Science Versus Serendipity

Progress in psychopharmacology is largely the story of serendipitous clinical observations followed by controlled clinical trials. The most recent chapter in this story is the unexpected finding of antidepressant properties for a substance P antagonist.¹ Scientific rationale predicts that such agents should be blockers of neurogenic inflammation or pain, but clinical testing for these actions has been disappointing.^2-4 That is, substance P is released locally during inflammatory responses that are neurogenically mediated. Also, substance P is released in the spinal cord in pain pathways. However, antagonists of substance P do not appear to reduce neurogenic inflammation nor do they block pain in clinical trials. On the other hand, unexpected observations of improved mood in some studies of substance P antagonists being tested in pain and inflammation led to one as yet unreplicated report¹ of antidepressant actions comparable to the selective serotonin reuptake inhibitor paroxetine.

Breakthrough or Hype?

Hopes of a breakthrough antidepressant have been reported not only in the scientific literature but also in the financial press, where positive and negative rumors of how the neurokinin (NK) antagonists are faring in clinical trials can cause wild fluctuations in stock prices.^5,6 Reasoned analysis does suggest that neurokinin antagonists might be novel psychotropic drugs. For example, substance P is located in brain areas associated with emotional behaviors, such as the hypothalamus and the amygdala and other areas of the limbic system.^1-4 Furthermore, substance P is also located near the cell bodies of dopaminergic and noradrenergic neurons. Since dopamine and norepinephrine play key roles in depression and psychosis, and in the actions of antidepressant and antipsychotic drugs, it seems possible that substance P could modulate these neurotransmitter systems and thus affect emotional functioning. Indeed, preclinical studies are beginning to confirm that substance P plays a role in emotion¹ as well as in inflammation and pain.^2-4

The Future

Currently, a number of companies are testing antagonists to substance P receptors (NK-1 antagonists) and to NK-B receptors (NK-3 antagonists) in both depression and schizophrenia. One published study¹ suggests an NK-1 antagonist causes less nausea and sexual dysfunction but more irritability than paroxetine, as well as comparable improvement in major depressive disorder.¹ Ongoing trials of various neurokinin antagonists are too early in testing to be conclusive, although recent reports of studies in the financial press⁶ suggest efficacy no better than placebo. However, these are early days in an exciting area of neuroscience. Neurokinin antagonists as novel psychotropics are still a provocative possibility.

Reminder

This is the last of a 3-part series on peptides and psychiatry. Part 1 is a visual lesson on how neuropeptide neurotransmitters are synthesized, stored, and released in the central nervous system.⁷ Part 2 discusses 3 specific peptide neurotransmitters and their corresponding receptors, which belong to a special family of neuropeptides known as tachykinins/neurokinins.⁷ The 3 neurokinins discussed are substance P, neurokinin A, and neurokinin B as well as their respective receptors, NK-1, NK-2, and NK-3. Here we have discussed how antagonists to each of these 3 receptors are being rapidly developed and tested for their potential as novel psychotropic drugs. To get the best sense of the excitement that is sweeping through this area of psychopharmacology and to understand the potential breakthrough implications of substance P antagonists in psychiatry, it is important to grasp how peptide neurotransmitters differ from the better known monoamine neurotransmitters. It is also critical to understand key aspects of the biochemistry and pharmacology of 3 specific peptide neurotransmitters from the neurokinin family, especially substance P. Thus, after viewing this feature, the reader may wish to review parts 1 and 2 of this series^7,8 and other reviews,^2-4 especially if the psychopharmacology of neuropeptides and neurokinins is an unfamiliar topic.

REFERENCES

1. Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998;281:1640-1645

2. Otsuka M, Yoshioka K. Neurotransmitter functions of mammalian tachykinins. Physiol Rev 1993;73:229-308

3. Feldman RS, Meyer JS, Quenzer LF. Principles of Neuropharmacology. Sunderland, Mass: Sinauer; 1997

4. Cooper JF, Bloom FE, Roth RH. The Biochemical Basis of Neuropharmacology. New York, NY: Oxford University Press; 1996

5. Langreth R. Merck reports positive test results for new type of antidepressant drug. Wall Street Journal, Sept 11, 1998

6. Langreth R. Merck & Co. hits a stumbling block in testing experimental antidepressant. Wall Street Journal, Jan 23, 1999

7. Stahl SM. Peptides and psychiatry, part 1: how synthesis of neuropeptides differs from classical neurotransmitters [Brainstorms]. J Clin Psychiatry 1999;60:5-6

8. Stahl SM. Substance P and the neurokinins: novel peptide neurotransmitters in psycho-pharmacology [Brainstorms]. J Clin Psychiatry 1999;60:77-78

Brainstorms aims to provide updates of novel concepts emerging from the neurosciences that have relevance to practitioners.

From the Clinical Neuroscience Research Center in San Diego and the Department of Psychiatry at the University of California San Diego.