Chapter 22 — Further Reading

Neuropeptide Y, Substance P, and the Peptides That Regulate Stress, Pain, and Appetite in the Brain

A note before the list. This chapter's argument rests on a comparison between a program that failed and one that succeeded, and the most valuable reading you can do is the primary literature of the failure. Negative results are underpublicized and underread, and the NK1 story is one of the few cases where the field wrote up its own disappointment carefully and in public. That material is in Tier 2 and Tier 3 below, and it is worth more than any number of enthusiastic reviews.

Where a work is technical, it is marked. Where a work has aged, that is noted — a 2000 review of NK1 antagonists is not out of date so much as usefully frozen at a moment when the question was still open, and reading it that way is instructive.

Tier 1 — Start here

These require no specialist background and give you the shape of each story.

On migraine and CGRP. Ashina M. "Migraine." New England Journal of Medicine (2020). A clinical review written for physicians but accessible to a careful lay reader. It covers the CGRP pathway, the provocation evidence, and the therapeutic classes in one place, and it is the single best entry point to §22.7.

On narcolepsy and orexin. Scammell TE. "Narcolepsy." New England Journal of Medicine (2015). Same format, same accessibility. It lays out the deficiency, the diagnostic use of CSF orexin-A, and why symptomatic treatment remains the standard — which is the material §22.6 compresses into three paragraphs.

On chemotherapy-induced nausea and vomiting. Hesketh PJ. "Chemotherapy-Induced Nausea and Vomiting." New England Journal of Medicine (2008). Explains where NK1 antagonists sit in combination antiemetic regimens and why delayed emesis was the unmet need they filled. Some specifics have been updated by newer guidelines, but the conceptual account holds.

On neuropeptides in general. Hökfelt T, Bartfai T, Bloom F. "Neuropeptides: opportunities for drug discovery." Lancet Neurology (2003). Written by people who built the field, at the moment when the NK1 failures were becoming clear. Read it for the tone as much as the content: it is a fair-minded assessment of promise and difficulty by authors with every reason to be optimistic.

Any current professional guideline on migraine preventive treatment. Guidelines from national neurology and headache societies are updated regularly and state plainly where the CGRP class sits relative to older preventives. They are also a good corrective to press coverage, which consistently overstates novelty and understates the comparative question.

Tier 2 — Go deeper

Reviews and syntheses. Some technical vocabulary, but the arguments are followable.

Hill R. "NK1 (substance P) receptor antagonists — why are they not analgesic in humans?" Trends in Pharmacological Sciences (2000). If you read one thing from this chapter's further reading, consider this. It is a short, honest post-mortem written while the wound was fresh, by someone inside the field, enumerating the candidate explanations for a failure nobody expected. It is the primary source for much of §22.5's framing, including the species-difference problem.

Edvinsson L, Haanes KA, Warfvinge K, Krause DN. "CGRP as the target of new migraine therapies — successful translation from bench to clinic." Nature Reviews Neurology (2018). The counter-case told by one of the people who built it. Note the subtitle: the authors are explicit that translation is the achievement, not the mechanism. That is exactly §22.9's argument, made by the program's own architects.

Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. "Pathophysiology of Migraine: A Disorder of Sensory Processing." Physiological Reviews (2017). Long and technical in places, but the definitive synthesis of what migraine is at the circuit level, including where CGRP sits and — importantly — what CGRP does not explain.

Sakurai T. "The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness." Nature Reviews Neuroscience (2007). From one of the peptide's co-discoverers. The flip-flop model of sleep state stabilization is what makes §22.6's "latch rather than on-button" description precise rather than metaphorical.

Banks WA. "Peptides and the blood–brain barrier." Peptides (2015). (Technical.) Banks is the authority on peptide transport across the barrier, and this review is the substance behind §22.8's three exceptions. Read it if you want to know exactly how much a "saturable transport system" does and does not permit — the answer is usually less than enthusiasts assume and more than skeptics do.

Reviews of neuropeptide Y in energy balance and in stress. The NPY literature is large and split across two communities that cite each other less than they should. Look for reviews in Physiological Reviews, Neuropeptides, or Progress in Neurobiology covering NPY receptor subtypes and feeding, and separately for reviews covering NPY in stress and post-traumatic stress. Reading one of each is the fastest way to see the gap §22.3 is pointing at: two coherent literatures, no bridge between them made of human intervention data.

Tier 3 — Primary literature

For readers who want the original claims and the original data. Several of these are short.

Tatemoto K, Carlquist M, Mutt V. "Neuropeptide Y — a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide." Nature (1982). The isolation paper. Worth seeing how quickly the family resemblance to PYY and PP was recognized — the relationship §22.2 uses to make its point about receptors determining outcome.

Erondu N et al. "Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults." Cell Metabolism (2006). The title is the finding. This is the primary source for §22.2's statement that the obvious obesity drug did not work, and the paper's own discussion of why is more candid than most.

Morgan CA 3rd et al. "Plasma neuropeptide-Y concentrations in humans exposed to military survival training." Biological Psychiatry (2000). The origin of nearly every "special forces have higher NPY" claim you will encounter. Read the methods section specifically, and note what was measured, in whom, and with what design. The paper is careful. The claims built on it are not.

Kramer MS et al. "Distinct mechanism for antidepressant activity by blockade of central substance P receptors." Science (1998). The landmark positive result. Read it knowing what came next, and ask yourself which features would have made you cautious at the time.

Keller M et al. "Lack of efficacy of the substance P (neurokinin-1 receptor) antagonist aprepitant in the treatment of major depressive disorder." Biological Psychiatry (2006). The replication failure, reported by the sponsor. Reading these two papers back to back is the most efficient education in replication available in the peptide literature.

Lassen LH et al. "CGRP may play a causative role in migraine." Cephalalgia (2002). The provocation study — the single experiment §22.9 argues separated CGRP from substance P. Note the hedged title, and note that the hedge was appropriate: a provocation study establishes causal sufficiency in susceptible people, not that CGRP explains all migraine.

de Lecea L et al., PNAS (1998), and Sakurai T et al., Cell (1998). The two independent discovery papers, published months apart, which is why the molecule has two names.

Chemelli RM et al., Cell (1999); Lin L et al., Cell (1999); Nishino S et al., Lancet (2000). Orexin-null mice, the canine narcolepsy receptor mutation, and hypocretin deficiency in human narcolepsy. Three papers, three species, one conclusion, inside roughly eighteen months. This is what a mechanism looks like when it is genuinely nailed down — and it is a useful benchmark against which to measure looser claims.

If you only do one thing

Read the two substance P depression papers side by side — Kramer 1998 and Keller 2006. One is the exciting positive result that made headlines; the other is the careful negative replication that did not. They are separated by eight years, hundreds of patients, and an enormous amount of money.

Read the first one and ask honestly whether you would have been convinced. Then read the second and notice how little in the first paper was wrong — the trial was real, the reasoning was sound, the mechanism was correct. What changed was that the question got asked again, with more patients, and the answer came back different.

That pair is the whole chapter in about ninety minutes of reading, and it will do more for your instincts about evidence than any summary — including this one — can.