CNS Spectr. 2010;15(8):522-530.
Dr. Olff is associate professor, and Drs. Langeland and Witteveen are senior researchers at the Center for Psychological Trauma in the Department of Psychiatry, Academic Medical Center, at the University of Amsterdam in The Netherlands. Dr. Denys is professor of the Center for Anxiety Disorders in the Department of Psychiatry, Academic Medical Center, at the University of Amersterdam.
Faculty Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Submitted for publication: January 17, 2010; Accepted for publication: June 23, 2010.
Please direct all correspondence to: Miranda Olff, PhD, Center for Psychological Trauma, Department of Psychiatry, Academic Medical Center, University of Amsterdam, Meibergdreef 5, 1100 AZ Amsterdam, The Netherlands. E-mail: firstname.lastname@example.org.
Although cognitive-behavioral therapy (CBT) is an effective treatment for posttraumatic stress disorder (PTSD), many patients fail to attain remission with CBT. The authors propose augmentation of CBT with oxytocin in the treatment of PTSD. Oxytocin has a combination of pharmacologic effects that result in a “sense of safety” for the patient, which is a prerequisite to successful treatment of PTSD. We suggest a dual explanatory mechanism as to why oxytocin may be effective: through a reduction of fear response (decreasing amygdala activation, inhibiting fear response, and enhancing extinction learning) and through an increase of social interaction (activating social reward-related brain regions increasing engagement in the therapeutic alliance). Given that PTSD is marked by deficits in anxiety/stress regulation and in social functioning, and that oxytocin is implicated in both of these areas, oxytocin seems a likely candidate for treatment of patients with PTSD. Further clinical studies of the therapeutic value of oxytocin are indicated.
• There is preclinical and clinical support for implication of oxytocin in the pathophysiology of psychiatric disorders involving disturbed stress regulation as well as disrupted attachment and/or social deficits.
• Oxytocin may exert an effect on posttraumatic stress disorder (PTSD) through a dual mechanism, including a reduction of fear response and increase of social functioning.
• Oxytocin has a combination of pharmacologic effects that result in a “sense of safety” for the patient, which is a prerequisite to successful treatment of PTSD.
Posttraumatic stress disorder (PTSD) involves a disturbed fear response as well as disrupted social interaction and emotional reward, particularly from social experiences. PTSD is a significant health problem with an overall estimated lifetime prevalence of ~8% in the general population, with 2–3 times higher rates of PTSD in women than in men.1-3 If untreated, the disorder typically follows a chronic, unremitting course leading to substantial impairments in social and relational functioning.
Regarding therapeutic strategies, trauma-focused cognitive-behavioral therapy (CBT) with exposure as its prominent element, is the treatment of choice for PTSD. Numerous randomized controlled trials (RCTs) and meta-analyses have demonstrated its efficacy in reducing symptoms of both acute and chronic PTSD when compared to other therapeutic strategies.4-8 However, not all patients seem to benefit fully from CBT, because a substantial percentage of patients drop out of treatment, remain symptomatic, or relapse after initially having responded to exposure therapy.7,9,10 Promising results in enhancing the effectiveness of treatments for PTSD come from studies that add a pharmacologic agent to exposure, eg, D-cycloserine (DCS).11 These novel strategies emerged from studies that have mapped some of the core pathways and neurotransmitters involved in fear extinction.12-14 All avenues to boost treatment response by adding a pharmacologic agent to CBT, however, have yet not been fully explored.15 A potential candidate for new augmenting treatments is the central hormone oxytocin. In the present paper a dual psychobiological mechanism by which oxytocin may exert an effect on PTSD is described.
It has been demonstrated that oxytocin may be implicated in the pathophysiology of psychiatric disorders involving disturbed stress regulation as well as disrupted attachment and/or social deficits (eg, social withdrawal) such as autism, obsessive-compulsive disorder, social phobia, mood disorders, borderline personality disorder, and PTSD.16-18 Given that PTSD is marked by deficits in social functioning and anxiety/stress regulation, and that oxytocin is implicated in both these areas, oxytocin seems a likely candidate for treatment of patients with PTSD.
Oxytocin administration has been found to reduce amygdala activation and decreased coupling to the brain regions involved in autonomic and behavioral responses to fear.19 This finding is of importance for PTSD research, since the amygdala, which is central in the biological response to danger signals, is highly responsive in patients with PTSD. In addition, PTSD has been associated with increased activity of the sympathetic nervous system and with a dysregulated hypothalamic-pituitary-adrenal (HPA) system, such as low basal cortisol levels and enhanced cortisol response to challenge. By dampening stress reactivity, oxytocin might help ameliorate (intensity and frequency of) stress symptoms associated with PTSD. Beyond the reduction of fear and anxiety, oxytocin positively influences social reward circuits,20 making it a promising candidate for treatment of PTSD. Initial promise for oxytocin as an augment to psychotherapy for PTSD comes from clinical trials already testing 3,4-methylenedioxymethamphetamine (MDMA) (the pharmaceutical version of “ecstasy”)-assisted psychotherapy in people with PTSD.21 Recent findings in humans22 show that MDMA robustly induces oxytocin release and that oxytocin may be involved in the characteristic prosocial effects of MDMA that could help patients with PTSD.
Psychobiological Mechanisms for Oxytocin as a Novel Treatment Approach
The authors suggest a dual explanatory mechanism as to why and how oxytocin may be effective in PTSD: through a reduction of fear response (decreasing amygdala activation, increasing extinction learning, and affecting the neuroendocrine stress response); and through an increase of social functioning (activating social reward-related brain regions increasing engagement in social support and therapeutic alliance).
Reduction of Fear Response
Oxytocin and Amygdala: Medial Prefrontal Cortex Interactions
The first biological mechanism through which oxytocin may be effective in PTSD concerns extinction of conditioned fear by strengthening (ventro)medial prefrontal cortex (vmPFC) inhibition of the amygdala-mediated fear response. PTSD may develop from impaired extinction of conditioned fear responses, and the exposure-based treatments of PTSD are thought to be effective through extinction learning. With this essential form of emotional learning, the patient is to re-learn the appropriate response to the trigger situation through repeated exposure to the safe but fear evoking conditioned stimulus (eg, through imaginary exposure to the traumatic experience) in the absence of the harmful unconditioned stimulus (eg, the real consequences of the trauma) with which it was paired previously.23 Inhibition of fear responses and improved emotional regulation is demonstrated in a range of anxiety disorders following extinction-based exposure therapy.13
Although strictly speaking, little is known about the exact mechanism through which oxytocin exerts its effects, both animal and human studies have shown that higher levels of oxytocin are associated with facilitation of fear extinction.24-28 Fear extinction is mediated by inhibitory control of the vmPFC over amygdala-based fear processes.29 Major trauma may disrupt the normal patterns of medial prefrontal and amygdala regulation.30 Dysfunctional activity in both these brain areas has been reported in PTSD.31,32 A recent meta-analysis showed that the prefrontal areas, corresponding to the same areas implicated in extinction learning, are deficient in PTSD.33 Hyperresponsivity of the amygdala in particular, may be relevant for treatment response to CBT for PTSD.31,34 Moreover, it has been shown that reduction of PTSD symptoms in exposure therapy is associated with reduced amygdala activation during fear processing.35
Higher levels of oxytocin are associated with decreases in stress and anxiety and facilitation of extinction of conditioned avoidance behavior.25,26 Both animal and human studies indicate that oxytocin affects amygdala activation. More particularly, oxytocin increases vmPFC activity and decreases amygdala activity which may improve emotion regulation and decrease avoidance behavior.36,37
In rodents, it has been shown that oxytocin acts on the amygdala to reduce fear38,39 and to modulate aggression.40 Huber and colleagues27 recently demonstrated that receptors for oxytocin and arginine vasopressin (AVP) are located within the central nucleus of the amygdala. These findings are consistent with those of Bale and colleagues,41 indicating central nervous system region-specific oxytocin receptor expression, with anxiolytic effects following infusion of oxytocin through activation of protein kinase A in the central nucleus of the amygdala. The central nucleus appears to be a place where the expression of fear is modulated,42 suggesting that these neuropeptides may be related to distinct aspects of the fear response. Studies in rodents show that oxytocin and vasopressin have opposing effects on the emotional expression of the fear response.43 It has been hypothesized that stimulation of oxytocin receptors leads to inhibition within the amygdala, suggesting an oxytocin-mediated downregulation of fear responses.27,44,45
In humans, several studies have provided evidence that oxytocin reduces fear-related amygdala activity.28,46-49 The action of oxytocin on the amygdala during the perception of threatening social cues has been outlined by research indicating that oxytocin attenuates negative affective evaluations associated with aversively conditioned stimuli through modulation of the amygdala and fusiform gyrus.48 For example, intranasal oxytocin administration markedly reduces amygdala responsiveness.28,46 A placebo-controlled study by Kirsch and colleagues28 indicated that oxytocin potently reduces activation of the amygdala and decreases coupling of the amygdala to brainstem regions implicated in autonomic and behavioral manifestations of fear. In line with this, oxytocin was shown to attenuate amygdala responses to positive facial expressions,46 aversively conditioned emotional response to social stimuli,48 to painful stimulation,49 and during prosocial behavior.47 These results indicate a role for oxytocin in social emotional processing, and provide a rationale for exploring therapeutic strategies in disorders in which abnormal amygdala function is implicated such as in PTSD.
As yet, there are few novel strategies that have been trying to increase extinction learning by augmenting the efficacy of CBT by adding DCS, which binds to neurotransmitter receptors N-methyl-d-aspartate receptors in the amygdala.50,51 It appears that DCS strengthens extinction memories, so they may be more easily retrieved during subsequent exposures to fear-relevant cues. Considering the focus of the current paper, one of the more exiting developments of recent years has been the augmentation of psychotherapy for anxiety disorders with MDMA. The first preliminary studies in PTSD show promising results.52,53 In addition, open-label trials of MDMA augmented psychotherapy54 and controlled human studies55,56 suggest that MDMA strengthens the therapeutic alliance, decreases avoidance behavior and improves tolerance for recall and processing of painful memories.21 MDMA has a combination of pharmacologic effects that could provide a balance of activating emotions while feeling safe and in control. What is particularly interesting about the reviewed findings on MDMA augmentation of CBT is the major possible biological explanation for why MDMA could help individuals with PTSD, namely that it is known to increase the release of oxytocin.57,58 We argue that a much more direct and possibly more powerful route would be to administer oxytocin itself. Overall, this research supports a new approach to the treatment of psychological disorders that enhances the adaptive learning via medication.
Oxytocin has been implicated in learning and memory processes,59,60 but whereas the effects of oxytocin on memory have been investigated very actively in animals, research in humans remains relatively limited.61-66 The small number of studies that were carried out showed inconsistent findings, possibly due to the variety of the experimental methods, including memory testing, stimulus material, and dose, route, and timing of oxytocin administration.67 It is interesting to note that Heinrichs and colleagues61 argue that there are gender-specific differences in the effect of oxytocin in reproduction-related memory. Future research on the role of oxytocin in learning and memory in humans taking into account possible gender differences is needed.
Oxytocin and Neuroendocrine Stress Responses
A large body of evidence links oxytocin with neuroendocrine and psychosocial stress reduction in non-human mammals.68-70 In line with this research, initial studies suggest similar stress-reducing effects of oxytocin in humans.71,72 Because increased levels of oxytocin serve to suppress both sympathetic arousal and HPA) axis responses to stress, it may be important in PTSD where both these systems are dysregulated.
Several studies in humans found support for a negative relationship between basal plasma oxytocin levels and norepinephrine, blood pressure, and heart rate.73-75 Oxytocin also inhibits stress-induced activity of the HPA axis.76-78 Higher oxytocin levels have also been associated with faster HPA recovery in women after an acute stress laboratory challenge.71 Heinrichs and colleagues72 explored the relationship between oxytocin and stress response by administering oxytocin during the Trier Social Stress Test. They found that oxytocin interacts with received social support by suppressing both the subjective and cortisol response to the stressor. The stress response was most affected by the combination of oxytocin and social support. The effect of receiving oxytocin alone appeared to be about equivalent to the effect of receiving social support alone with regard to measures of endocrine and subjective measures of anxiety. Comparisons of pre and poststress anxiety levels revealed an anxiolytic effect of oxytocin.
Figure 1 integrates the reviewed findings regarding the modulation of the fear response by oxytocin in a heuristic model.
Increase of Social Functioning
Oxytocin Activates Reward-Related Brain Regions
Oxytocin appears to interact with the brain’s reward system, with higher oxytocin levels being associated with increases in the experience of reward. The nucleus accumbens plays a central role in reward function,79,80 while the subgenual prefrontal cortex modulates reward processes81 and is implicated in the pathophysiology of PTSD.82,83 Preclinical findings that indicate a relationship between chronic stress exposure and striatal dopaminergic hypoactivity argue for a link between PTSD and reward deficits.84,85 PTSD is not only associated with a higher prevalence of substance abuse,86 but it bears diagnostic features that suggest a reward system dysfunction. The most notable of these are the emotional numbing symptoms, including loss of interest and pleasure (ie, anhedonia), which has been linked with reward function deficits in PTSD.87-89 This implies that the failure of individuals with PTSD to profit from offered social support as in emotional numbing, may reflect not only a desire to avoid fear reactions, but also the failure to appreciate social reward.
Oxytocin, Social Support, and the Therapeutic Relationship
On top of the well-documented “fear” system, there is evidence for a “safety” system on grounds of brain circuits responsible for social affiliation. Oxytocin may have a role in the stress response, social affiliation, and the readiness for experiencing attachment security.90 Oxytocin levels are increased by close relationships and social support and reduced by sad emotions or social isolation.91 There is a clear association between oxytocin and the experience of social support.92 Although little is known as of yet about oxytocin-mediated responses to trauma, the lack of social support after a trauma is one of the most significant predictors of PTSD.93,94
Intranasal oxytocin administration has been shown to increase the ratio of positive to negative behaviors during a marital conflict discussion.95 Among studies in which participants were engaged in an experimental task in the presence of a loved one, individuals who reported greater social support had higher oxytocin levels.74,75 An interesting recent study by Gouin and colleagues96 on marital behavior, oxytocin, and wound healing showed that individuals with higher oxytocin levels not only displayed more social bonding with the spouse (ie, positive communication behaviors during a structured social support task), but also healed experimental wounds faster than the remainder of the sample. It remains to be examined whether effects during psychotherapy are comparable to those of spousal support and whether effects of oxytocin administration during treatment may increase receptivity to positive social interactions on a long-term basis.
It has been shown that administration of oxytocin increases trust in humans.97 As such, oxytocin administration in psychotherapy may strengthen engagement in the therapeutic alliance. A substantial empirical literature has identified that the therapeutic alliance, defined broadly as the collaborative bond between therapist and patient, is the most consistent predictor of psychotherapy outcome. The strengths of the patient-therapist relationship appears to be a critical common factor across treatment modalities98,99 and may be of particular importance in PTSD, especially PTSD related to interpersonal trauma.100-102 The effect of therapeutic alliance (a warm and understanding bond) on PTSD symptom reduction (effect size=.46)101 was about twice the size typically reported in other studies on psychotherapy outcome.98,99 In addition, the therapeutic alliance may play an important role in the outcome of pharmacotherapy, possible by helping creating a “holding” environment where the patient feels taken care of, protected, understood, and accepted.103,104
Given the link between oxytocin and trust, prosocial behavior,22,47,97,105-106 and the subjective perception of attachment security,107 oxytocin may be a good candidate to target as an add-on treatment in the course of the psychotherapeutic process.108 Clients’ more secure attachments relationships may be related to more positive alliances with therapists and to outcome.109,110
In addition, oxytocin and attachment seem to interact in suppressing subjective anxiety and physiological stress responses.111 Early stress and abuse experiences (particularly childhood emotional abuse and neglect112,113 and early parental separation114) seem to disrupt the normal development of the oxytocin system in children, a mechanism critical to the regulation of emotional behaviors increasing the risk of developing PTSD.112,115,116 This may lead to long-term disruptions in the ability to be calmed and comforted by social bonding interactions. Providing a sense of safety and emphasizing the therapeutic relationship as a place of support may be enhanced by oxytocin.
Figure 2 integrates the reviewed findings regarding the modulation of social functioning by oxytocin in a heuristic model.
Sex Differences in the Oxytocin System and PTSD
Given that PTSD is two to three times more frequent in women than men and that oxytocin may play a role in this sex differences,3 there may be consequences for the efficacy of treatment with oxytocin across genders. However, human studies of oxytocin are rare and mostly done in males only. Studies comparing findings in males and females mostly derive from animal research. Oxytocin levels tend to be higher in females compared to males.117-120 Based on animal research, one may argue that the oxytocin system responds differently in males and females. The effects of oxytocin on brain and behavior are sexually dimorphic, especially during the course of development and rely on different neural substrates in males and females.120 One possible reason for the differences between the sexes may be because in males the developmental effects of oxytocin are mediated, at least in part, through differential effects on vasopressin (receptors).121,122 However, findings on sex differences in the oxytocin system do not directly mean that females would respond more to exogenous oxytocin administration.
Estrogen, with the well-documented capacity to increase the synthesis and possibly release of oxytocin, may help create the sex differences.123 Among the features of the oxytocin system that are at least partially estrogen-dependent are the synthesis of oxytocin and the oxytocin receptor.120-123 Estrogen appears to increase oxytocin receptor gene expression and receptor binding, and animal studies have found that greater oxytocin release occurs in females versus males in response to threat.123-125 In addition, the effect of oxytocin on neuroendocrine and autonomic reactions to threat or danger may be components of adaptive and sexually dimorphic responses to stressors. Estrogens activate the HPA axis,126 while androgens tend to inhibit the HPA axis,127 which may also have consequences for sex-specific pathogenesis of stress-related disorders.
Sexually dimorphic differences also exist in coping mechanisms, including the willingness to use social interactions to downregulate anxiety.91 Men typically use more active coping and overt defensive behaviors which may rely on AVP, while oxytocin is important to behaviors that are characterized by immobility and passive and social coping strategies123 typically used more by women. Actually, a meta-analysis on gender differences in coping showed that the largest differences were found for emotion-focused coping /seeking social support.128 A tendency to respond to threat by befriending behaviors or by seeking social support from others, as opposed using more active, instrumental coping styles may help explain gender differences in the prevalence of anxiety disorders, including PTSD.3,129 In addition, even if both genders lack social support, this lack is more strongly related to the development of posttraumatic stress symptoms in women than in men.130-132 Women also seem to be more sensitive to the effects of social reward than men.133
Overall, since women may be more vulnerable to not mounting an adequate oxytocin-response due to reduced social support in the (acute) aftermath of trauma, examining the oxytocin-mediated response to trauma may be of specific benefit to women. Whether women also may benefit more from oxytocin administration under circumstances where their stress system is being challenged needs to be tested. Much of the work investigating oxytocin in humans has been conducted in samples of all men.28,71,72,97,114,134 Further studies will tell us whether the results seen in male samples generalize to females as well.
It is notable that PTSD involves a disturbed fear response, a disruption of social behavior and emotional reward (particularly from social experiences), and that oxytocin may exert an effect on PTSD through several psychobiological mechanisms. Future clinical trials in PTSD should be developed to assess whether the effectiveness of CBT or exposure therapy may be increased by augmentation with oxytocin. A missing part of research in this area is the consideration of possible synergies between biochemical and behavioral interventions. Clearly, a key direction of further research is addressing optimal timing and dosing, for both acute trauma and chronic PTSD depending on the acute goal of treatment (eg, enhancing adaptive learning and therapeutic alliance). The peak central effects of oxytocin are expected 30–50 minutes after administration. For example, Born and colleagues135 showed that the levels of insulin and vasopressin already begin to rise within 10 minutes of administration, with peak levels attained in cerebrospinal fluid at least after 30 minutes following intranasal administration. Further studies will tell us whether oxytocin should be administered only once; for example, shortly after acute traumatization in combination with psychological first aid or social support, or more frequently during prescribed sessions in the case of PTSD or chronic traumatization, to increase building of the therapeutic alliance and reduce fear responses. In line with results reported for the use of DCS in fear learning, we expect that chronic administration of oxytocin to patients during weeks or months will not show effects on symptoms of anxiety.136 However, when administered in short bursts during (prescribed) psychological experiences, it may enhance treatment outcome. This may include emotionally significant learning experiences such as extinction-based learning or emotionally significant social interactions (promoting social bonding). More synergistic biobehavioral interventions in the sense of the aforementioned targeted biological-behavioral interactions in the treatment of trauma-related disorders need to be developed in the future.
In addition, neuroimaging studies of the oxytocin-targeted brain regions should further our understanding of the underlying neural mechanisms of the addition of oxytocin. Furthermore, since little is known about the effects of oxytocin administration on psychophysiological stress responses (sympathetic or autonomic nervous system) in PTSD,134 researchers should assess psychophysiological outcomes such as heart rate variability as well.
There is a clear need for RCTs investigating whether intranasal oxytocin, given in the context of CBT for PTSD, modulates therapeutic alliance and treatment outcome. Exploring new avenues for treatment is particular important for this debilitating disorder because current approaches fail to provide optimal efficacy. Treatment effects may be improved by exogenous oxytocin administration but also by increasing endogenous levels of oxytocin; for example, through optimalization of social support, and most likely through the combination of both. The literature is still largely based on animal studies, and it is hoped that this article will inspire more research in humans in this area of interest. Considering the preliminary nature of the literature we do present an innovative line of research with a potential to provide a substantial shift in the efficacy of treatment for PTSD. Further studies will tell us whether the findings reported here live up to their initial promise. CNS
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