Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia

Abstract

Most common central nervous system disorders — such as depression, bipolar disorder and schizophrenia — seem to be polygenic in origin, and the most effective medications have exceedingly complex pharmacologies. Attempts to develop more effective treatments for diseases such as schizophrenia and depression by discovering drugs selective for single molecular targets (that is, 'magic bullets') have, not surprisingly, been largely unsuccessful. Here we propose that designing selectively non-selective drugs (that is, 'magic shotguns') that interact with several molecular targets will lead to new and more effective medications for a variety of central nervous system disorders.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Neuronal circuits implicated in schizophrenia aetiology and treatment.
Figure 2: Screening the receptorome reveals multiple molecular targets implicated in antipsychotic drug actions.

References

  1. Shorter, E. Looking backwards: a possible new path for drug discovery in psychopharmacology. Nature Rev. Drug Discov. 1, 1003–1006 (2002).

    Article  CAS  Google Scholar 

  2. Carlsson, A. & Wong, D. T. Correction: a note on the discovery of selective serotonin reuptake inhibitors. Life Sci. 61, 1203 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Hippius, H. A historical perspective of clozapine. J. Clin. Psychiatry 60 (Suppl. 12), 22–23 (1999).

    PubMed  Google Scholar 

  4. Harrison, P. J. & Owen, M. J. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 361, 417–419 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Lewis, C. M. et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am. J. Hum. Genet. 73, 34–48 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Setola, V. & Roth, B. L. Why mice are neither miniature humans nor small rats: a cautionary tale involving 5-hydroxytryptamine-6 serotonin receptor species variants. Mol. Pharmacol. 64, 1277–1278 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Coyle, J. T. & Duman, R. S. Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 38, 157–160 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Roth, B., Sheffler, D. J. & Potkin, S. Atypical antipsychotic drugs: unitary or multiple mechanisms for 'atypicality'. Clin. Neurosci. Res. (in the press).

  9. Kane, J., Honigfield, G., Singer, J., Meltzer, H. Y. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch. Gen. Psychiatry 45, 789–796 (1988).

    Article  CAS  PubMed  Google Scholar 

  10. Meltzer, H. Y. et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch. Gen. Psychiatry 60, 82–91 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Colpaert, F. C. Discovering risperidone: the LSD model of psychopathology. Nature Rev. Drug Discov. 2, 315–320 (2003).

    Article  CAS  Google Scholar 

  12. Meltzer, H. Y., Matsubara, S. & Lee, J. -C. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J. Pharmacol. Exp. Ther. 251, 238–246 (1989).

    CAS  PubMed  Google Scholar 

  13. Altar, C. A., Wasley, A. M., Neale, R. F. & Stone, G. A. Typical and atypical antipsychotic occupancy of D2 and S2 receptors: an autoradiographic analysis in rat brain. Brain Res. Bull. 16, 517–525 (1986).

    Article  CAS  PubMed  Google Scholar 

  14. Leucht, S., Wahlbeck, K., Hamann, J. & Kissling, W. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet 361, 1581–1589 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Tuunainen, A., Wahlbeck, K. & Gilbody, S. Newer atypical antipsychotic medication in comparison to clozapine: a systematic review of randomized trials. Schizophr. Res. 56, 1–10 (2002).

    Article  PubMed  Google Scholar 

  16. Fontaine, K. R. et al. Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate. Psychiatry Res. 101, 277–288 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Kroeze, W. K. et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28, 519–526 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Meltzer, H. Y. & McGurk, S. R. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr. Bull. 25, 233–255 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Williams, G. V., Rao, S. G. & Goldman-Rakic, P. S. The physiological role of 5-HT2A receptors in working memory. J. Neurosci. 22, 2843–2854 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Woolley, M. L., Bentley, J. C., Sleight, A. J., Marsden, C. A. & Fone, K. C. A role for 5-HT6 receptors in retention of spatial learning in the Morris water maze. Neuropharmacology 41, 210–219 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Castner, S. A., Williams, G. V. & Goldman-Rakic, P. S. Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science 287, 2020–2022 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Bristow, L. J. et al. Schizophrenia and L-745,870, a novel dopamine D4 receptor antagonist. Trends Pharmacol. Sci. 18, 186 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Truffinet, P. et al. Placebo-controlled study of the D4/5-HT2A antagonist fananserin in the treatment of schizophrenia. Am. J. Psychiatry 156, 419–425 (1999).

    CAS  PubMed  Google Scholar 

  24. de Paulis, T. M-100907 (Aventis). Curr. Opin. Investig. Drugs 2, 123–132 (2001).

    CAS  PubMed  Google Scholar 

  25. Meltzer, H., Arvantis, L., Bauer, D., Rein, W. & Group, M. S. A placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Arch. Gen. Psychiatry (in the press).

  26. Rasmussen, T. et al. The muscarinic receptor agonist BuTAC, a novel potential antipsychotic, does not impair learning and memory in mouse passive avoidance. Schizophr. Res. 49, 193–201 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Clark, D. et al. Is 3-PPP a potential antip sychotic agent? Evidence from animal behavioral studies. Eur. J. Pharmacol. 83, 131–134 (1982).

    Article  CAS  PubMed  Google Scholar 

  28. Lahti, A. C. et al. Antipsychotic properties of the partial dopamine agonist (−)-3-(3-hydroxyphenyl)-N-n-propylpiperidine(preclamol) in schizophrenia. Biol. Psychiatry 43, 2–11 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Lahti, A. C., Weiler, M., Carlsson, A. & Tamminga, C. A. Effects of the D3 and autoreceptor-preferring dopamine antagonist (+)-UH232 in schizophrenia. J. Neural Transm. 105, 719–734 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Benkert, O., Muller-Siecheneder, F. & Wetzel, H. Dopamine agonists in schizophrenia: a review. Eur. Neuropsychopharmacol. 5, S43–S53 (1995).

    Article  Google Scholar 

  31. Kikuchi, T. et al. 7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-qui nolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J. Pharmacol. Exp. Ther. 274, 329–336 (1995).

    CAS  PubMed  Google Scholar 

  32. Kane, J. M. et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin. Psychiatry 63, 763–771 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Inoue, T., Domae, M., Yamada, K. & Furukawa, T. Effects of the novel antipsychotic agent 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597) on prolactin release from the rat anterior pituitary gland. J. Pharmacol. Exp. Ther. 277, 137–143 (1996).

    CAS  PubMed  Google Scholar 

  34. Burris, K. D. et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J. Pharmacol. Exp. Ther. 302, 381–389 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Hemrick–Luecke, S. et al. Pharmacological activity of aripiprazole at presynaptic and postsynaptic dopamine receptors and in antipsychotic models. Proc. Soc. Neurosci. 894.9 (2002).

  36. Lawler, C. P. et al. Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 20, 612–627 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Kenakin, T. Efficacy at G-protein-coupled receptors. Nature Rev. Drug Discov. 1, 103–110 (2002).

    Article  CAS  Google Scholar 

  38. Roth, B. L. & Chuang, D. M. Multiple mechanisms of serotonergic signal transduction. Life Sci. 41, 1051–1064 (1987).

    Article  CAS  PubMed  Google Scholar 

  39. Shapiro, D. A. et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 28, 1400–1411 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Anderson, I. M. Meta-analytical studies on new antidepressants. Br. Med. Bull. 57, 161–178 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Thase, M. E., Entsuah, A. R. & Rudolph, R. L. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br. J. Psychiatry 178, 234–241 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Briley, M. New hope in the treatment of painful symptoms in depression. Curr. Opin. Investig. Drugs 4, 42–45 (2003).

    CAS  PubMed  Google Scholar 

  44. Zubenko, G. et al. Genome-wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early-onset, major depression. Am. J. Med Genet. 123B, 1–18 (2003).

    Article  PubMed  Google Scholar 

  45. Brunner, D., Nestler, E. & Leahy, E. In need of high-throughput behavioral systems. Drug Discov. Today 7, S107–S112 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Bohannon, J. Animal models. Can a mouse be standardized? Science 298, 2320–2321 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Amsterdam, J. D., Brunswick, D. J. & Hundert, M. A single-site, double-blind, placebo-controlled, dose-ranging study of YKP10A — a putative, new antidepressant. Prog. Neuropsychopharmacol. Biol. Psychiatry 26, 1333–1338 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Feighner, J. P. et al. Double-blind, placebo-controlled study of INN 00835 (netamiftide) in the treatment of outpatients with major depression. Int. Clin. Psychopharmacol. 16, 345–352 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Palfreyman, M. G. et al. Novel directions in antipsychotic target identification using gene arrays. Curr. Drug Target CNS Neurol. Disord. 1, 227–238 (2002).

    Article  CAS  Google Scholar 

  50. Suessbrich, H., Waldegger, S., Lang, F. & Busch, A. E. Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole. FEBS Lett. 385, 77–80 (1996).

    Article  CAS  PubMed  Google Scholar 

  51. Rothman, R. B. et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102, 2836–2841 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Remington, G. & Kapur, S. SB-277011 GlaxoSmithKline. Curr. Opin. Investig. Drugs 2, 946–949 (2001).

    CAS  PubMed  Google Scholar 

  53. Kramer, M. S., Last, B., Getson, A. & Reines, S. A. The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group. Arch. Gen. Psychiatry 54, 567 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Gewirtz, G. R. et al. BMY14802, a σ receptor ligand for the treatment of schizophrenia. Neuropsychopharmacology 10, 37–40 (1994).

    Article  CAS  PubMed  Google Scholar 

  55. Muller, M. J. et al. Antipsychotic effects and tolerability of the sigma ligand EMD 57445 (panamesine) and its metabolites in acute schizophrenia: an open clinical trial. Psychiatry Res. 89, 275–280 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. van Berckel, B. et al. Efficacy and tolerance of D-cycloserine in drug-free schizophrenic patients. Biol. Psychiatry 40, 1298 (1996).

    Article  CAS  PubMed  Google Scholar 

  57. Evins, A. E., Amico, E., Posever, T. A., Toker, R. & Goff, D. C. D-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia. Schizophr. Res. 56, 19–23 (2002).

    Article  PubMed  Google Scholar 

  58. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 361, 799–808 (2003).

  59. Stahl, S. M., Entsuah, R. & Rudolph, R. L. Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression. Biol. Psychiatry 52, 1166–1174 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Perez, V., Gilaberte, I., Faries, D., Alvarez, E. & Artigas, F. Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 349, 1594–1597 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Berman, R. M. et al. The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial. Biol. Psychiatry 45, 1170–1177 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Nichols, D. E. Hallucinogens. Parmacol. Ther. 101, 131–181 (2004).

    Article  CAS  Google Scholar 

  63. Kroeze, W. K., Sheffler, D. J. & Roth, B. L. G-protein-coupled receptors at a glance. J. Cell Sci. 116, 4867–4869 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work in the authors' laboratories is supported by the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bryan L. Roth.

Ethics declarations

Competing interests

B.L.R. is a consultant for Arena Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Pfizer, Otsuka Pharmaceuticals, SK Corp. and Neotherapeutics. B.L.R. holds US patents on 5-HT-selective drugs.

Related links

Related links

DATABASES

LocusLink

CREB1

FURTHER INFORMATION

National Institutes of Mental Health Psychoactive Drug Screening Program

PDSP Ki Database

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Roth, B., Sheffler, D. & Kroeze, W. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 3, 353–359 (2004). https://doi.org/10.1038/nrd1346

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1346

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing