How and why does the pharmaceutical management of PTSD differ between men and women?

KEYWORDS:

• Posttraumatic stress disorder
• pharmacotherapy
• gender
• healthcare utilization
• antidepressants
• depression
• substance use disorder
• insomnia
• clinical trials

1. Introduction

Women have typically been found to develop posttraumatic stress disorder (PTSD) at twice the incidence and prevalence rates as men [1]. One explanation for this difference is that women endure more sexual and physical abuse, types of trauma that contribute to increased rates of various psychiatric disorders including PTSD and depression [1]. Yet, the trauma type difference may only partially account for the disparity in PTSD risk as genetic factors may also contribute to increased vulnerability to the development of PTSD [2].

Women are more likely than men to seek mental health services and prefer to get treatment in primary-care clinics [3]. Men, however, are more likely to receive what is considered an ‘adequate dose’ of mental health treatment compared to women [3]. It is possible that gender-related differences in co-occurring disorders may contribute to a difference in provider specialty. Primary-care physicians may be more willing to treat women with PTSD with antidepressant pharmacotherapy, especially when they also present with insomnia, depressive, or anxiety symptoms. On the other hand, primary-care physicians may be more likely to refer men, than women, to mental health specialists, because they present more often with co-occurring substance use disorders (SUD). Such a referral may be more likely to result in psychotherapy, an option increasingly seen as the most effective treatment recommendation for PTSD [4].

Women are more likely than men to be prescribed psychotropic medications overall [5], a difference in medication management that is neither unique to the United States nor limited to a diagnosis of PTSD. Results from a psychotropic drug utilization study of six European countries found that women receive anxiolytics at significantly higher rates than men [6]. Women veterans with PTSD are more likely to receive psychotropic medications across all drug classes (including those not recommended to be used such as benzodiazepines), with the single exception of prazosin, an agent recommended for trauma-related nightmares [5].

In this editorial, we offer an overview of how gender differences have been noted in PTSD pharmacotherapy practice and discuss special considerations regarding treatment of women with PTSD. We share an expert opinion on why an improved sociocultural and neurobiological understanding of gender differences in PTSD may inform the field and help to address treatment recommendations for women. It is critically important to offer clinical guidance on PTSD treatment recommendations for women that take factors such as pregnancy and co-occurring disorders into account.

2. PTSD pharmacotherapy recommendations

Currently, first-line pharmacotherapy treatment recommendations for PTSD according to several guidelines are selective serotonin reuptake inhibitors (SSRIs) and the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine [4]. Recent findings note improved outcomes from specific S/NRIs, rather than the entire SSRI class of medications, that include sertraline and venlafaxine, as well as the serotonergic antidepressant, nefazodone [4]. An often overlooked fact is that women greatly outnumbered men in the original randomized controlled trials that led to FDA approval of SSRIs as first-line treatment for PTSD. According to the comparative effectiveness review of 15 SSRI trials, all studies included females with a low of 19% of participants to a high of 91% with nine trials enrolling two-thirds or more female subjects with a variety of trauma types [7]. Similarly, the more recent trials of the SNRI venlafaxine included approximately 50% women [7]. Importantly, the data do not show gender to be an influential determinant of study outcome, so men and women both appear to benefit from the guideline-recommended agents. At the same time, it should be recognized that current available pharmacotherapy options are limited by moderate effect sizes at best [4] and do not always work for individual patients.

3. Gender differences in pharmacologic management of PTSD

Among privately insured Americans with PTSD, women are more than 1.5 times as likely as men to receive psychotropic intervention [8]. Sixty percent of patients with PTSD were prescribed psychotropic medication, with older patients and women more likely to receive antidepressants and anxiolytics or sedative-hypnotics [8]. Women veterans receiving care for PTSD are more likely to have co-occurring depressive and anxiety disorders whereas male veterans have higher rates of SUD and a history of traumatic brain injury (TBI) [5]. When adjusted for these psychiatric comorbidities, higher rates of psychotropic prescribing to women are still observed compared to men [5]. The most notable discrepancy in this study was observed for benzodiazepine prescriptions which, for male veterans with PTSD, decreased over a 10-year study period (36.7–29.8%), yet steadily increased for female veterans (33.4–38.3%) during the same time period [5]. Furthermore, relatively more benzodiazepines were dispensed to female veterans with co-occurring SUD and a history of TBI, practices specifically discouraged by the Veterans Affairs/Department of Defense Clinical Practice Guideline for PTSD [9]. Higher rates of benzodiazepine prescribing for women with these comorbidities increase the risk of development of a wide range of harmful side effects.

It has been noted that women are more likely to take sleep medications than men. It is possible that increased prescribing of low-dose atypical antipsychotics (especially quetiapine), zolpidem, and benzodiazepines in this sample of women veterans is in response to complaints of insomnia symptoms [5]. Despite such prescribing trends, it is not clear whether there are actually gender differences in sleep disturbances in PTSD. Inconsistencies in research findings indicate that gender differences in PTSD-related insomnia are also moderated by age, military trauma, and comorbid depression or SUD [10].

Regarding benzodiazepines, women with PTSD have been found to have reduced sensitivity to gamma-aminobutyric acid (GABA)--A receptor active substances [11]. In this study, diazepam had a significantly lower effect on sedation among female PTSD patients than among healthy female controls. As a result, the authors speculated that benzodiazepines, as a class in addition to other agents that act on GABA-_A receptors may be less effective for women with PTSD [11]. This finding, if it holds, may be critically important since it appears that, although a large proportion of psychotropic medications prescribed to women with PTSD are to ameliorate sleep problems, the medications that are usually prescribed are probably not working effectively.

It is also possible that the prescribing rates are a reflection of greater willingness among women with PTSD to take medications for mental health concerns, particularly for the commonly co-occurring insomnia and depressive symptoms. Several studies have suggested that the SSRIs are more effective in the presence of estrogen [12] and have contributed to an ongoing controversy about gender differences in response to antidepressant medications. New evidence suggests that, rather than presynaptic serotonin reuptake blockade, a major antidepressant mechanism of action of SSRIs is exerted on the progesterone pathway through increased production of allopregnanolone, an endogenous inhibitory neurosteroid [13]. This would suggest a biological advantage for women as far as SSRIs are concerned. Another, potentially important action of SSRIs may be at GABA-_A (rather than serotonin) receptors where aforementioned gender differences may account for more favorable efficacy in women. Unfortunately, little systematic data are available concerning the potential clinical relevance of such gender-related differences in pharmacodynamics. What is recognized is that there are both gender and age effects observed in the metabolism of antidepressant medications that could impact treatment response [14].

Finally, women in their childbearing years in particular need gender-specific PTSD care that considers a woman’s pregnancy intentions as medications used to treat PTSD are potentially harmful to the fetus (teratogenic). These risks (see Table 1) can be reduced when clinicians ask their patients about pregnancy intentions and discuss medication treatment strategies based on childbearing plans. Studies from multiple clinic settings including the VA have found that women of childbearing age are frequently prescribed potentially teratogenic medications [15].

Table 1. Former FDA classifications.

Generic name	Brand name	Pregnancy category
Recommended for PTSD
Fluoxetine	Prozac	C
Paroxetine	Paxil	D
Sertraline	Zoloft	C
Venlafaxine	Effexor	C
Prazosin	Minipress	C
Mirtazapine	Remeron	C
Amitriptyline	Elavil	C
Nefaxodone	Serzone	C
Not recommended for PTSD
Alprazolam	Xanax	D
Clonazepam	Klonopin	D
Diazepam	Valium	D
Lorazepam	Atavan	D

Recently, the FDA-revised drug labeling to better identify potential risks related to reproduction. Instead of pregnancy categories A–X, drug labels will contain risk summary, clinical considerations, pregnancy exposure registry information and available data on pregnancy, lactation, and reproductive effects on males and females. As the new labeling is not yet available for all products, the old categories will be cited for mental health drugs with potential risks: C – no adequate studies, D – evidence of risk. Decisions between clinicians and patients can be further informed at va.reprotox.us or mothertobaby.org.

4. Expert opinion on the pharmacotherapy management of PTSD in women

In short, pharmacologic management of PTSD in women is clearly complicated. It is uncertain if prescribing clinicians treat women differently, if there is something about the way women seek mental health care for PTSD that results in differences, or if gender-related pharmacodynamic differences might influence prescribing patterns. All of these factors need to be investigated. It is also possible that pharmaceutical companies target women with direct-to-consumer advertising which results in increased pharmaceutical prescribing, particularly as pertains to insomnia treatment. If the medications prescribed for insomnia carry increased risks of harmful effects, women need to be informed of safer effective treatment options. Evidence-based psychotherapies for PTSD and for symptoms such as insomnia and anxiety should be offered as treatment choices and do not pose any risks of harm to women who might be planning a pregnancy.

Qualitative research that clarifies interactions between prescribing clinicians and patients of both genders might help elucidate some of these questions. A better understanding of the relationship between the SSRIs, the GABA-A receptors and the increasingly recognized role of allopregnanolone is needed. What is clear is that the development of a comprehensive treatment plan for PTSD for both men and women requires coordinated medical and mental health care and can be challenging. A critical part of that treatment planning is learning what not to do. Given the prescribing results noted in the aforementioned studies, efforts are needed to ensure that women in particular receive appropriate information regarding potential risks when medications to treat PTSD are prescribed.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.