To Name :
To Email :
From Name :
From Email :
Comments :

Psychotropic Drug Update Antidepressants in the Pipeline: NK-1 antagonists: the next generation of depression therapy?

Vol. 1, No. 3 / March 2002

Underdiagnosis and undertreatment of depression are leaving their mark on society. About 15% of patients suffering from severe depression will commit suicide. 1,2 The annual cost of depression to the U.S. economy has been estimated to be at least $80 billion, attributable to medical expenditures, lost productivity, and other costs. 3

Although more than 30 medications are available in this country to treat depression, the search is on for novel compounds with greater efficacy, faster onset of action and fewer side effects. Currently, more than 60 new drug entities that collectively affect more than 30 types of receptors are being examined in clinical trials for depression treatment.

One of the newer classes, the NK-1 (substance P) antagonists, entered development for depression about 10 years ago. These drugs work differently than the wellknown selective serotonin reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors. They block receptors (NK-1) in the brain and in the gastrointestinal tract for the endogenous neurotransmitter, substance P.

Substance P, a peptide made up of 11 amino acids, was first discovered in an extract by Von Euler in 1931 and later sequenced by Chang. 4 It is part of the group of peptides known as the tachykinins that cause a number of physiological effects including smooth muscle contraction, inflammatory responses, pain transmission, and central nervous system neurotransmission. 5 Of the 3 peptides that have been elucidated, substance P has the highest affinity for the NK-1 receptor, neurokinin A for the NK-2 receptor, and neurokinin B for the NK-3 receptor. NK-1 receptors are widely distributed both in the central nervous system and in peripheral tissues.

NK-1 ANTAGONISTS UNDER DEVELOPMENT

Drug

Company

Phase of development

Prospective indication

Other prospective indications

MK-869

Merck & Co.

Phase III clinical trial

Depression

Anxiety, chemotherapy-induced nausea

Compound A

Merck & Co.

Phase III clinical trial

Depression

 

CP-122721

Pfizer Inc.

Phase III clinical trial

Depression

Chemotherapy-induced nausea

CJ-11974

Pfizer Inc.

Phase III clinical trial

Depression

Chemotherapy-induced nausea

GW-597599

GlaxoSmithKline

Phase I clinical trial

Depression

Anxiety

R-673

Hoffmann-La Roche

In preparation for phase II clinical trial

Depression

 

R-1124

Hoffmann-La Roche

Preclinical

Chemotherapy-induced nausea

 

TAK-637

Takeda

Phase II clinical trial

Depression

Irritable bowel syndrome, urinary incontinence

The connection between substance P and depression is based on a number of preclinical and clinical observations. Substance P was found to be associated with both norepinephrine and serotonergic systems in the rat brain; an introduction of antidepressants decreased its production. In humans, researchers saw an increased level of substance P in the cerebrospinal fluid of depressed patients and a decreased level in that of patients treated with fluoxetine. 6

Merck’s compound, MK-869, was the first NK-1 antagonist to be examined for treatment of major depression. Initially, a phase II study 7 of 213 depressed and/or anxious patients comparing MK-869 (300 mg/d) to paroxetine (20 mg/d) or placebo showed no difference between the two agents in rates of clinical improvement of depression across 6 weeks. The drug also showed a significant antianxiety effect. Similar rates of adverse experiences were seen across both drugs except for a substantially lower rate of sexual dysfunction (3%) among patients taking MK-869 (vs. 26% in the paroxetine group and 4% among those taking placebo).

Unfortunately, in a subsequent study, neither MK-869 nor fluoxetine showed a significant difference in efficacy from placebo. Although the development of MK-869 as a depression treatment has been suspended, the drug is currently under development as an antiemetic for use in patients undergoing cancer treatment. 8

A later-generation Merck NK-1 antagonist, “Compound A,” is in phase III trials for treatment of depression. In a recent randomized, double-blind, place-bo-controlled trial of outpatients with major depression with melancholic features, Compound A contributed to patients’ clinical global improvement. The compound was well tolerated and exhibited a side-effect profile similar to that of placebo. 9

Both CP-122721 and CJ-11974, Pfizer’s NK-1 antagonists, are in trials for treatment of chemotherapy-induced nausea. CP-122721 also showed similar efficacy when compared to fluoxetine in depressed patients. In another trial comparing CP-122721 to paroxetine and placebo, the drug exhibited fewer sexual side effects. 10 CP-122721 is currently in phase II trials for depression. 11

GW-597599, GlaxoSmithKline’s NK-1 antagonist, is currently in phase I testing. Studies of the agent’s use in depression and anxiety are planned. 12 Hoffmann-LaRoche has two NK-1 antagonists in the pipeline, one of which (R-673) is in preparation for phase II testing for depression. The other, R-1124, is in preclinical testing for chemotherapy-induced nausea. 13

TAK-637, an NK-1 antagonist owned by Takeda, is being developed in both the U.S. and Europe through a joint licensing arrangement with Abbott Laboratories. Phase II studies are being conducted for such indications as depression, irritable bowel syndrome, and urinary incontinence. 14

Related resources

  • Greenberg PE, Leong SA, Birnbaum HG. Cost of depression: current assessment and future directions. Expert Rev Pharmacoeconomics Outcomes Res. 2001;1(1):69.76. Available through Future Drugs Ltd. www.future-drugs.com.

Drug brand names

  • Fluoxetine • Prozac, Prozac Weekly
  • Paroxetine • Paxil

Disclosure

The author reports that he serves as a co-investigator on clinical research projects funded by Merck & Co., Pfizer Inc., GlaxoSmithKline, Takeda, and Abbott Laboratories, but does not receive direct financial compensation from these companies, nor does he have any proprietary or financial interest in the test products.

References

1. National Institute of Mental Health, www.nimh.nih.gov/publicat/burden.cfm.

2. National Mental Health Association, www.nmha.org/infoctr/factsheets/index.cfm28.cfm.

3. National Depressive and Manic-Depressive Association: Facts About Depression. www.ndmda.org/DepressionFacts.html.

4. Stout SC, Owens MJ, Nemeroff CB. Neurokinin(1) receptor antagonists as potential antidepressants. Annu Rev Pharmacol Toxicol. 2001;41:877-906.

5. Sigma RBI Handbook, www.sigmaaldrich.com/cgibin/hsrun/Distributed/HahtShop/HAHTpage/HS_FramesetPDF.

6. Baby S, Nguyen M, Tran D, Raffa RB. Substance P antagonists: the next breakthrough in treating depression? J Clin Pharm Ther. 1999;24(6):461-469.

7. Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science. 1998;281:1640-1644.

8. Rupniak NM, Kramer MS. Discovery of the antidepressant and anti-emetic efficacy of substance P receptor (NK1) antagonists. Trends Pharmacol Sci. 1999;20(12):485-490.

9. Kramer MS, Ball WA, Reines SA. Replication of the efficacy and tolerability of substance P antagonists in patients with major depression. American College of Neuropsychopharmacology meeting, Hawaii, 2001.

10. Pfizer Press Release, http://www.pfizer.com/pfizerinc/investing/analystrelease1211.html.

11. Pfizer U.S., medical information.

12. GlaxoSmithKline R&D Pipeline Oct 2001 www.gsk.com/tomorrow/product_pipeline.htm.

13. Roche Pipeline 2001, www.roche.com/pages/downloads/investor/pdf/praesentations/smk01fbhsle.pdf.

14. Takeda company information, www.takeda.co.jp/english/product/index.html.

Did you miss this content?
Managing first-episode psychosis: An early stage of schizophrenia with distinct treatment needs