Bristow and L. Young, ibid. 254, 245 (1994); E. A. Graham, M. P. Turpin, C. M. Stubbs, Neuropeptides 24, 228 (1993); A. Vassout et al., ibid. 26, S38 (1994); N. M. J. Rupniak et al., Eur. J. Pharmacol. 326, 201 (1997).
39. N. M. J. Rupniak and A. R. Williams, Eur. J. Pharmacol. 265, 179 (1994); L. J. Bristow and L. Young, ibid. 254, 245 (1994); E. A. Graham, M. P. Turpin, C. M. Stubbs, Neuropeptides 24, 228 (1993); A. Vassout et al., ibid. 26, S38 (1994); N. M. J. Rupniak et al., Eur. J. Pharmacol. 326, 201 (1997).
40. N. M. J. Rupniak and A. R. Williams, Eur. J. Pharmacol. 265, 179 (1994); L. J. Bristow and L. Young, ibid. 254, 245 (1994); E. A. Graham, M. P. Turpin, C. M. Stubbs, Neuropeptides 24, 228 (1993); A. Vassout et al., ibid. 26, S38 (1994); N. M. J. Rupniak et al., Eur. J. Pharmacol. 326, 201 (1997).
41. N. M. J. Rupniak and A. R. Williams, Eur. J. Pharmacol. 265, 179 (1994); L. J. Bristow and L. Young, ibid. 254, 245 (1994); E. A. Graham, M. P. Turpin, C. M. Stubbs, Neuropeptides 24, 228 (1993); A. Vassout et al., ibid. 26, S38 (1994); N. M. J. Rupniak et al., Eur. J. Pharmacol. 326, 201 (1997).
42. N. M. J. Rupniak and A. R. Williams, Eur. J. Pharmacol. 265, 179 (1994); L. J. Bristow and L. Young, ibid. 254, 245 (1994); E. A. Graham, M. P. Turpin, C. M. Stubbs, Neuropeptides 24, 228 (1993); A. Vassout et al., ibid. 26, S38 (1994); N. M. J. Rupniak et al., Eur. J. Pharmacol. 326, 201 (1997).
43. P. J. Brent, P. A. Johnston, L. A. Chahl, Neuropharmacology 27, 743 (1988); P. A. Johnston and L. A. Chahl, Arch. Pharmacol. 343, 283 (1991); G. S. Mason, C. A. Graham, P. J. Elliott, Br. J. Pharmacol. 105, 251P (1992); N. M. J. Rupniak and A. Jackson, Eur. J. Pharmacol. 262, 171 (1994).
44. P. J. Brent, P. A. Johnston, L. A. Chahl, Neuropharmacology 27, 743 (1988); P. A. Johnston and L. A. Chahl, Arch. Pharmacol. 343, 283 (1991); G. S. Mason, C. A. Graham, P. J. Elliott, Br. J. Pharmacol. 105, 251P (1992); N. M. J. Rupniak and A. Jackson, Eur. J. Pharmacol. 262, 171 (1994).
45. P. J. Brent, P. A. Johnston, L. A. Chahl, Neuropharmacology 27, 743 (1988); P. A. Johnston and L. A. Chahl, Arch. Pharmacol. 343, 283 (1991); G. S. Mason, C. A. Graham, P. J. Elliott, Br. J. Pharmacol. 105, 251P (1992); N. M. J. Rupniak and A. Jackson, Eur. J. Pharmacol. 262, 171 (1994).
46. P. J. Brent, P. A. Johnston, L. A. Chahl, Neuropharmacology 27, 743 (1988); P. A. Johnston and L. A. Chahl, Arch. Pharmacol. 343, 283 (1991); G. S. Mason, C. A. Graham, P. J. Elliott, Br. J. Pharmacol. 105, 251P (1992); N. M. J. Rupniak and A. Jackson, Eur. J. Pharmacol. 262, 171 (1994).
47. Dunkin-Hartley guinea pigs (250 to 300 g) were anesthetized and a 27-gauge needle was inserted into the cerebral ventricles, 7.5 to 8 mm below bregma. GR73632 was injected icv (5 μl) and spontaneous behavior was recorded upon recovery from anesthesia (n = 4 to 6).
48. J. P. Scott, Excerpta Med. Int. Congr. Ser. 359, 735 (1974); J. Panksepp et al., Biol. Psychiatry 13, 607 (1978); B. Herman and J. Panksepp, Pharmacol. Biochem. Behav. 9, 213 (1978); Science 211, 1060 (1981); R. D. Porsolt, S. Roux, M. Jalfre, Pharmacol. Biochem. Behav. 20, 979 (1983); T. R. Insel, J. L. Hill, R. B. Mayor, ibid. 24, 1263 (1986); N. H. Kalin, S. E. Shelton, C. M. Barksdale, Brain Res. 408, 192 (1987); J. D. Newman, J. T. Winslow, D. L. Murphy, ibid. 538, 24 (1991); K. A. Miczek et al., Psychopharmacology 121, 38 (1995); H. E. Molewijk et al., ibid. 128, 31 (1996).
49. J. P. Scott, Excerpta Med. Int. Congr. Ser. 359, 735 (1974); J. Panksepp et al., Biol. Psychiatry 13, 607 (1978); B. Herman and J. Panksepp, Pharmacol. Biochem. Behav. 9, 213 (1978); Science 211, 1060 (1981); R. D. Porsolt, S. Roux, M. Jalfre, Pharmacol. Biochem. Behav. 20, 979 (1983); T. R. Insel, J. L. Hill, R. B. Mayor, ibid. 24, 1263 (1986); N. H. Kalin, S. E. Shelton, C. M. Barksdale, Brain Res. 408, 192 (1987); J. D. Newman, J. T. Winslow, D. L. Murphy, ibid. 538, 24 (1991); K. A. Miczek et al., Psychopharmacology 121, 38 (1995); H. E. Molewijk et al., ibid. 128, 31 (1996).
50. J. P. Scott, Excerpta Med. Int. Congr. Ser. 359, 735 (1974); J. Panksepp et al., Biol. Psychiatry 13, 607 (1978); B. Herman and J. Panksepp, Pharmacol. Biochem. Behav. 9, 213 (1978); Science 211, 1060 (1981); R. D. Porsolt, S. Roux, M. Jalfre, Pharmacol. Biochem. Behav. 20, 979 (1983); T. R. Insel, J. L. Hill, R. B. Mayor, ibid. 24, 1263 (1986); N. H. Kalin, S. E. Shelton, C. M. Barksdale, Brain Res. 408, 192 (1987); J. D. Newman, J. T. Winslow, D. L. Murphy, ibid. 538, 24 (1991); K. A. Miczek et al., Psychopharmacology 121, 38 (1995); H. E. Molewijk et al., ibid. 128, 31 (1996).
51. J. P. Scott, Excerpta Med. Int. Congr. Ser. 359, 735 (1974); J. Panksepp et al., Biol. Psychiatry 13, 607 (1978); B. Herman and J. Panksepp, Pharmacol. Biochem. Behav. 9, 213 (1978); Science 211, 1060 (1981); R. D. Porsolt, S. Roux, M. Jalfre, Pharmacol. Biochem. Behav. 20, 979 (1983); T. R. Insel, J. L. Hill, R. B. Mayor, ibid. 24, 1263 (1986); N. H. Kalin, S. E. Shelton, C. M. Barksdale, Brain Res. 408, 192 (1987); J. D. Newman, J. T. Winslow, D. L. Murphy, ibid. 538, 24 (1991); K. A. Miczek et al., Psychopharmacology 121, 38 (1995); H. E. Molewijk et al., ibid. 128, 31 (1996).
52. J. P. Scott, Excerpta Med. Int. Congr. Ser. 359, 735 (1974); J. Panksepp et al., Biol. Psychiatry 13, 607 (1978); B. Herman and J. Panksepp, Pharmacol. Biochem. Behav. 9, 213 (1978); Science 211, 1060 (1981); R. D. Porsolt, S. Roux, M. Jalfre, Pharmacol. Biochem. Behav. 20, 979 (1983); T. R. Insel, J. L. Hill, R. B. Mayor, ibid. 24, 1263 (1986); N. H. Kalin, S. E. Shelton, C. M. Barksdale, Brain Res. 408, 192 (1987); J. D. Newman, J. T. Winslow, D. L. Murphy, ibid. 538, 24 (1991); K. A. Miczek et al., Psychopharmacology 121, 38 (1995); H. E. Molewijk et al., ibid. 128, 31 (1996).
53. J. P. Scott, Excerpta Med. Int. Congr. Ser. 359, 735 (1974); J. Panksepp et al., Biol. Psychiatry 13, 607 (1978); B. Herman and J. Panksepp, Pharmacol. Biochem. Behav. 9, 213 (1978); Science 211, 1060 (1981); R. D. Porsolt, S. Roux, M. Jalfre, Pharmacol. Biochem. Behav. 20, 979 (1983); T. R. Insel, J. L. Hill, R. B. Mayor, ibid. 24, 1263 (1986); N. H. Kalin, S. E. Shelton, C. M. Barksdale, Brain Res. 408, 192 (1987); J. D. Newman, J. T. Winslow, D. L. Murphy, ibid. 538, 24 (1991); K. A. Miczek et al., Psychopharmacology 121, 38 (1995); H. E. Molewijk et al., ibid. 128, 31 (1996).
54. J. P. Scott, Excerpta Med. Int. Congr. Ser. 359, 735 (1974); J. Panksepp et al., Biol. Psychiatry 13, 607 (1978); B. Herman and J. Panksepp, Pharmacol. Biochem. Behav. 9, 213 (1978); Science 211, 1060 (1981); R. D. Porsolt, S. Roux, M. Jalfre, Pharmacol. Biochem. Behav. 20, 979 (1983); T. R. Insel, J. L. Hill, R. B. Mayor, ibid. 24, 1263 (1986); N. H. Kalin, S. E. Shelton, C. M. Barksdale, Brain Res. 408, 192 (1987); J. D. Newman, J. T. Winslow, D. L. Murphy, ibid. 538, 24 (1991); K. A. Miczek et al., Psychopharmacology 121, 38 (1995); H. E. Molewijk et al., ibid. 128, 31 (1996).
55. J. P. Scott, Excerpta Med. Int. Congr. Ser. 359, 735 (1974); J. Panksepp et al., Biol. Psychiatry 13, 607 (1978); B. Herman and J. Panksepp, Pharmacol. Biochem. Behav. 9, 213 (1978); Science 211, 1060 (1981); R. D. Porsolt, S. Roux, M. Jalfre, Pharmacol. Biochem. Behav. 20, 979 (1983); T. R. Insel, J. L. Hill, R. B. Mayor, ibid. 24, 1263 (1986); N. H. Kalin, S. E. Shelton, C. M. Barksdale, Brain Res. 408, 192 (1987); J. D. Newman, J. T. Winslow, D. L. Murphy, ibid. 538, 24 (1991); K. A. Miczek et al., Psychopharmacology 121, 38 (1995); H. E. Molewijk et al., ibid. 128, 31 (1996).
56. J. P. Scott, Excerpta Med. Int. Congr. Ser. 359, 735 (1974); J. Panksepp et al., Biol. Psychiatry 13, 607 (1978); B. Herman and J. Panksepp, Pharmacol. Biochem. Behav. 9, 213 (1978); Science 211, 1060 (1981); R. D. Porsolt, S. Roux, M. Jalfre, Pharmacol. Biochem. Behav. 20, 979 (1983); T. R. Insel, J. L. Hill, R. B. Mayor, ibid. 24, 1263 (1986); N. H. Kalin, S. E. Shelton, C. M. Barksdale, Brain Res. 408, 192 (1987); J. D. Newman, J. T. Winslow, D. L. Murphy, ibid. 538, 24 (1991); K. A. Miczek et al., Psychopharmacology 121, 38 (1995); H. E. Molewijk et al., ibid. 128, 31 (1996).
57. J. P. Scott, Excerpta Med. Int. Congr. Ser. 359, 735 (1974); J. Panksepp et al., Biol. Psychiatry 13, 607 (1978); B. Herman and J. Panksepp, Pharmacol. Biochem. Behav. 9, 213 (1978); Science 211, 1060 (1981); R. D. Porsolt, S. Roux, M. Jalfre, Pharmacol. Biochem. Behav. 20, 979 (1983); T. R. Insel, J. L. Hill, R. B. Mayor, ibid. 24, 1263 (1986); N. H. Kalin, S. E. Shelton, C. M. Barksdale, Brain Res. 408, 192 (1987); J. D. Newman, J. T. Winslow, D. L. Murphy, ibid. 538, 24 (1991); K. A. Miczek et al., Psychopharmacology 121, 38 (1995); H. E. Molewijk et al., ibid. 128, 31 (1996).
58. The study protocol was approved by investigational review boards. Patients gave informed consent to the requirements and restrictions of the study. Male and female depressed outpatients in good physical health, ages 18 to 65, were eligible. Females were required to use adequate contraceptive methods during the study. Patients were excluded if they were considered to be at risk for suicide or violence. Patients with ≥25% decrease on the HAM-D17 between the screening and end-of-washout evaluations were disqualified from entry. Patients were required to have DSM-IV diagnosis of MDD [single or recurrent; American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders (Washington, DC, ed. 4, 1994)], a current episode of ≥4 weeks but <2 years in duration; and the following scores at screening and end-of-washout visits: ≥22 (moderately depressed) on the 17-item version of the HAM-D, ≥15 (moderately high anxiety) on the HAM-A scale, and ≥4 (moderately ill) on the CGI scale [Early Clinical Drug Evaluation Unit (ECDEU) Assessment Manual (Department of Health, Education and Welfare Publication ADM 76-338, 1976), pp. 583-585]. Safety observations included physical examination, weight, laboratory evaluations, vital signs, and electrocardiogram and AE reporting.
59. The study protocol was approved by investigational review boards. Patients gave informed consent to the requirements and restrictions of the study. Male and female depressed outpatients in good physical health, ages 18 to 65, were eligible. Females were required to use adequate contraceptive methods during the study. Patients were excluded if they were considered to be at risk for suicide or violence. Patients with ≥25% decrease on the HAM-D17 between the screening and end-of-washout evaluations were disqualified from entry. Patients were required to have DSM-IV diagnosis of MDD [single or recurrent; American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders (Washington, DC, ed. 4, 1994)], a current episode of ≥4 weeks but <2 years in duration; and the following scores at screening and end-of-washout visits: ≥22 (moderately depressed) on the 17-item version of the HAM-D, ≥15 (moderately high anxiety) on the HAM-A scale, and ≥4 (moderately ill) on the CGI scale [Early Clinical Drug Evaluation Unit (ECDEU) Assessment Manual (Department of Health, Education and Welfare Publication ADM 76-338, 1976), pp. 583-585]. Safety observations included physical examination, weight, laboratory evaluations, vital signs, and electrocardiogram and AE reporting.
60. The drug washout period was 7 ± 3 days except for fluoxetine (4 weeks) and monoamine oxidase inhibitors (2 weeks). Chloral hydrate (500 to 1000 mg daily) could be prescribed sparingly for insomnia during the study, but this was not to be taken within 24 hours before clinic visits. All other psychotropic medications were prohibited.
61. All medications were to be taken orally, once daily in the evening, for 6 weeks. MK-869 (three 100-mg tablets per dose, with matching placebo capsules to paroxetine) and encapsulated paroxetine 20-mg tablets (with matching placebo to MK-869) were used in a double-dummy design. Paroxetine tablets were placed in opaque capsules to maintain the blind; these had comparable stability and dissolution to the unencapsulated form.
62. The primary efficacy analysis compared mean changes from baseline between MK-869 and placebo on HAM-D21 total score at week 6 using an "all patients treated, last observation carried forward" approach. For a two-tailed test with p = 0.05, the power to detect a 4-point difference of change (a clinically significant effect) between MK-869 and placebo was 84% (based on standard deviation of 8.0). Pairwise comparisons of MK-869 or paroxetine versus placebo were performed at each week by analysis of variance (ANOVA) with treatment group and investigative site included as factors. Statistical testing at early time points was performed post hoc and was not adjusted for multiplicity. Similar analyses evaluated secondary efficacy variables. Pairwise comparisons of clinical AEs, or discontinuations for AEs, used Fisher's exact test.
63. Seventy-one patients were treated with MK-869 (300 mg/day), 72 with paroxetine (20 mg/day), and 70 with placebo. About 70% of the patients in each group completed the full 6-week course of therapy. The demonstration of antidepressant efficacy of MK-869 was not confounded by different rates of discontinuation in the treatment groups. The treatment × site effect was significant (ANOVA, p = 0.031). The interactions were not qualitative between any two treatment groups. Therefore, the ANOVA model with treatment and site was applied for treatment comparisons. See Science Online (www.sciencemag.org) for details on demographics and baseline comparability, an accounting of patients who completed or discontinued from the study, and statistics on interaction of treatment × investigative site (with respect to mean change from baseline to week 6 in HAM-D21 total scores).
64. See Science Online (www.sciencemag.org) for details on mean changes from baseline in Hamilton Depression Scale factors with MK-869, paroxetine, and placebo, with pairwise comparison p values for MK-869 and paroxetine versus placebo.
65. Mild transaminase elevations (1.5 to 2.5 times the upper limit of normal) were observed in three patients receiving MK-869 and caused discontinuation. High titers of Epstein-Barr antibodies (immunoglobulin G) and clinical signs of viral infection were observed in two of these patients; in the third, AST was mildly elevated on entry into the study. One patient was discontinued on paroxetine for elevated transaminases. Mild transient increases in transaminases (AST, ALT, or both) were regarded as laboratory AEs in two additional patients on MK-869, four on paroxetine, and one on placebo.
66. See Science Online (www.sciencemag.org) for details on mean changes from baseline in HAM-D21 data ("as observed" approach) with MK-869, paroxetine, and placebo, with pairwise comparison p values for MK-869 and paroxetine versus placebo.
67. M. Bourin et al., Arzneim. Forsch. Drug Res. 33, 1173 (1983); J. Maj et al., Pol. J. Pharmacol. Pharm. 35, 49 (1983).
68. M. Bourin et al., Arzneim. Forsch. Drug Res. 33, 1173 (1983); J. Maj et al., Pol. J. Pharmacol. Pharm. 35, 49 (1983).
69. 1 receptor [C. J. Gardner et al., Regul. Pept. 65, 45 (1996)], was administered by osmotic mini-pump (3 mg/kg per day) for 14 days and did not down-regulate cortical β-adrenoceptors in rats (P. H. Hutson, unpublished data).
70. S. J. Peroutka, R. M. Lebovitz, S. H. Snyder, Science 212, 827 (1981); B. F. Koe et al., J. Pharmacol. Exp. Ther. 226, 686 (1983).
71. S. J. Peroutka, R. M. Lebovitz, S. H. Snyder, Science 212, 827 (1981); B. F. Koe et al., J. Pharmacol. Exp. Ther. 226, 686 (1983).
72. GR 205171 did not affect 5-HT efflux in the hippocampus when administered to rats at 10 mg/kg, as measured using in vivo microdialysis [P. H. Hutson, unpublished data; methods as described by P. H. Hutson et al., Neuropharmacology 34, 383 (1995)].
73. Z. P. Horovitz et al., Int. J. Neuropharmacol. 5, 405 (1966); G. E. Duncan et al., J. Pharmacol. Exp. Ther. 238, 758 (1986).
74. Z. P. Horovitz et al., Int. J. Neuropharmacol. 5, 405 (1966); G. E. Duncan et al., J. Pharmacol. Exp. Ther. 238, 758 (1986).
75. B. Dubinsky and M. E. Goldberg, Neuropharmacology 10, 537 (1971).
76. M. B. Shaikh, A. Steinberg, A. Siegel, Brain Res. 625, 283 (1993).
77. E. M. Nikulina et al., Soc. Neurosci. Abstr. 23, 126 (1997).
78. P. W. Mantyh et al., Proc. Natl. Acad. Sci. U.S.A. 92, 2622 (1995); A. M. Garland et al., Mol. Pharmacol. 49, 438 (1996).
79. P. W. Mantyh et al., Proc. Natl. Acad. Sci. U.S.A. 92, 2622 (1995); A. M. Garland et al., Mol. Pharmacol. 49, 438 (1996).
80. 1 receptor immunoreactivity was examined with an antibody supplied by R. Shigemoto [R. Shigemoto et al., Neurosci. Lett. 153, 157 (1993)] using standard indirect enzymatic detection techniques.
81. 1 receptor immunoreactivity was examined with an antibody supplied by R. Shigemoto [R. Shigemoto et al., Neurosci. Lett. 153, 157 (1993)] using standard indirect enzymatic detection techniques.
82. 1 receptor-positive endosomes were counted in three consecutive sections to establish mean cell counts.
83. We thank D. Slaughter, C. Assang, M. Beer, S. Patel, C. Barton, P. H. Hutson, F. Kelleher, M. Rigby, S. Boyce, and R. Shigemoto for their contributions to the preclinical studies.