Thursday, July 10, 2014

Can a Failed Schizophrenia Drug Prevent PTSD?



In the 2000s, enthusiasm was high that a novel class of drugs would reach the market as blockbuster treatments for psychiatric disorders. These drugs act on receptors for a group of neuropeptides known as tachykinins (or neurokinins). These peptides — substance P (SP), neurokinin A (NkA), and neurokinin B (NkB) — function as neurotransmitters or neuromodulators in the central nervous system, but are quite different from the usual monoamines targeted by current psychotropic medications prescribed for schizophrenia, depression, and other mental illnesses.

The tachykinin receptors (NK1, NK2, NK3) have varying affinities for the different peptides, being greatest for SP, NkA, and NkB respectively. A series of clinical trials with NK1 antagonist compounds (i.e., SP blockers) was conducted as potential treatments for major depression, generalized anxiety disorder, alcohol craving, and post-traumatic stress disorder (PTSD). Substance P is released during times of increased stress and localized in brain regions implicated in the stress response (Ebner et al., 2009), so the idea was that dampening the effects of SP would lead to symptom amelioration in these disorders.  However, except for some mildly promising results in stressed alcoholics, the trials were disappointing in patients with generalized anxiety and PTSD. Results were mixed in major depression. But those trials, with a GSK compound called orvepitant, were terminated to due serious adverse events (seizures) in several patients.

In contrast, the most promising target for schizophrenia seemed to be the neurokinin 3 (NK3) receptor. This was because of prominent expression on the midbrain dopamine (DA) cells implicated in the pathophysiology of schizophrenia, and because selective NK3 antagonists can block NkB-induced excitation of dopamine neurons (Spooren et al., 2005). The original “typical” antipsychotic medications are DA antagonists, which can have untoward side effects with chronic use. Because NK3 antagonists lack the major extrapyramidal and metabolic side effects of typical and atypical antipsychotics, they were heralded as “the next generation of antipsychotics” in 2005.

How well have they fared since then?

(1) The NK3 antagonist osanetant was under development by Sanofi-Synthélabo as a potential treatment for schizophrenia:
In October 1999, Lehman Brothers predicted that the probability of the product reaching the market was 10%, with a possible launch in 2003 and potential peak sales of US $200 million in 2011.
However, Sanofi-Aventis stopped any further development of osanetant in 2005.


(2) The NK3 antagonist talnetant was under development by GlaxoSmithKline, with several clinical trials conducted between 2002 and 2005. But it too was discontinued (in 2007).

In other words, these drugs have not lived up to their original promise as novel treatments for schizophrenia.


“Repurposing” of Drugs

“We should continue to repurpose treatments and to recognise the role of serendipity,” said Geddes and Miklowitz (2013) in a recent review on new treatments for bipolar disorder. Although the article did not hint at any impending pharmacological breakthroughs, the idea that existing drugs can find new indications is especially pertinent in this era of shrinking investment in neuro/psych drug development.

Sometimes the serendipity and repurposing comes from mechanistic preclinical studies that can then be retranslated back to the clinic. Jumping ahead to that possibility, a press release from Emory declares:
Potential drug target for PTSD prevention

Scientists at Yerkes National Primate Research Center, Emory University have identified a drug that appears to make memories of fearsome events less durable in mice.

The finding may accelerate the development of treatments for preventing PTSD. The drug, called osanetant, targets a distinct group of brain cells in a region of the brain that controls the formation and consolidation of fear memories.
. . .

“Potentially, drugs that act on this group of cells could be used to block fear memory consolidation shortly after exposure to a trauma, which would aid in preventing PTSD,” says Kerry Ressler, MD, PhD, professor of psychiatry and behavioral sciences... “PTSD is unique among psychiatric disorders in that we know when it starts – at the time of the trauma. Finding ways to prevent its development in the first place – in the emergency department or the battlefield - is an important and exciting avenue of research in this area.”

NkB and the Consolidation of Fear Memories 

A new study in mice found that osanetant could block the consolidation of fear memories when administered within a narrow time window (Andero et al., 2014):
Notably, when osanetant is dosed from 30 min before auditory FC [fear conditioning] up to 1 hr after training, it does not affect fear acquisition but impairs fear memory consolidation as shown by decreased freezing in the fear expression test. 

Furthermore, mice previously traumatized by 2 hours of immobilization (a rodent model of PTSD-like behaviors that include impaired fear extinction) also showed reductions in fear memory consolidation when given osanetant (IMO-Osa), compared to placebo (IMO-Veh).


Modified from Fig. 4 (Andero et al., 2014). G: Osanetant given immediately after FC impaired fear memory consolidation in mice that had been previously exposed to a traumatic stress as shown by reduced freezing in the fear expression test, ∗p ≤ 0.05. n = 8 per group.


The starting point of this study, however, was not to test the effects of osanetant on the formation of fear memories. Rather, Andero et al. (2014) began by casting a wide net in search of genes that are regulated during fear conditioning. They found that the Tac2 gene (TACR3 gene in humans) is regulated during fear memory consolidation, specifically in the central nucleus of the amygdala (a “fear learning central” of sorts).
Furthermore, increased expression of the Tac2 gene, NkB peptide, and activation of Nk3R may be involved in stress sensitization and overconsolidation of fear. In contrast, genetic silencing of Tac2-expressing neurons impairs fear consolidation. Blockade of this pathway may provide for a novel therapeutic approach for disorders with altered fear learning such as PTSD.

The clinical potential of this finding is not lost on the authors. If given shortly after a traumatic event (e.g., in an emergency room or combat situation), it's possible that osanetant could reduce the emotional potency of trauma memories:
Finally, one of the most interesting aspects of our data is the potential use of the Nk3R antagonist osanetant as a pharmacological agent to block fear memory consolidation shortly after exposure to a trauma. Additionally, we found that osanetant prevented the upregulation of the Adcyap1r1 gene, which encodes the PAC1 receptor. The PACAP-PAC1R pathway is involved in PTSD, fear conditioning, amygdala excitatory neurotransmission, and stress. All this could be relevant in PTSD prevention since it has previously been found that osanetant is safe in humans, although additional preclinical studies, such as those described herein, are needed first to establish the mechanisms involved. This gives our findings an exciting potential approach to translation to human patients.

This study also provides a perfect example of NIMH's new mandate for specifying a hypothesized mechanism of action for interventions that will be tested in funded clinical trials. Does peri-trauma osanetant (vs. placebo) reduce later development of PTSD symptoms and attenuate amygdala activation to trauma script-driven imagery in fMRI? Is TAC3 gene expression altered in primate models? [The distribution of Nk3R likely differs between mice and primates.] Are there declines in PACAP blood levels in traumatized individuals given osanetant (vs. placebo)? Are there longer-term effects on methylation of ADCYAP1R1 in peripheral blood? These latter measures are biomarkers of an abnormal stress response in PTSD that are currently studied by the Ressler Lab.

At any rate, NIMH Director Insel might as well hand over the money right now...


References

Andero, R., Dias, B., & Ressler, K. (2014). A Role for Tac2, NkB, and Nk3 Receptor in Normal and Dysregulated Fear Memory Consolidation Neuron DOI: 10.1016/j.neuron.2014.05.028

Ebner K, Sartori SB, Singewald N. (2009). Tachykinin receptors as therapeutic targets in stress-related disorders. Curr Pharm Des. 15:1647-74.

Maggi CA. (2000). The troubled story of tachykinins and neurokinins. Trends Pharmacol Sci. 21(5):173-5.

Spooren, W., Riemer, C., & Meltzer, H. (2005). NK3 receptor antagonists: the next generation of antipsychotics? Nature Reviews Drug Discovery, 4 (12), 967-975 DOI: 10.1038/nrd1905





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