Female Soldiers, PTSD, and Norepinephrine

Francisco Goya, The Disasters of War
[idea for using this image stolen from Mixing Memory's latest post on mirror neurons]

The 4th anniversary of the Iraq war was on Sunday, and some news outlets ran an obvious (but highly neglected) story: Violence takes severe mental toll on Iraqis.

Much more common are stories on the psychological toll of war in U.S. military personnel. There's a depressing article in the New York Times Magazine about post-traumatic stress disorder in women soldiers stationed in Iraq.

The Women’s War

By SARA CORBETT

Many female soldiers have lived through the terrible violence of the war in Iraq. Others have experienced sexual assault — or worse, a combination of the two. They have found themselves struggling to cope with their lives.

Among other examples, the article recounts the ordeal of Suzanne Swift, a 21-year-old Army specialist, who went AWOL rather than return to a second tour of duty in Iraq:

Despite the fact that military procedure for dealing with AWOL soldiers is well established - most are promptly court-martialed and, if convicted, reduced in rank and jailed in a military prison - Suzanne Swift's situation raised a seemingly unusual set of issues. She told Army investigators that the reason she did not report for deployment was that she had been sexually harassed repeatedly by three of her supervisors throughout her military service: beginning in Kuwait; through much of her time in Iraq; and following her return to Fort Lewis. She claimed too to be suffering from post-traumatic stress disorder, or PTSD, a highly debilitating condition brought on by an abnormal amount of stress. According to the most recent edition of The Diagnostic and Statistical Manual of Mental Disorders, used by mental-health professionals to establish diagnostic criteria, PTSD symptoms can include, among other things, depression, insomnia or "feeling constantly threatened." It is common for those afflicted to "re-experience" traumatic moments through intrusive, graphic memories and nightmares.

Given their current track record of providing adequate medical care to returning veterans, will the current administration find the funds to improve the standard of care not only for the physically wounded (see the Walter Reed debacle), but also for the astonishingly large number of vets (33%) diagnosed with mental illnesses?

The V.A. notes that as of last November, [almost] one-third [see Seal et al., 2007] of the veterans of Iraq and Afghanistan treated at its facilities were given diagnoses of a mental-health disorder, with PTSD being the most common. So far, the V.A. has diagnosed possible PTSD in some 34,000 Iraq and Afghanistan veterans; nearly 3,800 of them are women. Given that PTSD sometimes takes years to surface in a veteran, these numbers are almost assuredly going to grow.

What are the appropriate treatments for women with PTSD? Surely not this one:

While serving in a mostly male reserve unit in Kuwait, [another soldier] was sexually assaulted. After returning home to Michigan, she began exhibiting symptoms of PTSD - jumpiness, intrusive thoughts and nightmares - and promptly went to her local V.A. hospital for help. She was then put into group therapy - which has long been shown to be an economical and reasonably effective way of helping trauma survivors process their experiences - but her "group" was made up entirely of male Vietnam vets, some of whom were trying to work through sex crimes they committed during military service. Others came home from war and beat their wives. "I freaked out," the female reservist told me. "It sent me into a complete tailspin."

In addition to psychotherapy (including Exposure Therapy (Jaycox et al., 2002; Schnurr et al., 2007) -- a Cognitive Behavioral intervention -- and Eye Movement Desensitization and Reprocessing (Rothbaum et al., 2005; van der Kolk et al., 2007)) for those with PTSD, drugs that affect the neurotransmitter norepinephrine have been tested. A recent clinical trial of guanfacine was a complete failure (Neylan et al., 2006):

Neylan TC, Lenoci M, Samuelson KW, Metzler TJ, Henn-Haase C, Hierholzer RW, Lindley SE, Otte C, Schoenfeld FB, Yesavage JA, Marmar CR. (2006). No improvement of posttraumatic stress disorder symptoms with guanfacine treatment. Am J Psychiatry 163: 2186-8.

OBJECTIVE: The authors report an 8-week, double-blind, randomized controlled trial of guanfacine versus placebo for posttraumatic stress disorder (PTSD). METHOD: Veterans with chronic PTSD who were medication-free or receiving stable pharmacotherapy were randomly assigned to guanfacine (N=29) versus placebo (N=34). RESULTS: Guanfacine had no effect on PTSD symptoms, subjective sleep quality, or general mood disturbances. Guanfacine was associated with a number of side effects. CONCLUSIONS: These results do not support the use of alpha 2 agonists in veterans with chronic PTSD.

Guanfacine is an antihypertensive drug and an alpha-2 adrenergic agoninst that binds to autoreceptors on locus coeruleus (Berridge & Waterhouse, 2003) neurons [when administered at high doses¹], thereby inhibiting their activity and hence, the release of norepinephrine. When administered at low doses, guanfacine binds to post-synaptic alpha-2 receptors in places like the prefrontal cortex (Arnsten et al., 1988).

Another blood pressure medication, propranolol (a beta blocker), has been more widely used as a potential treatment for anxiety disorders and PTSD (e.g., Strawn & Geracioti, 2007). Similar to the use of alpha-2 agents, the idea behind propranolol is to normalize the hyperactive noradrenegic system in PTSD (a state produced by exposure to extreme levels of stress). Excessive norepinephrine (and the associated signal transduction activity) is thought to result in a trauma-induced enhancement of memory encoding for the harrowing event (Debiec & LeDoux, 2006).

Animal models of fear conditioning have been used to assess possible pharmacological treatments targeting the amygdala, a critical region for fear learning (Debiec & LeDoux, 2006). These treatments aim to impair memory consolidation and reconsolidation (reactivating a memory by retrieving it):

...propranolol, injected either systemically or directly into LA [lateral amygdala] lastingly impaired fear memory. Postreactivation propranolol significantly weakened fear responses measured 48 h later. ... Interestingly, our published findings indicate that propranolol disrupts reconsolidation of a memory 2 months after training. Therefore, even well-consolidated old fear memories undergo reconsolidation and may be disrupted by means of pharmacological manipulation.

For a more selective approach to PTSD, is it possible to

Wipe out a single memory (original source: Nature news) [??]

A single, specific memory has been wiped from the brains of rats, leaving other recollections intact.

The study adds to our understanding of how memories are made and altered in the brain, and could help to relieve sufferers of post-traumatic stress disorder (PTSD) of the fearful memories that disrupt their lives.

All very Lacuna Inc. (as other observers have noted). Original paper:

Doyere V, Debiec J, Monfils MH, Schafe GE, Ledoux JE. (2007). Synapse-specific reconsolidation of distinct fear memories in the lateral amygdala. Nat Neurosci. Mar 11; [Epub ahead of print].

When reactivated, memories enter a labile, protein synthesis–dependent state, a process referred to as reconsolidation. Here, we show in rats that fear memory retrieval produces a synaptic potentiation in the lateral amygdala that is selective to the reactivated memory, and that disruption of reconsolidation is correlated with a reduction of synaptic potentiation in the lateral amygdala. Thus, both retrieval and reconsolidation alter memories via synaptic plasticity at selectively targeted synapses.

In that experiment (and others like it), rats were treated with the MEK Inhibitor, U0126 [which inhibits the kinase activity of MAP kinase kinase, or MEK -- aka MKK or MAP2K²], not propranolol. U0126 is not exactly approved for human use³.

So what about propranolol for PTSD? According to Strawn & Geracioti (2007),

The utility of these anti-adrenergics in the clinical treatment of PTSD remains to be determined, though it is possible that they may prove to have primary roles in a disorder that is only modestly responsive to antidepressant treatment.

Footnotes

¹ Or so the story went, a story that motivated the idea of guanfacine treatment in the first place. However, recent work (Ramos & Arnsten, 2005; Arnsten & Li, 2007) has shown that alpha-2 receptors are much more prominent post-synaptically, and guanfacine is more selective for those than for pre-synaptic autoreceptors (and is selective to a greater extent than clonidine, another alpha-2 blood pressure med known to produce sedation).

² Also see the fun MAP Kinase Signal Transduction Animation by Dr. Vic Lemas.

³ We're getting way out of my league here, but apparently U0126 is in the very "early clinical phase" for cancer treatment (a "Target for the Future") and is viewed as a "radical approach to stroke therapy." The only published studies have been done with cell cultures, with a few in live rodents.


References

Arnsten AF, Cai JX, Goldman-Rakic PS. (1988). The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci. 8:4287-98.

Arnsten AF, Li BM. (2005). Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 57:1377-84.

Berridge CW, Waterhouse BD. (2003). The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev. 42:33-84.

Debiec J, LeDoux JE. (2006). Noradrenergic signaling in the amygdala contributes to the reconsolidation of fear memory: treatment implications for PTSD. Ann NY Acad Sci. 1071:521-4.

Jaycox LH, Zoellner L, Foa EB. (2002). Cognitive-behavior therapy for PTSD in rape survivors. J Clin Psychol. 58:891-906.

Ramos BP, Arnsten AF. (2007). Adrenergic pharmacology and cognition: Focus on the prefrontal cortex. Pharmacol Ther. 113:523-36.

Rothbaum BO, Astin MC, Marsteller F. (2005). Prolonged Exposure versus Eye Movement Desensitization and Reprocessing (EMDR) for PTSD rape victims. J Trauma Stress. 18:607-16.

Schnurr PP, Friedman MJ, Engel CC, Foa EB, Shea MT, Chow BK, Resick PA, Thurston V, Orsillo SM, Haug R, Turner C, Bernardy N. (2007). Cognitive behavioral therapy for posttraumatic stress disorder in women: a randomized controlled trial. JAMA 297:820-30.

Seal KH, Bertenthal D, Miner CR, Sen S, Marmar C. (2007). Bringing the war back home: mental health disorders among 103,788 US veterans returning from Iraq and Afghanistan seen at Department of Veterans Affairs facilities. Arch Intern Med. 167:476-82.

Strawn JR, Geracioti TD Jr. (2007). Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder. Depress Anxiety Mar 12; [Epub ahead of print].

van der Kolk BA, Spinazzola J, Blaustein ME, Hopper JW, Hopper EK, Korn DL, Simpson WB. (2007). A randomized clinical trial of eye movement desensitization and reprocessing (EMDR), fluoxetine, and pill placebo in the treatment of posttraumatic stress disorder: treatment effects and long-term maintenance. J Clin Psychiatry 68:37-46.