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Learning to forget: Making the case for sex-specific approaches to the treatment of PTSD

Author: Dr. Luzia Troebinger, Post-Doctoral Fellow, University College London - Clinical Psychopharmacology Unit

What’s your worst memory? If I offered you a pill that could erase it, would you take it? Or let’s rephrase the question: How bad would your worst memory have to be to take that pill? What if you couldn’t leave your house without reliving this memory? You might think this scenario is exaggerated, but for people suffering from post-traumatic stress disorder (PTSD), this might be a daily reality. For many people with PTSD, the impact on quality of life is so severe that they would not hesitate to take that pill. 

Research suggests that women are twice as likely to develop PTSD, even though rates of trauma exposure are higher in men.[1-3]  The reason for this disparity is complicated and dependent on environmental and biological factors.[4]  With regard to biological factors, the role of sex hormones in the context of stress and fear memory has become a primary target for research in this area.[5-7]

Studying fear memories in the laboratory can help improve our understanding of the mechanisms involved in PTSD. In the lab, a ‘fear memory’ is first established through a learnt association between a neutral and an adverse stimulus (e.g. a tone paired with an electric shock). This is similar to what happens in PTSD: a previously neutral stimulus becomes associated with the traumatic event. Extinction learning refers to the process of suppressing or reversing that learnt association. This is typically accomplished through repeated exposure to the neutral but not the adverse stimulus. Finally, extinction recall refers to how well this ‘extinction memory’ is remembered when confronted with the neutral stimulus later in time. 

Fear extinction plays an important role in exposure therapy, a type of behavioural treatment commonly prescribed in PTSD.[8-10] Briefly, this type of therapy involves repeated exposure to trauma-related memories in a safe context. Just as in the laboratory models, the idea is that repeated exposure will result in the ‘extinction’ of learnt associations between environmental stimuli and the traumatic event. Although this type of treatment is effective for many people, it has limitations. 

Try to think about your worst memory again.  Now imagine doing this over and over again. Not exactly pleasant, is it?

There is a host of factors that influence if exposure therapy will benefit an individual. One aspect that might be highly relevant for women is the level of sex hormones at the time of treatment.

Evidence from rodent studies suggests that low estrogen levels in females are associated with poor extinction recall. These findings also seem to translate to studies in human subjects, with extinction recall being worse during low-estrogen stages of the menstrual cycle.[5,11] Moreover, the suppression of the body’s natural estrogen through the administration of hormone-based contraceptives has also been found to impair extinction recall.[12] This is an issue because impaired extinction recall could render exposure therapy ineffective or even counter-productive. If patients go through the difficult process of recalling traumatic memories without an understanding that doing so is safe and effective, they may lose motivation to continue treatment.

What are the possible implications of this in a clinical context? Timing could be a crucial factor in prescribing exposure therapy in naturally cycling women. Also, women with chronically low estrogen levels may benefit from pairing exposure therapy with pharmacological interventions. For instance, a recent study in rodents has shown that a certain type of blood pressure drug could reverse the adverse effects of low estrogen on extinction recall, possibly by making up for low-estrogen-related deficits in the regulation of the physiological stress response.[13]

Another approach to dealing with intrusive, distressing trauma memories is to reduce their impact near the time they are formed. This could be achieved by using pharmacological treatments to prevent traumatic memories from being further strengthened. As with exposure therapy, the case can be made that such treatments should take sex into account.

Previous research suggests that high progesterone levels at the time of trauma exposure could contribute to a strengthening of the traumatic memory, resulting in the type of intrusive, ‘flashback’ memories associated with PTSD.[14] Another study found that women who had been exposed to sexual assault had differing levels of PTSD depending on if they received hormone-based emergency contraceptives and what hormone the contraceptive contained. [15] One of two types of emergency contraceptives was administered, with one containing both synthetic estrogen and progestin (Ogestrel), while the other drug contained a synthetic progestin-only (Plan B). Interestingly, the women who took Ogestrel reported fewer intrusive memories than those who took Plan B. This might point to a combined effect of estrogen and progesterone on the formation of trauma memories. In any case, these studies highlight the importance of considering sex in the development of pharmacological treatments intended for use in the immediate aftermath of a trauma.

Given this research, why are we not prescribing treatments – behavioural or pharmacological – in a sex-specific way?  

Treatments need to be well-studied before they can be used in clinical practice. Particularly in the case of pharmacological interventions, this process can be lengthy, costly and complex. The reality of research is that resources are limited, and drug studies are expensive. Testing for the influence of the menstrual cycle phase would increase the sample size required and would also put further demand on resources by necessitating the acquisition, storage, and analysis of biological samples for rigorous testing of hormone levels.  At this time, there is a need for more evidence regarding hormonal influences on PTSD treatments. With the emergence of funding opportunities dedicated to the field of women’s health, there is hope that this will change. What is clear from the evidence is that there are hormonal influences on the development of PTSD. By including sex differences, we are presented with an opportunity to drastically improve the treatment of mental health disorders.

About the author

Dr. Luzia Troebinger currently works as a postdoctoral research fellow in Professor Sunjeev Kamboj’s group at University College London’s Clinical Psychopharmacology Unit. Her research focuses on both behavioural and pharmacological approaches to the treatment of PTSD and is funded by the Sir Bobby Charlton Foundation.

Twitter: @UCL_SBCF

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