Nasal Spray, the New Suicide Prevention Tool?

Here’s one to wonder about. CNN posted a story about Thyrotropin Releasing Hormone (TRH) being an effective antisuicide agent (Can nasal spray help prevent military suicides? – This Just In – CNN.com Blogs). The gist is that the U.S. Military is reaching for every conceivably feasible solution to stem the rising rate of suicides in the Army. There were 38 confirmed or suspected suicides in July and there’s no end in sight. The Army has recently given a research grant to Indiana University of Medicine Associate Professor of Neurobiology Dr. Michael Kubek to study whether a nasal spray could be a safe and effective way to deliver TRH to the brain to “help calm suicidal thoughts.” According to the article, Dr. Kubek helped discover TRH. I don’t know if that’s true or not. I’m not a neurobiologist nor a historian of neurobiological research nor a huge fan of Wikipedia (though I did add a couple of external links for the American Delirium Society (ADS) and the European Delirium Association (EDA) to the pretty good entry for delirium,  Delirium – Wikipedia, the free encyclopedia), but I didn’t find Kubek’s name in the Wikipedia TRH entry, Thyrotropin-releasing hormone – Wikipedia, the free encyclopedia.

In any case, the idea for delivering TRH to the brain quickly via a nasal spray probably does get its impetus from Dr. Kubek’s impressive work on developing ways to deliver neuropeptides by this route using nanoparticles. He and his colleagues have received a patent for their discoveries and he’s looking into forming his own company to develop this technology for use in direct patient care, Fund Research: Success Stories: About: IURTC.

More power to him, and I’m all for doing everything possible to help veterans.The challenge to health care professionals to do what they can to stem the tide of suicide is clear:

PsychiatryOnline | Psychiatric News | News Article

http://www.afhsc.mil/viewMSMR?file=2012/v19_n02.pdf

PsychiatryOnline | Psychiatric News | News Article

NIMH · Army STARRS Preliminary Data Reveal Some Potential Predictive Factors for Suicide

However, I could not find any recent literature about the use of TRH as an antidepressant, much less an antisuicide agent. Much of the literature seems to be from the 1970s, although there are a couple from my quick search that are more recent (see reference list below). There are some obvious methodological issues, including small numbers of patients and confounders; for example, how do you know the patients in the Furlong study didn’t get better just from the electroconvulsive therapy (ECT) alone?

I contacted a couple of research psychiatrists in our department and asked them about their thoughts on this issue, and their comments were:

“This is the first I’ve seen anything on this.  Don’t even recall seeing stuff presented at conference poster sessions on this.  On first blush makes me a little uncomfortable.”

“Light years from clinical practice – and a need for more thyroid is only the tiniest fraction of our veterans problems.”

I think the most telling part of the CNN story was the quote from a high-ranking Army officer who reportedly told Deputy Washington Bureau Chief Mark Thompson, “there are promising techniques that the military could deploy against suicide, but they involve an initial two-hour screening, a sit-down, a one-on-one with a psychiatrist that this nation is just not willing to pay for.”

What this probably means is that somebody thinks we can’t afford to pay for the application of a standard intervention involving a psychiatric diagnostic evaluation in which a psychiatrist sits down and listens to a soldier, tries to understand the pain, asks general and specific questions in a systematic suicide risk assessment, identifies the modifiable risk factors for suicide and puts them into the spiritual, psychological, emotional, cultural, social, and medical context of a suffering human being–and proposes a safe, practical, and effective treatment plan (Amos, J. J., M.D. (2010). Suicide risk assessment. Psychosomatic Medicine: An Introduction to Consultation-Liaison Psychiatry. J. J. Amos, M.D., and R. G. Robinson, M.D. New York, Cambridge University Press: 51-57; Fiedorowicz, J. G., K. Weldon, et al. (2010). “Determining suicide risk (hint: a screen is not enough).” J Fam Pract 59(5): 256-260).

But it looks like somebody is willing to pay for nasal spray. In my opinion, I think we need to ask ourselves and our soldiers whether we can afford not to apply what we already know to be effective, evidence-based, interventions available right now to address the suffering that leads to suicide for sons and daughters who are laying it on the line for us in battle. And we need to stop stigmatizing mental illness and mental health issues.

REFERENCE LIST:

Callahan, A. M., M. A. Frye, et al. (1997). “Comparative antidepressant effects of intravenous and intrathecal thyrotropin-releasing hormone: Confounding effects of tolerance and implications for therapeutics.” Biological Psychiatry 41(3): 264-272.
A significant amount of preclinical and human data indicate that thyrotropin-releasing hormone (TRH) has antidepressant effects. Although early studies showing these effects using intravenous TRH were not consistently replicated, it has been suggested that this could be explained by its poor blood—brain barrier penetration. For this reason we compared the antidepressant effect of intrathecal and intravenous TRH administered in a double-blind design to 2 treatment-refractory patients with bipolar II disorder. Each experienced a robust antidepressant response by both routes; subsequent open trials of intravenous TRH also were effective until apparent tolerance developed. Intrathecal TRH was readministered and both subjects again experienced robust antidepressant responses. These preliminary data suggest a differential mechanism of tolerance to the two routes of administration and raise the possibility that a subgroup of patients may be responsive to the antidepressant effects of TRH independent of its route of administration.

Eugene Pekary, A., K. F. Faull, et al. (2005). “TRH-like antidepressant peptide, pyroglutamyltyroslyprolineamide, occurs in rat brain.” Journal of Mass Spectrometry 40(9): 1232-1236.
We have previously reported the occurrence of pGlu-Glu-Pro-NH2(Glu-TRH, EEP), Val-TRH, Tyr-TRH, Leu-TRH, Phe-TRH, and Trp-TRH in rat brain using a combination of HPLC and radioimmunoassays with antibodies that cross-react with the general structure pGlu-X-Pro-NH2 where ‘X’ maybe any amino acid residue (Peptides 2004; 25 : 647). This new family of TRH-like peptides, along with TRH (pGlu-His-Pro-NH2), has neuroprotective, anticonvulsant, antidepressant, euphoric, anti-amnesic, and analeptic effects. We now report that a combination of affinity chromatography using a rabbit antibody specific for Tyr-TRH and Phe-TRH, along with HPLC and tandem mass spectrometry operating in the multiple reaction monitoring (MRM) mode, provide conclusive evidence for the presence of Tyr-TRH in rat brain. Furthermore, synthetic Tyr-TRH is active in the Porsolt Swim Test suggesting that it is a fourth member of this family of in vivo neuroregulatory agents that have psychopharmacotherapeutic properties. Copyright © 2005 John Wiley & Sons, Ltd.

Furlong, F. W., G. M. Brown, et al. (1976). “Thyrotropin-releasing hormone: differential antidepressant and endocrinological effects.” The American Journal of Psychiatry 133(10): 1187-1190.
In a double-blind study, three depressed subjects received thyrotropin-releasing hormone (TRH) on three successive days, and one subject similarly received placebo; all subjects were then given ECT. Two of the patients given TRH responded to ECT. One patient’s reaction is of special significance because of her response to ECT, diminished thyroid-stimulating hormone response to TRH, increased growth hormone and prolactin response to stress, and antidepressant effect of TRH. These findings raise the possibility that previous conflicting reports about TRH’s antidepressant effects stem from the combined study of endocrinologically distinct depressive subgroups and strongly suggest that there may be a specific subgroup that is responsive to TRH.

Kastin, A., R. Ehrensing, et al. (1972). “IMPROVEMENT IN MENTAL DEPRESSION WITH DECREASED THYROTROPIN RESPONSE AFTER ADMINISTRATION OF THYROTROPIN-RELEASING HORMONE.” The Lancet 300(7780): 740-742.
Five patients with mental depression received thyrotropin (T.S.H.)-releasing hormone (T.R.H.) for 3 days as part of a double-blind, cross-over study. All patients showed improvement in the symptoms of depression. The plasma-T.S.H. response to T.R.H. was distinctly diminished in four of the five patients, suggesting an abnormality in the hypothalamic/pituitary axis.

Koranyi, L., V. Tamásy, et al. (1976). “Effect of thyrotropin-releasing hormone (TRH) and antidepressant agents on brain stem and hypothalamic multiple unit activity in the cat.” Psychopharmacology 49(2): 197-200.
The EEG and MUA (multiple unit activity) of mesencephalic reticular formation (MRF), area hypothalami posterior (PH), and area hypothalami anterior (AH) were studied in chronically implanted freely moving cats. The effects of thyrotropin-releasing hormone (TRH) and some antidepressant agents were tested on neuronal activity. Desipramine and imipramine resulted in a dose-dependent decline of MUA of all structures with the most significant decrease of activity in PH. A single injection of TRH resulted in slight or moderate gross behavioral changes and vegetative excitation lasting for 30–50 min with variable MUA levels. In the course of repetitive TRH treatment on consecutive days the gross behavioral changes and the vegetative symptoms failed to develop by the 3rd or 4th day. By that time the MUA changes of PH and MRF showed similar characteristics in response to TRH administration which was observed following the injection of desipramine and imipramine. The drugs, except for TRH, induced a suppression of paradoxical sleep cycles.

Metcalf, G. (1982). “Regulatory peptides as a source of new drugs — the clinical prospects for analogues of TRH which are resistant to metabolic degradation.” Brain Research Reviews 4(3): 389-408.
The biological properties of several analogues of TRH (Pyr-His-Pro-NH2) are reviewed. Analogues discussed include those with modifications to the Pyr moiety (e.g. DN-1417, CG 3509 and CG 3703), the Pro moiety (e.g. RX 77368) and MK-771 which has both terminal residues modified. The analogues have enhanced biological half-lives compared to TRH because of their resistance to enzymatic degradation. Neuropharmacological evaluation indicates the analogues to be active in antidepressant screening tests, to reverse the effects of diverse CNS depressants and to promote arousal when given alone. The analogues all exhibit enhanced potency compared to TRH in such tests. In contrast they appear equipotent to TRH in endocrine tests. An explanation is offered for this paradox in terms of metabolic stability and bioavailability to the requisite sites of action. The prospects for clinical utilization of the neuropharmacological properties common to TRH and its analogues are considered.

Plotnikoff, N. P., A. J. Prange, Jr., et al. (1972). “Thyrotropin releasing hormone: enhancement of dopa activity by a hypothalamic hormone.” Science 178(4059): 417-418.
Thyrotropin releasing hormone potentiates the behaviorial effects of dopa plus pargyline in mice. Because the potentiation occurs in hypophysectomized mice, as well as in normal mice, the phenomenon is independent of the release of thyroid stimulating hormone from the pituitary. Possible mechanisms and clinical implications are discussed.

Sattin, A., A. E. Pekary, et al. (1994). “TRH Gene Products Are Implicated in the Antidepressant Mechanisms of Seizuresa.” Annals of the New York Academy of Sciences 739(1): 135-153.

Szuba, M. P., J. D. Amsterdam, et al. (2005). “Rapid Antidepressant Response After Nocturnal TRH Administration in Patients With Bipolar Type I and Bipolar Type II Major Depression.” Journal of Clinical Psychopharmacology 25(4): 325-330.
Background: Thyrotropin-releasing hormone (TRH) is a tripeptide that produces endocrine and behavioral effects in animals and humans. Some studies have shown transient antidepressant activity after morning administration of TRH. We hypothesized that nocturnal administration of TRH, when the circadian sensitivity of the TRH receptor is at its peak, may result in a more robust antidepressant effect. Methods: Twenty patients with bipolar (BP) type I or BP type II major depressive episode (MDE) were given nocturnal intravenous TRH 500 [mu]g (n = 10) or saline (n = 10) at midnight in a randomized, double-blind fashion. Antidepressant activity was assessed using the Hamilton Depression Rating (HAM-D), Young Mania Rating (YMR), and Profile of Mood (POMS) scales over a 48-hour period. Thyrotropin (TSH), total T4, and free T3 concentrations were measured before and after TRH administration. Data were analyzed using [chi]2 test, Fisher exact test, and repeated-measures ANOVA. Results: Sixty percent of the TRH group and 10% of the saline group showed a >=50% reduction in baseline total HAM-D score within 24 hours (P = 0.03). HAM-D ratings fell by an average of 52% after TRH administration versus 12% after saline administration (P = 0.038). There was a modest increase in YMR scores after TRH compared with saline (P < 0.032). No manic or hypomanic episodes were observed. Antidepressant effects of TRH lasted up to 48 hours. There was no correlation between [DELTA]TSH, [DELTA]T4, or [DELTA]T3 measures after TRH (or saline) administration and the change in HAM-D scores. Conclusions: Nocturnal TRH administration may produce a rapid antidepressant effect in some patients with BP I and BP II MDE. (C) 2005 Lippincott Williams & Wilkins, Inc.

Takahashi, S., H. Kondo, et al. (1973). “Antidepressant Effect of Thyrotropin-Releasing Hormone (TRH) and the Plasma Thyrotropin Levels in Depression.” Psychiatry and Clinical Neurosciences 27(4): 305-314.
Twenty-four patients with mental depression received thyrotropin-releasing hormone (TSH). 14 patients in Group A were treated with a series of TRH injections 500 μg three times a week, for two to three weeks, and 150 mg/day of imipramine administration in a cross-over comparison. Only three patients showed mild improvement in their depressive symptoms, while imipramine, which was administered in place of TRH, revealed to have more effect on their depression. Antidepressant effect of TRH can be evaluated as not exceeding that of the tricyclics. A single dose of 500 μg TRH in Group B, consisting of 10 depressed inpa-tients, caused neither subjective feelings of improvement nor behavioral changes. Twenty-five percent of depressed patients showed an inadequate TSH response to TRH injection, although all the patients were euthyroid in their thyroid function tests. Three of four neurotic-depressives, with pro longed mental symptoms of several years, revealed a distinctly diminished plasma TSH response to TRH injection. These findings suggest an abnormality in the hypothalamic-pituitary axis, which may cause the fixation of mental symptoms. Neurotic-depressive symptomatology protracted for many years may be based on an unknown neuroendocrine dysfunctions. The implications of these findings remain to be explored.

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