Translating Molecular and Neuroendocrine Findings in PTSD

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Translating Molecular and Neuroendocrine Findings in Posttraumatic Stress Disorder and Resilience to Novel Therapies Supplemental Information

Table S1. Extended summary of candidate PTSD pharmacotherapies

Treatment Target Rationale for use in Effect Status Reverse Translation Engagement PTSD Size SSRIs (1, 2) Serotonergic M ainly to treat 0.48 A Perhaps PTSD involves (several 5-HT comorbid symptoms; diminished capacity to receptors) perhaps PTSD involves downregulate 5-HT1B receptors; diminished capacity to alterations of serotonergic downregulate 5-HT1B receptors in the amygdala; receptors connection of serotonin, trauma, MANUSCRIPT and hippocampal volume Venlafaxine (2) Monoaminergic Treatment of 0.48 B Not thoroughly investigated (serotonergic, symptoms overlapping norepinephrinergic) with depression; adrenergic involvement Trazodone (2) Monoaminergic I mprove sleep n/a B, but Not thoroughly investigated (5-HT2; alpha-1 disturbance may for antagonist) improve symptoms comorbid insomnia only Atypical Dopaminergic treat psychotic-like 0.1-0.41 C Not thoroughly investigated Antipsychotics (2) (D2 antagonism)ACCEPTED symptoms Benzodiazepines GABAergic treat anxiety 0.28 C Alterations of GABA (2) (GABA-A positive receptors allosteric modulator)

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Treatment Target Rationale for use in Effect Status Reverse Translation Engagement PTSD Size Clonidine/ Adrenergic Reduction of -0.08 C Modest effects suggest that Guanfacine (3-5) (alpha-2-agonist) hyperadrenergic PTSD symptom improvement activity may additionally require manipulation of other targets Prazosin (2, 6-8) Adrenergic Reduction of 0.78 C Specific effects on nightmares (alpha-1-antagonist) hyperadrenergic and sleep suggest these activity symptoms are underpinned by noradrenergic dysregulation Propranolol (9-11) Adrenergic Reduction of n/a C Modest effects in preventing (beta-2-antagonist) hyperadrenergic consolidation of aversive activity with the memories in PTSD compared to specific intent of robust effects in preclinical blocking studies highlights gap in reconsolidation of fear translatability of fear models to memory; possible PTSD treatment prophylactic MANUSCRIPT immediately after trauma Topiramate (12) GABAergic? Use of other 1.20 C Stress-activated limbic (voltage-gated anticonvulsants in kindling effect of PTSD sodium channels, refractory PTSD; avoid voltage-activated side effects seen with calcium channels, SSRIs GABA-A, AMPA) Typical Monoaminergic treat psychotic-like n/a C Not thoroughly investigated Antipsychotics (2) (5-HT2A symptoms antagonism, fast D2 dissociation, 5ACCEPTED- HT1A agonism)

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Treatment Target Rationale for use in Effect Status Reverse Translation Engagement PTSD Size Mirtazapine Monoaminergic successful treatment 0.27 C-D Not thoroughly investigated (13, 14) (Adrenergic, of other anxiety and antihistamine) sleep disorders Yohimbine (15) Adrenergic Since this n/a D Intrusive and hyperarousal (alpha-2-antagonist) medication induces symptoms may be underpinned flashbacks it may by noradrenergic dysregulation; enhance arousal during enhancing these symptoms in exposure therapy, psychotherapy do not promote facilitating extinction symptom reduction learning Bupropion (16) Monoaminergic SSRIs have been 0.21 D Not thoroughly investigated (dopaminergic, helpful but have more norepinephrinergic) side-effects than Bupropion Gabapentin Anxiety Reduction of anxiety n/a D Not thoroughly investigated symptoms, after trauma to prevent MANUSCRIPT mechanism PTSD; decrease unknown (voltage comorbid symptoms gated calcium such as alcohol use, channel) sleep disorder, which may contribute to PTSD severity Nefazodone (17) Monoaminergic Anxiolytic helpful n/a D1 Not thoroughly investigated (5-HT2; alpha-1 with sleep without side antagonist) effect burden of SSRIs MAOIs (2) Monoaminergic antidepressant 0.21 D1 Not thoroughly investigated ACCEPTEDeffects TCAs (2) Monoaminergic antidepressant 0.36 D1 Not thoroughly investigated effects

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Treatment Target Rationale for use in Effect Status Reverse Translation Engagement PTSD Size Riluzole (16, 18) Glutamatergic; because of anti- n/a E Not specific to PTSD, but in GABAergic; glutamatergic (NMDA) GAD, correlation between excitotoxic target, trialed in other improvement in anxiety pathways, anxiety disorders with symptoms and increase in mitochondrial some signal hippocampal volume function, fat metabolism, sodium channel function, calcium-dependent potassium currents (VGNC, kainate and NMDAR, GABA-A receptors) buprenex/vivitrol Opiate (kappa Observation that n/a E1 Development of KOR PET (19, 20) opioid receptor patients self-medicate radiotracer which lead to finding antagonist) with opioids to MANUSCRIPT that KOR in ventral striatal alleviate PTSD circuit involved in trauma- symptoms; preclinical related dysphoria, perhaps data demonstrating mediated by HPA improved behavioral responses to stress Hydrocortisone HPA axis enhancement of n/a E1 Elevated or diminished levels (21) synthetic hormone reduced glucocorticoid of glucocorticoids during a replacement signaling to improve critical window immediately stress response following trauma may cause immediately following permanent cytoarchitectural trauma to prevent changes which contribute to ACCEPTEDPTSD; may have pathophysiology effects on memory reconsolidation

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Treatment Target Rationale for use in Effect Status Reverse Translation Engagement PTSD Size Hydrocortisone- HPA axis facilitation of n/a E1 Hydrocortisone may diminish augmented exposure- synthetic hormone extinction, therapeutic fear during reactivation of therapy (22) administration prior reconsolidation memory which allows patient to to exposure sessions more meaningfully engage material Pregnenolone (23) GABAergic, Low levels of the n/a E1 Trials still underway unknown (GABA- hormone observed in A; downstream PTSD; GABA-A targets of steroid receptors metabolites) downregulated in chronic stress Neuropeptide Y HPA axis; regulates HPA axis, n/a E1 Trials still underway (24) neurogenesis may contribute resilience during uncontrollable stress; levels found to be low MANUSCRIPT in PTSD Ketamine Glutamatergic observational studies n/a E1 Glutamatergic pathway in (25, 26) system; dendritic that patients who PTSD still under investigation, spine? (NMDA received ketamine after but likely related to the effect of receptor antagonist) trauma may have a chronic stress on learning and lower incidence of memory; ketamine may rapidly PTSD promote neuroplasticity in PTSD

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Treatment Target Rationale for use in Effect Status Reverse Translation Engagement PTSD Size MDMA-assisted Creation of ideal Fostering trust in the 0.8-2.8 E1 Probing the pathway of psychotherapy setting for a therapeutic alliance, opening/closing of critical (27, 28) psychotherapeutic maintaining optimal periods of plasticity experience that leads arousal during memory to meaningful re- retrieval and appraisal of trauma reconsolidation, feelings of self- compassion 7-Keto DHEA HPA axis/GABA- DHEA may promote n/a E1 Results of trial not yet (29) A antagonist, resilience after trauma published positive NMDA modulation, metabolizes cortisol Pregabalin Glutamatergic Has been helpful in n/a E1 Plan is to probe (voltage-gated alcohol use disorder endophenotype with genetic calcium channel that plus GAD in the past MANUSCRIPT variant glutamate transporter modulates glutamate so may be helpful for transporter 1) GAD plus PTSD; case reports of adjunctive pregabalin ameliorating PTSD symptoms GSK561679 HPA axis PTSD 0.277 in E1 Towards development of (Verucerfont) (CRF-1 antagonist) endophenotype with child abuse endophenotypes and (30) exposure to child abuse NR3C1 personalized medicine and also have a SNP of methyl- the receptor gene have ation group CRF1 receptor ACCEPTEDhyperactivity/ suppresses ACTH response to stress

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Treatment Target Rationale for use in Effect Status Reverse Translation Engagement PTSD Size Methylene blue Stimulates enhance extinction n/a E1 Trials still underway (+imaginal exposure) mitochondrial learning (31) oxidative metabolism and cerebral oxygen consumption; enhances memory consolidation/ extinction D-cycloserine- Glutamatergic? Induce LTP during 0.61 E1 Relevance of NMDA- assisted exposure (NDMA agonist) therapy and enhance mediated learning and plasticity therapy extinction of memory during exposure therapy (32) Oxytocin Glucocorticoid; reduced intensity of n/a E1 Oxytocin receptor methylation (33) social bonding fear memory by may be implicated in (oxytocin receptors; decreasing amygdala MANUSCRIPT pathophysiology; Oxytocin’s increase social activation; increased role in critical period plasticity, cognition/feelings of pro-social behavior regulation of HPA system in closeness) lacking in PTSD PTSD; may mediate social cognition deficits in PTSD Cannabidiol Endocannabinoid patients have n/a E1 Involvement of the ECB (34, 35) (inhibition of the increased CB1 system in the expression of uptake or of the receptors which may be contextual fear conditioning; a enzymatic caused by a chronic potential new target in the degradation of deficiency of the adenosinergic system endocannabinoids) endocannabinoid AEA CB1 agonist Endocannabinoid enhance fear n/a E1 Trials still underway (Nabilone) ACCEPTEDextinction via endocannabinoid system

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Treatment Target Rationale for use in Effect Status Reverse Translation Engagement PTSD Size Nitrous Oxide Consolidation of may block n/a E1 Research still preliminary (36, 37) memories; NMDA; consolidation of kindling (? NMDA) memories after trauma; some preclinical evidence of role of NO as mediator of stress and hippocampal degeneration and cognitive deficits SRX246 HPA axis/parvo- preclinical and n/a E1 Involvement of AVPR1a (38) cellular preliminary clinical signaling involvement in circuits vasopressinergic data suggesting relevant to processing aversive (vasopressin V1A antagonist may correct social and emotional receptor antagonist) a dysregulation of information vasopressinergic signaling in stress -MANUSCRIPT related illnesses Doxazosin Adrenergic same mechanism as n/a E1 Still in trials (39) (alpha-1 antagonist) prazosin but once daily dosing, less hypotension TNX-102/Tonmya Monoaminergic sleep disturbance n/a E1/ E2 Meaningful improvement at (Cyclobenzaprine) (5-HT2A may lead to week 4, but this signal never (40) antagonism, alpha 1 development and further examined to investigate antagonist, maintenance of other underlying mechanism histamine PTSD symptoms antagonism) ACCEPTED

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Treatment Target Rationale for use in Effect Status Reverse Translation Engagement PTSD Size Mifepristone HPA axis may restore n/a E2 Modest effects in relation to (41, 42) GR type-2 receptor homeostasis to cognition suggest HPA antagonist alterations in HPA axis involvement in cognitive aspects seen in PTSD through of PTSD elevation in cortisol and ACTH, resulting in recalibration of axis Tiagabine GABAergic perhaps correct n/a E2 Some signal in symptom (43, 44) (selective GABA PTSD deficits in reduction perhaps helped reuptake inhibitor) GABA signaling confirm GABA involvement Orvepitant Substance P/ substance P- n/a E2 Potential to dissect and clarify (GW823296) tachykinin pathway neurokinin1 involved role of substance P/tachykinin (45) (tachykinin receptor in experimental models pathway in PTSD 1) of stress, fear, reward; substance P elevated in PTSD CSF MANUSCRIPT Ganaxolone GABAergic previous data n/a E2 Likely role for neuro-steroids (synthetic analog of (GABA-A positive indicating neuroactive in pathophysiology, but still allopregnanolone) allosteric modulator) steroids with GABA-A unclear; perhaps endophenotype (46) activity involved in pathophysiology of PTSD BNC210 Nicotinic anti - inflammatory n/a E2 Anxiolytic without cognitive (47) (α7-nicotinic or sedating effects of acetylcholine benzodiazepines receptor negative allosteric modulator)ACCEPTED

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Treatment Target Rationale for use in Effect Status Reverse Translation Engagement PTSD Size Nepicastat (48) Adrenergic r educe the elevated n/a E2 Clarifying an endophenotype (inhibitor of NE activity in PTSD and its treatment response dopamine-β- and therefore reduce hydroxylase) PTSD hyper-arousal symptom Sirolimus Protein Synthesis i nhibit mTOR to n/a E2 Traumatic memories that are (49) (mTOR inhibitor) alter amygdala and more recent may be less hippocampal dendritic entrenched and therefore arborization during possibly more possible to change exposure to modify reconsolidation of traumatic memory Neurokinin 1 Substance substance P- 0.22 E2 Signal for substance P- antagonist P/tachykinin neurokinin1 involved neurokinin system involvement (GR205171) pathway (tachykinin in experimental models in at least hyperarousal (50) receptor 1) of stress, fear, reward; MANUSCRIPT symptoms substance P elevated in PTSD CSF SNC-102 (51, 52) Glutamatergic, n/a n/a E2 None-data never published GABAergic (co-agonist of NMDA receptors)

Note: Applying VA/DoD guidelines (53) and clinical usage data from a recent review (54): A=FDA Approved; B = Not approved but VA/DoD guidelines support use; C = Used clinically but not recommended in guidelines; D = Use is not common practice; D1 = Guidelines recommend, but not commonly used; E1 = Experimental use/Active trials; E2 = Experimental use/Failed trials. ACCEPTED

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