Investigational drugs for assisting psychotherapy for posttraumatic stress disorder (PTSD): emerging approaches and shifting paradigms in the era of psychedelic medicine

Only two FDA-approved medications exist for PTSD, both SSRIs, which have limited efficacy: 40% of patients do not respond, only 20-30% achieve remission, and the advantage over placebo is 10-20%. Psychotherapy also has high dropout rates, with 55.8% for Prolonged Exposure and 46.6% for Cognitive Processing Therapy. There is an urgent need for novel treatments. Psychoplastogens such as ketamine, MDMA, psilocybin, and 5-MeO-DMT, which rapidly promote neural plasticity, show potential for fast and robust improvements in trauma-related symptoms. Ketamine's rapid-acting antidepressant effects have prompted a paradigm shift toward targeting synaptic dysconnectivity underlying chronic stress pathology, rather than focusing on single neurotransmitter systems.

Study at a glance

Abstract

The unfortunate reality of the mental health crisis plaguing much of the world, in tandem with and exacerbated by the COVID-19 pandemic [1–3], highlights the limited effective pharmacologic treatments in our toolbox for posttraumatic stress disorder (PTSD). There are only two FDA-approved medications indicated for PTSD, both selective serotonin reuptake inhibitors (SSRIs). Though these traditional medications work very well for a restricted population, they have significant limitations [4]. Even when optimally delivered, 40% of the patients do not respond to SSRIs, and only about 20% to 30% achieve remission, and the magnitude of the difference from placebo ranges from 10% to 20% [5,6]. The rates of non-response or partial response to these medications among combat-exposed individuals, particularly those with chronic PTSD, are comparable or worse to those of civilian patient populations [7,8]. Further, even when traditionally available SSRIs are effective, they are slow-acting antidepressants (SAADs) with a delayed onset of action, meaning it can take weeks to months before patients experience clinical benefit. This latency period is quite troubling as it significantly increases the risk for suicide and self-harm as well as other destructive behaviors [9]. Treatment guidelines for PTSD have often designated psychotherapy as the first line of intervention given the limited efficacy of SAADs; however, a recent trial comparing two gold standard trauma-focused psychotherapies reported high dropout rates (55.8% for Prolonged Exposure and 46.6% for Cognitive Processing Therapy) [10]. After psychotherapy (sometimes multiple rounds), PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity [11] and significantly impacted quality of life. There is no doubt that SSRIs and gold standard talk therapies are criticaland beneficial interventions; however, they are not enough. There is an urgent need to investigate novel treatments with the potential to offer relief and healing to individuals who have been failed by current treatments, especially those that can offer rapid and robust improvements. Mounting evidence suggests psychoplastogens [12], fast-acting therapeutics like ketamine, MDMA, psilocybin, and 5-MeODMT, which rapidly promote structural and functional neural plasticity [12–18] have great potential to provide fast-tracked, robust improvements in stressand trauma-related symptoms [5,11,19–29]. The serendipitous discovery of ketamine’s rapid-acting antidepressant (RAAD) effects approximately two decades ago [30,31] has prompted a paradigm shift in neuropsychiatry and novel drug development – looking beyond the monoaminergic system and focus on normalizing neurochemical imbalances toward a glutamateor synaptic-based hypothesis of chronic stress pathology (CSP) aimed to optimize, adapt, enhance, and/or modulate neural circuitry [4,12,13,32]. Investigators have posited that synaptic dysconnectivity may underly much of the symptom constellation and clinical presentation of PTSD [12–14]. The complexity and heterogeneity of PTSD makes pharmacological targeting of one specific neurotransmitter system (e.g. targeting stress reactivity with SSRIs or hyperarousal and fear with beta-blockers) insufficient [11]. Further, the focus on fear response and sensitization may over-simplify PTSD as though these are cardinal phenomena, other constructs can be highly distressing, such as guilt, shame, and demoralization, are not as easily addressed by shifting neurochemicals without other therapeutic support and processing. Perhaps if we administer dynamic therapeutics that both rapidly target dysregulated neurotransmitter systems and alter synaptic connectivity in a robust and durable surge, this would then promote increased capacity (e.g. heightened emotional and cognitive processing and regulation including insightfulness and introspection, diminished fear and hyperarousal, a sense of increased connection to self/others/universe/ divine/nature, perhaps strengthened therapeutic alliance, etc.) for individuals to meaningfully engage in psychotherapy and create significant durable change (see [11,20] for reviews of psychedelic-assisted therapies). Psychedelic-assisted therapy also represents a paradigm shift in the way treatment is conceptualized and delivered, emphasizing the role of set and setting. These interventions