





































Berkeley
Pharma Tech
Journal of Medicine

Correspondence:
jpopovich@luc.edu

Keywords:
PTSD, Post-traumatic stress disorder, 
hyperbaric oxygen therapy, 
stem cell therapy, 
stellate ganglion block, 
topiramate, immunotherapy

Submitted: December 11, 2022 
Accepted: January 27, 2023 
Published: June 30, 2023

Full Open Access

Creative Commons Attribution 
License 4.0

Abstract
Post-traumatic stress disorder (PTSD) is a psychological disorder that 
affects about 12 million Americans every year. The main treatments for 
PTSD are selective serotonin reuptake inhibitors (SSRIs) and serotonin 
and norepinephrine reuptake inhibitors (SNRIs). Although SSRIs have 
been shown to produce a response rate of about 60% in patients with 
PTSD, the complete remission rate is only about 20% to 30%. The SSRIs 
sertraline and paroxetine hydrochloride are the only two FDA-approved 
PTSD treat-ments, though they are highly outdated. PTSD is a widely 
misunderstood disorder that extends far beyond its classification as 
solely a psychiatric disorder. PTSD has been correlated with elevated 
levels of gene expression, an overactive immune system, and elevated 
levels of norepinephrine (NE), all of which contribute to physical and 
psychological symptoms. This systematic review aims to evaluate novel 
therapeutic approaches which can be used in concert with psychotherapy 
to further improve the symptoms of PTSD compared to current 
treatments.

Novel Therapies for Post-Traumatic 
Stress Disorder: A Systematic Review

By: Jillian Popovich, Atoosa Heidari-Bigvand, Emma Son and Vanloan Nguyen



 Introduction 

 1.1  Post-Traumatic Stress Disorder 

 Post-traumatic  stress  disorder  (PTSD)  is  a  psychological  disorder  that 
 people  often  experience  after  a  traumatic  event,  including  but  not  limited  to 
 sexual  assault,  combat,  child  abuse,  and  natural  disasters  1  .  The  psychological 
 response  to  enduring  this  type  of  event  is  not  solely  panic.  The  most 
 common  lasting  e�ects  include  insomnia,  hyperarousal  and  hypervigilance, 
 panic  attacks,  night  terrors,  depression,  anxiety,  and  physical  pain  2  .  The  �rst 
 line  of  treatment  for  these  symptoms,  once  a  diagnosis  has  been 
 documented,  is  the  use  of  selective  serotonin  reuptake  inhibitors  (SSRIs) 
 and  serotonin  and  norepinephrine  reuptake  inhibitors  (SNRIs)  along  with 
 psychotherapy and harmful benzodiazepines  2  . 

 The  pathophysiology  of  PTSD  is  complex  and  includes  several 
 neurobiological  systems.  The  hypothalamic-pituitary-adrenal  (HPA)  axis  is 
 a  focus  of  PTSD  research  because  of  the  involvement  of  the 
 neurotransmitters  in  associated  pathways  1  as  well  as  the  decreased 
 hypothalamus  size  commonly  associated  with  PTSD.  The  HPA  axis  is  an 
 intricate  neuroendocrine  pathway  responsible  for  the  stress  response  and  the 
 link between the CNS and endocrine system  1  . 

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 1.2  Current Interventions for PTSD 

 The  interventions  approved  for  PTSD  show  low  success  rates  compared  to 
 more  novel  therapeutic  approaches.  These  are  commonly  prescribed 
 simultaneously  with  psychotherapy,  exposure  therapy,  or  cognitive 
 processing therapy (CPT)  3  . 

 1.3  Novel Therapeutic Approaches 

 Novel  therapeutic  approaches  that  have  been  proven  to  be  e�ective  are 
 greatly  underutilized  in  part  because  they  are  not  FDA-approved  for  PTSD 
 treatment,  meaning  that  many  of  these  promising  treatments  are  o�-label. 
 O�-label  use  of  medication  complicates  access  for  individuals  looking  for 
 therapy  as  the  medication  or  treatment  is  often  much  more  expensive.  With 
 the  expense  of  o�-label  medication  and  the  limited  FDA-approved 
 treatments, individuals with PTSD are limited in their options. 

 Hyperbaric  oxygen  therapy  (HBOT)  is  an  approach  that  is  often  used  for 
 healing  large  wounds.  HBOT  has  recently  been  tested  on  individuals  with 
 PTSD  without  a  history  of  traumatic  brain  injury  (TBI)  4  .  Among  other 
 brain  structures,  HBOT  has  been  found  to  improve  hippocampal  activity 
 which  is  responsible  for  fear  extinction,  a  process  those  with  PTSD  often 
 exhibit  lower  levels  of.  HBOT  can  also  improve  mitochondrial  function, 
 induce hyperoxia, and assist in resurfacing memories for those with trauma  4  . 

 Stellate  ganglion  blocks  (SGBs)  are  injections  of  local  anesthetic,  commonly 
 lidocaine  or  ropivacaine,  inserted  into  the  stellate  ganglion  nerve  bundle. 
 Studies  have  indicated  several  immediate  e�ects  of  SGBs,  most  notably 
 reduced hyperarousal related to the oversensitive �ght-or-�ight response  5  . 

 Stem  cell  therapy  for  PTSD  only  has  one  in  vitro  study  testing  the  e�cacy 
 of  the  treatment,  conducted  with  rats  6  .  Though  the  research  is  limited,  the 
 use  of  stem  cell  transplantation  for  reducing  the  symptoms  of  PTSD  is 
 promising and warrants further research. 

 No  controlled  clinical  studies  have  been  completed  to  evaluate  the  e�cacy 
 of  immunotherapy  for  PTSD  speci�cally  7  .  Still,  research  has  been 
 conducted  in  pain  management  clinics  to  track  the  results  and  correlation 
 between  physical  pain  from  an  overactive  immune  system  and  the  severity  of 

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 the  psychological  e�ects  of  PTSD  7  .  The  use  of  glucocorticoids  and  other 
 non-steroidal  anti-in�ammatory  drugs  (NSAIDs)  aims  to  reduce  pain,  and 
 in  PTSD  patients,  the  severity  of  the  psychological  symptoms  is  remediated 
 along with physical pain when treated with anti-in�ammatory drugs  7  . 

 Topiramate  is  an  anticonvulsant  commonly  used  for  epileptic  seizures  and 
 migraines.  Though  its  widespread  use  is  for  neurological  disorders,  it  has 
 also  been  shown  to  be  e�ective  for  psychological  disorders  such  as  PTSD 
 and alcohol use disorder (AUD)  8  by acting as a GABA agonist. 

 1.4  Mechanisms of Interventions 

 The  mechanism  of  hyperbaric  oxygen  therapy  and  its  therapeutic  e�ects 
 have  been  the  focus  of  research  now  more  than  ever  since  HBOT’s  �rst  use 
 in  1662.  HBOT  works  to  induce  hyperoxia  by  forcing  100%  oxygen  into  the 
 bloodstream  and  surrounding  cells  4  instead  of  the  22%  oxygen  that  is 
 normally  perfused  under  standard  atmospheric  conditions.  The  unusual 
 hyperbaric  pressure  of  100%  oxygen  on  cells  can  activate  or  deactivate  both 
 oxygen-sensitive  and  pressure-sensitive  genes,  which  can  lead  to  the  e�ective 
 regulation  of  gene  expression  and  inhibition  of  more  damage  by  PTSD  4  . 
 The  elevated  levels  of  dissolved  oxygen  in  body  tissues  contribute  to  restored 
 mitochondrial  function,  proliferation  and  maturation  of  neural  stem  cells, 
 and  increased  neuroplasticity  multiple  years  after  injury  4  .  It  also  works  to 
 promote  anti-in�ammatory  biological  properties.  HBOT  has  been  used  as  a 
 treatment  for  a  variety  of  disorders  and  has  shown  to  be  e�ective  in  many 
 di�erent  aspects.  However,  a  main  risk  of  HBOT  is  oxygen  toxicity  8  . 
 Neurological  status  must  be  observed  throughout  the  course  of  treatment 
 because  of  this  possibility.  Oxygen  toxicity  induced  by  HBOT  can  manifest 
 in  several  ways  such  as  tonic-clonic  convulsions  or  oxidative  cellular 
 damage  8  . 

 A  stellate  ganglion  block  is  a  single  injection  of  local  anesthetic  into  the 
 stellate  ganglion  nerve  bundle  in  the  cervical  spine.  This  location  in  the 
 cervical  sympathetic  trunk  has  been  described  as  an  “anatomical  funnel” 
 because  it  allows  the  passage  of  all  sympathetic  nerve  �bers  that  lead  to  the 
 thorax  as  well  as  to  structures  of  interest  in  the  neck  and  head  5  .  These 
 ganglia  provide  a  connection  to  the  central  nucleus  of  the  amygdala  and 
 hypothalamus,  two  of  the  main  nervous  structures  altered  by  PTSD.  The 

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 SGB  injection  aims  to  block  the  typical  hyperarousal  during  the 
 �ght-or-�ight  response  and  other  high-stress  situations  5  .  The  mechanism  by 
 which  SGBs  function  is  still  unknown,  though  it  may  indirectly  work  by 
 altering  levels  of  norepinephrine  (NE)  in  the  brain  5  .  Norepinephrine  is  a  key 
 neurotransmitter  in  the  hyperarousal  and  hypervigilance  observed  in 
 individuals  with  PTSD.  NE  �oods  the  brain  when  signals  arrive  in  response 
 to  sympathetic  stimulation  and  increases  the  heart  rate,  alertness,  arousal, 
 and  amount  of  energy  available  to  the  body.  This  further  contributes  to  the 
 stress response reported by those with PTSD. 

 Topiramate  is  typically  used  as  an  anticonvulsant  medication  though  it  has 
 recently  been  tested  for  its  e�cacy  in  reducing  PTSD  symptoms  9  . 
 Topiramate  is  an  agonist  of  GABA,  an  inhibitory  neurotransmitter  involved 
 in  creating  inhibitory  postsynaptic  potentials  (IPSPs).  Another  notable  fact 
 is  that  topiramate  blocks  glutamate  binding  8  .  Glutamate  is  an  excitatory 
 small-molecule  neurotransmitter  that  increases  action  potential  �ring  when 
 it  binds  to  ligand-gated  receptors  kainate  and  AMPA.  Dysregulation  of 
 AMPA  receptors  (AMPARs)  can  in�uence  mental  health  and  its  e�ects  10  . 
 AMPARs  are  dynamic  and  changes  in  the  quantity  of  AMPAR  at  a  synapse 
 alter  the  e�cacy  of  neurotransmitters  completing  synaptic  transmission  10  . 
 Kainate  receptors,  which  share  a  similar  structure  and  function  with  AMPA 
 receptors,  partly  make  up  nociceptive  signaling  pathways  11  .  Kainate  receptor 
 antagonists  that  target  a  single  subunit  (GluK1)  have  been  shown  to 
 produce  analgesic  e�ects  for  migraines,  indicating  their  potential  use  for 
 other  painful  chronic  disorders  11  .  Their  stimulation  not  only  leads  to 
 chronic  pain  but  also  increased  severity  of  PTSD  symptoms.  Because 
 topiramate  inhibits  glutamate  signaling,  learning  and  memory  function  are 
 often  transiently  impaired.  Over  the  duration  of  treatment,  however,  this 
 impairment is nearly restored  9  . 

 Immunotherapy  as  an  intervention  for  PTSD  is  not  common  practice.  The 
 research  done  on  this  topic  related  to  PTSD  is  extremely  limited  and  no 
 relevant  controlled  clinical  trials  have  been  conducted.  Because  PTSD  is 
 classi�ed  as  a  psychological  disorder,  the  main  symptoms  that  are 
 well-de�ned  are  behavioral  and  psychological,  not  physical.  Many 
 individuals  with  PTSD  exhibit  elevated  levels  of  several  in�ammatory 
 markers  such  as  C-reactive  protein  (CRP),  tumor  necrosis  factor-α,  and 

 Berkeley Pharma Tech Journal of Medicine |  30 



 interleukin-6  10  .  Additionally,  autoimmune  disorders  are  often  comorbid 
 with  PTSD.  Though  numerous  factors  can  contribute  to  in�ammation,  the 
 elevated  levels  of  in�ammatory  markers  indicate  a  correlation  between 
 PTSD  and  the  immune  system.  Since  in�ammation  can  alter  neural  circuits 
 in  brain  regions  that  regulate  emotions  such  as  anxiety  and  fear,  a 
 hyperactive  immune  system  causing  in�ammation  can  have  a  detrimental 
 e�ect  on  those  with  PTSD  10  .  However,  glucocorticoids  and  NSAIDs  have 
 been  shown  to  indirectly  reduce  PTSD  symptom  severity  through  pain 
 relief,  providing  a  basis  for  further  research.  Aiming  to  reduce 
 in�ammation,  which  can  restore  neural  circuits  and  neurotransmitter 
 activity  to  normal  levels,  can  help  regulate  the  stress  response  and  overall 
 severity of symptoms  10  . 

 Stem  cell  therapy  is  a  therapeutic  approach  that  is  being  investigated  for 
 several  di�erent  disorders,  both  physical  and  psychological.  For  PTSD,  there 
 has  been  one  study  with  stem  cells  di�erentiated  in  vitro  that  investigated 
 the  use  of  induced  human  pluripotent  stem  cells  di�erentiated  into  neural 
 progenitor  cells  (iPSC-NPCs)  6  .  The  iPSC-NPCs  are  di�erentiated  in  a 
 laboratory  before  being  transplanted  into  the  rat  model  brain.  Once  they  are 
 transplanted  as  neural  progenitor  cells,  symptom  severity  can  be  evaluated 
 throughout  the  course  of  treatment.  As  cells  mature  in  the  brain,  they  can 
 reverse  hippocampal  tissue  damage,  promote  regeneration,  and  induce 
 motor  function  recovery  in  rat  models  of  PTSD  6  .  Adapted  assessments  were 
 performed  on  the  rat  models  that  showed  similar  responses  to  stimuli  as 
 humans  with  PTSD.  At  the  end  of  treatment,  it  was  found  that  iPSC-NPCs 
 can  reduce  symptom  severity,  speci�cally  the  fear  response,  and  reverse  the 
 physical neural damage that PTSD causes  6  . 

 1.5  Outcomes 

 The  clinician-administered  PTSD  scale  for  DSM-5  (CAPS-5)  is  a  30-item 
 interview  that  can  give  clinicians  and  clinical  researchers  more  information 
 about  an  individual’s  past  history  of  PTSD,  present  symptoms,  symptom 
 severity,  and  more  12  .  Questions  aim  to  assess  the  impact  of  PTSD  symptoms 
 on  daily  activities,  including  one’s  social  and  occupational  life.  The  scale  can 
 also  classify  a  subject  within  the  dissociative  subtype  as  well  as  assess  the 
 overall  PTSD  severity  and  symptom  improvement  12  .  For  the  studies 

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 included  in  this  review,  the  CAPS-5  is  a  common  outcome  used  to  evaluate 
 the  e�cacy  of  an  intervention.  Another  outcome  assessment  includes  the 
 brief  symptom  inventory-18  (BSI-18)  which  questions  the  subject  on  three 
 symptom  scales:  depression,  anxiety,  and  somatization.  Furthermore,  the 
 Beck  Depression  Inventory-II  (BDI-II)  is  a  widely  used  and  accepted 
 psychometric  test  to  assess  the  severity  of  depression  in  a  subject  and 
 includes  21  multiple-choice  questions  along  with  a  self-reported  inventory 
 about  recent  feelings,  emotions,  and  well-being  13  .  In  addition  to  these  tests, 
 several  imaging  techniques  were  used  including  fMRI  and  di�usion  tensor 
 imaging-fractional  anisotropy  (DTI-FA),  which  evaluates  the  white  matter 
 microstructures  in  the  brain.  For  non-imaging  tests,  higher  scores  are 
 associated  with  more  severe  symptoms  12  .  What  warrants  signi�cant  changes 
 in  CAPS-5  scores  changes  with  the  study,  though  it  is  commonly  a  change 
 of 10 points that indicates signi�cant improvement or deterioration. 

 1.6  Objective 

 The  objective  of  this  paper  is  to  qualitatively  analyze  the  e�cacy  of  these  �ve 
 interventions  for  PTSD.  This  analysis  is  based  on  several  clinical  trials, 
 randomized control trials, in vivo and in vitro studies, and one review paper. 

 1.7  Method 

 This  systematic  review  follows  the  standard  principles  for  search  strategies. 
 A  comprehensive  search  using  PubMed  was  performed  on  September  16th, 
 2022.  Another  search  was  performed  on  October  12th,  2022  to  ensure  that 
 all  relevant  articles  are  being  utilized.  This  search  included  published 
 manuscripts  and  abstracts.  The  two  abstracts  provided  useful  information 
 pertaining  to  these  therapeutic  approaches,  warranting  their  inclusion.  The 
 PubMed  search  included  the  following  terms:  post-traumatic  stress 
 disorder[MeSH],  PTSD[MeSH],  stellate  ganglion  block[MeSH], 
 hyperbaric  oxygen  therapy[MeSH],  topiramate[MeSH], 
 immunotherapy[MeSH],  and  stem  cell[MeSH].  The  Boolean  operator  used 
 in  these  search  terms  is  ‘and’.  Included  are  all  primary  research  studies  that 
 are  published.  There  are  �ve  interventions  with  both  in  vivo  and  in  vitro 
 studies  being  considered.  All  included  studies  are  relevant  to  the  topic  and 
 published  in  English.  This  systematic  review  is  from  the  latest  studies 
 published  related  to  PTSD  and  its  interventions.  Each  study  is  screened  by 

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 two  group  members.  The  key  elements  of  the  study  design  were  assessed 
 and  reported  for  each  study,  including  clinical  trials,  randomized  clinical 
 research  studies,  and  in  vivo  studies.  The  snowballing  technique  was  also 
 used  to  acquire  additional  articles  through  citations  in  previously  included 
 articles. 

 After  applying  the  search  strategy  stated  above,  9  stem  cell  studies,  3  stellate 
 ganglion  block  studies,  1  topiramate  study,  1  immunotherapy  study,  and  11 
 hyperbaric  oxygen  therapy  studies  were  found.  After  applying  the  snowball 
 technique,  14  studies  have  been  included  in  this  paper  based  on  relevance 
 and  inclusion  criteria.  This  includes  1  stem  cell  study,  1  immunotherapy 
 study,  6  stellate  ganglion  block  studies,  4  hyperbaric  oxygen  therapy  studies, 
 and  2  topiramate  studies.  Endpoints  include  the  e�ects  of  hyperbaric 
 oxygen  therapy,  stellate  ganglion  blocks,  topiramate,  immunotherapy,  and 
 stem cell therapy on PTSD symptoms severity. 

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 Results 

 2.1  Hyperbaric Oxygen therapy 

 A  US  military-sponsored,  randomized  clinical  trial  was  conducted  in  2018, 
 testing  the  e�ects  of  hyperbaric  oxygen  therapy  (HBOT)  on  71  participants 
 with  PTSD  and/or  a  traumatic  brain  injury  (TBI)  14  .  The  participants  were 
 randomized  to  either  the  treatment  group  (n=36)  or  the  sham  group 
 (n=35),  and  at  baseline,  49%  of  participants  met  PTSD  criteria.  The  primary 
 outcome  of  this  study  was  the  Neurobehavioral  Symptom  Inventory  which 
 was  assessed  at  baseline,  13  weeks,  and  six  months,  in  addition  to  several 
 other indicators of PTSD symptom severity and neurocognitive tests  14  . 

 This  study  administered  daily  one-hour  sessions,  5  days  a  week,  for  40 
 sessions  total.  The  treatment  group  received  >99%  oxygen  at  1.5  atmosphere 
 absolute  (ATA)  while  the  sham  group  received  regular  air  at  1.2  ATA  (25% 
 oxygen). The sessions were completed within 12 weeks. 

 The  participants  in  the  HBOT  group  were  all  older  with  more  combat 
 deployments,  exhibiting  worse  anger  control  and  more  frequent  traumatic 
 axonal  injury  14  .  Though  these  may  indicate  that  the  treatment  group 
 encountered  worse  brain  injuries,  the  baseline  post-concussive  and  PTSD 
 symptom  scores  were  similar  to  the  sham  group.  The  Rivermead 
 Post-Concussion  Symptom  Questionnaire  (RPQ)  total,  RPQ-13,  and 
 PTSD  Checklist-Civilian  Version  hyperarousal  scores  showed  more  severe 
 symptoms in the treatment group at baseline  14  . 

 At  13  weeks,  univariate  and  longitudinal  analysis  was  used  to  assess 
 symptoms  based  on  the  outcomes.  The  RPQ-3  domain,  which  includes 
 headaches,  dizziness,  and  nausea,  was  improved  compared  to  the  sham 
 group  (p=0.01).  The  Neurobehavioral  Symptoms  Inventory  total  score  and 
 a�ective  domain  change  scores  indicated  success  in  the  treatment  group 
 compared  to  the  sham  group,  but  only  using  univariate  testing.  At  13  weeks, 
 several  tests  indicated  an  improvement  in  anger  subscores  with  both 
 univariate  and  longitudinal  assessment  but  the  results  were  not  statistically 
 signi�cant  14  .  Additionally,  at  13  weeks  and  6  months,  19  out  of  36 
 participants  in  the  HBOT  group  reported  feeling  the  bene�ts  of  HBOT 
 versus  10  out  of  33  participants  from  the  sham  group.  At  6  months,  19 

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 participants  from  HBOT  and  �ve  participants  from  the  sham  group 
 reported  the  same  e�ect.  Other  neuropsychological  tests  were  performed, 
 with  improvements  for  the  HBOT  group  at  13  weeks,  but  most  did  not 
 reach  statistical  signi�cance.  However,  the  sham  group  never  exhibited 
 statistically  signi�cant  results  in  any  total  or  subscore  assessments  at  13 
 weeks  14  .  With  all  of  these  analyses,  participants  who  had  PTSD  had  larger 
 improvements  than  those  without  PTSD.  Furthermore,  participants 
 without  PTSD  had  no  signi�cant  improvements  in  both  the  treatment  and 
 control groups  14  . 

 This  indicates  that  HBOT  may  work  better  as  a  treatment  for  PTSD  as 
 opposed  to  TBI.  By  6  and  12  months,  any  distinct  di�erences  between 
 groups  had  diminished,  with  improvements  at  six  months  no  longer  being 
 signi�cant  as  they  were  at  13  weeks.  Both  post-concussive  and  PTSD 
 symptoms  were  worse  at  12  months  post-HBOT  compared  to  baseline  for 
 participants  in  both  groups.  HBOT  participants  improved  on  six  out  of 
 seven  California  Verbal  Learning  Test-II  subtests  compared  to  the  sham 
 group  at  13  weeks,  and  two  subtests  reached  statistical  signi�cance  in 
 univariate  and  longitudinal  assessments.  By  6  months,  most  score 
 di�erences  between  groups  were  no  longer  statistically  signi�cant.  Sleep 
 issues  within  the  HBOT  participants  exhibited  improvement  at  13  weeks, 
 but  the  results  between  groups  were  not  signi�cant.  Both  groups  also 
 reported  improved  sensory  organization  scores.  In  addition  to  these 
 outcomes,  participants  with  PTSD  who  received  HBOT  were  able  to  walk 
 further in the six-minute walk test after treatment at 13 weeks  14  . 

 These  results  indicate  that  HBOT  may  be  better  utilized  as  a  treatment  for 
 PTSD  rather  than  post-concussive  symptoms  or  TBI  symptoms. 
 Furthermore,  this  study  exhibits  �ndings  that  support  long-term  treatment 
 of  HBOT  to  keep  symptoms  reduced  for  longer.  Though  many  of  the 
 �ndings  were  not  statistically  signi�cant,  those  with  PTSD  showed  more 
 improvement  than  participants  without  the  disorder,  warranting  further 
 research  on  the  use  of  HBOT  for  PTSD.  This  study  was  quite  small  with 
 about an equal number of participants in both groups. 

 Additionally,  all  of  the  participants  were  military  personnel  which  limits 
 generalizability  to  other  populations  of  individuals  with  PTSD.  Further 

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 analysis  needs  to  be  done  on  HBOT  for  PTSD  because  of  the  lack  of 
 statistical  signi�cance  in  this  study  though  it  did  show  to  alleviate  PTSD 
 symptoms more than TBI symptoms. 

 A  randomized  case-control  study  published  in  2022  completed  a  hyperbaric 
 oxygen  therapy  study  on  29  veterans  with  PTSD  4  .  Compared  to  the  control 
 (n=15),  the  treatment  group  (n=14)  showed  signi�cant  improvement  in 
 CAPS-5  scores  by  the  end  of  the  trial.  The  study  focused  on  male  veterans 
 aged  25-60  who  had  treatment-resistant  PTSD  with  debilitating  symptoms 
 for at least four years prior. 

 Participants  underwent  baseline  evaluation  which  included  brain  imaging 
 and  psychological  interviews  by  clinicians.  The  participants  also  completed 
 an  evaluation  three  months  after  HBOT  or  control  exposure.  The  HBOT 
 was  administered  in  concert  with  the  subjects’  pre-trial  psychotherapy.  The 
 participants  underwent  60  daily  sessions,  �ve  days  a  week.  During  each 
 HBOT  session,  the  treatment  group  was  exposed  to  100%  oxygen  at  2  ATA 
 with a �ve-minute break every 20 minutes. 

 The  primary  objective  of  this  study  was  a  change  in  CAPS-5  score  compared 
 to  baseline  evaluations.  The  secondary  objective  included  the  BSI-18  and 
 BDI-II  questionnaires.  Other  outcomes  included  imaging  data  acquisition 
 which  measured  gradient-echo  blood  oxygen  level-dependent  contrast 

 Berkeley Pharma Tech Journal of Medicine |  36 



 sequences.  A  functional  task  design,  in  which  participants  had  to  perform  a 
 memory recall test, was also used to test their results. 

 Table  1  indicates  the  signi�cance  of  results  in  the  treatment  arm  (p<0.0001) 
 compared  to  the  control  group,  which  didn’t  improve  in  any  subscores  or 
 total  score  4  .  Similarly,  BSI  scores  (p=0.024)  as  well  as  BDI  scores  (p=0.01) 
 signi�cantly  improved  4  .  In  the  HBOT  group,  there  were  improvements  in 
 group-time  interactions  in  frontal  white-matter  �ber  bundles  that  connect 
 the  thalamus  and  frontal  lobe.  There  were  also  improved  clusters  found  in 
 parietal  white  matter  and  the  anterior  limb  of  the  internal  capsule  and 
 cerebral  peduncle.  The  same  patients  in  both  groups  were  used  for 
 task-related  functional  imaging,  and  there  were  no  signi�cant  functional 
 di�erences  between  the  fMRI  images  except  for  improved  activity  after 
 HBOT in several regions of the brain including the hippocampus  4  . 

 This  study  is  limited  by  its  size  with  only  35  randomized  patients. 
 Additionally,  there  was  no  blinding  for  either  group.  The  results  of  this 
 study  support  the  fact  that  HBOT  is  highly  e�ective  in  treating  PTSD 
 symptoms  based  on  CAPS  scores  and  brain  imaging.  There  is  evidence  that 
 this  treatment  should  be  more  widespread,  though  it  is  limited  by  the  fact 
 that  HBOT  is  a  historically  di�cult  treatment  to  be  covered  by  insurance 
 and  it  requires  specialized  physicians  to  perform  and  oversee  the  treatment. 
 Hyperbaric  oxygen  therapy  has  revealed  the  pressure-sensitive  and 
 oxygen-sensitive  genes  involved  in  the  etiology  of  PTSD.  These  genes  could 

 Berkeley Pharma Tech Journal of Medicine |  37 



 be  further  investigated  and  possibly  manipulated  with  gene  therapy,  though 
 this has not been done yet. 

 In  addition  to  these  trials,  an  observational  cohort  study  was  conducted  to 
 investigate  any  persistent  post-concussive  symptoms  (PCS)  in  participants 
 from  two  completed  United  States  military  trials  of  hyperbaric  oxygen 
 therapy  (HBOT).  Individual  changes  varied  widely,  ranging  from  -23  to 
 +28 points  15  .

 2.2  Stellate Ganglion Block 

 Stellate  ganglion  blocks  were  �rst  used  to  treat  PTSD  in  2010  16  .  They  have 
 been  used  to  treat  dysautonomia,  vasomotor  symptoms,  pain  in  the  upper 
 extremities,  and  most  recently,  psychiatric  disorders.  The  �rst  multisite, 
 randomized  clinical  trial  of  stellate  ganglion  block  e�ects  on  PTSD 
 symptoms  severity  was  published  in  February  2020  16  .  This  trial  pulled 
 participants  from  three  US  Army  Interdisciplinary  Pain  Management 
 Centers  which  included  active-duty  service  members  as  the  �rst  inclusion 
 criteria.  The  participants  were  randomized  2:1  to  a  sham  group  (n=39)  or 
 treatment  group  (n=74),  and  baseline  characteristics  were  similar  in  both 
 groups  based  on  mean  CAPS-5  scores  16  .  Participants  were  administered  a 
 right-sided  SGB  at  0  and  2  weeks,  and  they  were  assessed  at  0  and  8  weeks 
 post-injection.  The  injections  were  performed  using  ultrasonography.  7-10 
 mL  of  0.5%  ropivacaine  was  administered  to  the  treatment  group  and  the 
 sham  group  received  1-2  mL  of  normal  saline  at  the  same  anatomical 
 location,  the  C6  anterior  tubercle  16  .  Measures  were  taken  so  as  to  not 
 unblind  participants  due  to  the  di�erence  in  medication  and  medical 
 instruments,  and  conversations  were  scripted  for  medical  personnel  who 
 were not blinded. 

 The  primary  outcome  of  this  trial  was  a  decrease  in  CAPS-5  total  symptom 
 severity  scores  (CAPS-5  TSSS),  indicating  improvement.  This  assessment 
 ranges  from  0-80  points,  with  higher  scores  indicating  more  severe  PTSD 
 symptoms  and  a  10-point  change  per  individual  indicating  the  results  as 
 signi�cant and clinically meaningful  16  . 

 Berkeley Pharma Tech Journal of Medicine |  38 



 Table  2  highlights  the  overall  trend  of  improvement  for  the  treatment  arm  as 
 well  as  the  sham  group.  Though  both  groups  improved  by  some  amount, 
 the  treatment  group  had  a  greater  overall  decrease  in  symptom  severity 
 scores,  though  not  statistically  signi�cant.  However,  there  were  clinically 
 signi�cant  improvements  in  subsets  of  PTSD-symptom  assessments, 
 including but not limited to depression and distress  16  . 

 This  study  heavily  supports  the  use  of  SGB  injections  for  those  with  PTSD 
 as  a  way  to  signi�cantly  reduce  the  most  common  and  detrimental 
 symptoms  of  PTSD.  Limitations  of  this  study  include  unblinding  of  the 
 participants  in  the  treatment  arm  due  to  the  onset  of  Horner’s  syndrome. 
 This  is  a  side  e�ect  and  indication  of  a  successful  injection  in  which  there  is 
 a  disrupted  nerve  pathway  going  from  the  brain  to  the  face,  resulting  in  a 
 smaller  pupil  on  the  a�ected  side,  a  drooping  eyelid  (ptosis),  and  a  reduction 
 in  sweat  16  .  The  medical  personnel  performing  the  procedure  on  the 
 participants  were  also  unblinded  to  ensure  the  safety  of  the  participants, 
 though  their  interactions  were  limited  and  scripted.  Other  limitations 
 include  generalizability,  as  this  study  only  included  active-duty  military 
 personnel  with  only  10  females  and  3  females  in  the  treatment  and  sham 
 groups respectively. 

 Because  of  the  limited  studies  done  on  this  intervention  as  a  treatment  for 
 PTSD,  there  is  little  evidence  of  whether  a  right-sided  SGB  or  left-sided 
 SGB  is  more  e�ective  with  the  use  of  �uoroscopy  versus  ultrasonography,  or 
 if  they  produce  the  same  results.  In  2021,  however,  a  cadaveric  study  was 
 performed  and  published  testing  vertebral  body  spread  of  the  injectate  based 
 on  sidedness  17  .  Ten  soft-cured  human  cadavers  were  administered  both 
 �uoroscopic  and  ultrasound-guided  injections  each.  The  injection  was  a 

 Berkeley Pharma Tech Journal of Medicine |  39 



 mixture  of  7  mL  of  omnipaque  and  methylene  blue  and  was  used  as  the 
 injectate  on  both  sides.  The  cadavers  were  then  dissected  to  visualize  the 
 staining  of  the  sympathetic  trunk  associated  with  methylene  blue  17  .  The 
 primary  outcome  was  the  staining  of  methylene  blue  at  the  cervical 
 sympathetic trunk upon dissection. 

 The  secondary  outcome  was  a  craniocaudal  spread  of  the  dye.  After 
 performing  two  injections  on  each  cadaver  for  a  total  of  20  injections,  they 
 were  dissected.  Fluoroscopic  guidance  of  SGB  injections  had  a  successful 
 stain  rate  of  60%,  six  out  of  ten  cadavers  17  .  For  the  ultrasound-guided  SGB, 
 the  successful  stain  rate  of  the  sympathetic  chain  was  nine  out  of  ten  for  a 
 90%  success  rate  17  .  The  failed  injections  were  because  the  injections  were 
 administered  in  the  wrong  location,  such  as  the  carotid  sheath  and  within  or 
 beneath  the  longus  Colli  muscle,  instead  of  the  stellate  ganglion  nerve 
 bundle  at  the  C6  anterior  tubercle  17  .  The  study  found  no  statistically 
 signi�cant  di�erences  in  approach  using  �uoroscopy  versus 
 ultrasonography, though there was greater staining using ultrasonography. 

 Limitations  of  this  study  include  the  fact  that  it  was  performed  on  cadavers 
 which  may  not  accurately  represent  the  spread  of  injectate  in  living  subjects. 
 The  fascial  layers  play  a  large  role  in  the  spread  of  injectate,  and  the 
 compositional  properties  of  the  fascial  layers  in  cadavers  are  altered 
 compared  to  living  humans.  In  addition,  no  functional  outcomes  can  be 
 assessed on cadavers. 

 A  study  examining  clinical  endpoints  in  people  with  PTSD  was  completed 
 in  May  of  2013,  analyzing  1,462  data  points  from  the  PTSD 
 Checklist-Military  (PCL-M)  18  .  This  study  analyzed  the  data  points  of  26 
 patients  in  a  military  clinic,  all  of  whom  had  several  combat  deployments 
 that  consisted  of  receiving  and  returning  direct  �re.  The  subjects  were  all 
 male  ranging  in  age  from  29  to  45.  The  participants  were  administered  7  mL 
 of  0.5%  ropivacaine  injected  over  two  minutes,  and  a  successful  injection 
 was indicated by the presence of Horner’s syndrome. 

 The  primary  outcome,  PCL-M  score,  was  tested  at  baseline  and  at  two 
 follow-up  appointments  18  .  The  16-point  decrease  in  mean  PCL-5  score  is 
 signi�cant  (p<0.001),  but  the  mean  score  at  the  second  follow-up  did  not 
 show signi�cant improvement from 1-week post-injection. 

 Berkeley Pharma Tech Journal of Medicine |  40 



 All  three  symptom  cluster  scores  were  signi�cantly  improved  (p<0.001) 
 one-week  post-injection,  except  for  one  item  in  a  single  cluster  18  .  These 
 results  support  the  use  of  SGB  injections  for  military  personnel  who  su�er 
 from  combat-related  PTSD.  The  limitations  of  this  study  are  similar  to 
 others:  many  studies  for  PTSD  generally  test  on  active-duty  personnel  or 
 veterans  only,  as  well  as  speci�cally  men  of  certain  age  ranges  and  ethnicities. 
 This  limits  generalizability  for  other  PTSD-a�ected  populations  including 
 women,  children,  and  civilians  who  have  never  served  in  the  military  or  have 
 experienced combat. 

 In  addition  to  the  cadaveric  study  and  in  vitro  trials,  an  in  vivo  study  done 
 on  rats  was  conducted  and  published  in  2021  19  .  This  study  di�ers  in  that  it 
 tested  the  e�ects  of  PTSD-related  sleep  deprivation  on  memory  dysfunction 
 and  hippocampal  injury.  Sleep  deprivation  is  a  common  symptom  of  PTSD 
 because  of  insomnia  and  night  terrors.  Sleep  deprivation  can  detrimentally 
 a�ect the brain and the body and lead to a cascade of other symptoms. 

 It  has  been  found  that  sleep  deprivation  is  associated  with  cognitive 
 dysfunction,  which  is  mediated  through  melatonin  19  .  Stellate  ganglion 
 blocks  have  been  found  to  exhibit  similar  e�ects  as  those  of  therapeutic 
 interventions  with  melatonin  in  that  they  prevent  the  breaking  of  cervical 
 sympathetic  preganglionic  �bers,  reduce  sympathetic  nerve  tension,  and 
 help  regulate  the  balance  in  multiple  body  systems,  including  the 
 autonomic  nervous  system,  endocrine  system,  and  immune  system.  Sleep 
 deprivation  has  also  been  shown  to  impair  hippocampal  coding  activity, 
 cause  hippocampal  mitochondrial  dysfunction,  neurodegeneration, 
 microglia activation, and neuronal apoptosis in the hippocampus  19  . 

 Furthermore,  there  has  been  con�rmation  of  increased  white  blood  cell 
 counts  and  in�ammatory  factors,  including  C-reactive  protein  (CRP), 
 IL-1β, IL-6, and TNF. There are also decreased serum melatonin levels  19  . 

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 This  study  tested  whether  alleviating  the  hippocampal  tissue  damage  can 
 improve  spatial  learning  and  memory  dysfunction  caused  by  sleep 
 deprivation  in  a  rat  model  of  PTSD.  65  male  Sprague  Dawley  rats  were 
 randomized  to  four  di�erent  groups.  These  groups  were  control,  sleep 
 deprivation  (SD),  SGB,  and  SGB  +  SD  (n=16).  The  SGB  and  SGB  +  SD 
 groups  were  administered  one  right-sided  stellate  ganglion  block  once  per 
 day.  The  SD  and  SD  +  SGB  groups  were  subjected  to  a  multi-platform 
 water  environment  for  96  hours  to  induce  sleep  deprivation.  Their  body 
 weights  were  also  analyzed  at  this  time.  The  Morris  water  maze  was  used  to 
 detect  the  spatial  learning  and  memory  function  of  rats.  The  escape  latency, 
 the  time  it  took  from  the  rats  entering  the  water  to  �nding  the  security 
 platform,  was  measured  as  an  outcome.  After  the  water  maze,  eight  rats  each 
 had  3  mL  of  inferior  vena  cava  blood  samples  analyzed  for  serum  melatonin 
 content. 

 The  SGB  and  SGB  +  SD  groups  were  given  a  right-sided  SGB  six  days  prior 
 to  sleep  deprivation  induction  up  until  the  end  of  the  day,  with  one  SGB  of 
 0.2  mL  of  0.2%  bupivacaine  per  day.  The  onset  of  Horner’s  syndrome 
 indicated  that  the  injection  dissipated  into  the  correct  anatomical  area.  Rats 
 in  the  SD  group  were  given  the  same  volume  of  normal  saline,  and  the 
 control  group  was  not  treated.  After  the  injections  were  administered,  the 

 Berkeley Pharma Tech Journal of Medicine |  42 



 escape  latency  time  of  the  SD  group  was  signi�cantly  longer  compared  to 
 the  control  group.  The  SD  +  SGB  group  was  shortened,  and  the  escape 
 latency  in  the  SGB  and  control  groups  tended  to  be  consistent  19  .  The 
 number  of  rats  that  crossed  the  platform  was  much  lower  in  the  SD  than  in 
 the  control  group  (p<0.05),  and  those  in  the  SD  +  SGB  was  signi�cantly 
 higher  compared  to  the  SD  group  (p<0.05)  19  .  The  platform  was  removed 
 and  resident  time  and  frequency  of  crossing  the  platform  were  recorded. 
 The  SD  +  SGB  group  showed  higher  crossing  and  resident  times  in  the  test 
 compared to the SD group. 

 The  body  weight  of  the  rats  in  the  SD  group  was  reduced  compared  to  the 
 control  group.  The  SD  +  SGB  group  showed  signi�cantly  increased  body 
 weight  after  injection  compared  to  the  SD  group.  In  comparison  with  the 
 control  group,  there  was  no  signi�cant  distinction  between  IL-6,  IL-1β,  and 
 serum MT content in the hippocampus of the rats in the SGB group. 

 However,  there  were  elevated  levels  of  IL-6  and  IL-1β  content  in  the 
 hippocampus  of  SD  rats  compared  to  the  control.  A  Western  blot  of  the 
 relative  expression  of  Caspase-3  protein  in  SD  rats’  hippocampus  was 
 signi�cantly  higher,  and  the  relative  expression  of  the  same  protein  in  the 
 hippocampus  of  SD  +  SGB  rats  was  signi�cantly  lower  with  no  di�erence  in 
 the  protein’s  expression  between  SGB  and  control  groups  19  .  Histological 
 analysis  of  hippocampal  tissue  showed  that  the  stress  damage  and  the 

 Berkeley Pharma Tech Journal of Medicine |  43 



 number  of  hippocampal  neurons  that  were  injured  in  the  SD  group  were 
 very  elevated,  most  prominent  in  the  vertebral  neurons  in  the  hippocampal 
 CA3  region.  The  vertebral  cells  were  decreased  in  size,  irregular,  loose,  and 
 fuzzy.  The  neuronal  damage  in  the  SD  +  SGB  group  was  signi�cantly 
 improved  compared  to  the  control  group,  and  the  cells  were  more  ordered 
 with a clearer structure. 

 In  addition,  the  serum  MT  levels  decreased  with  more  sleep  deprivation. 
 The  serum  MT  content  signi�cantly  improved  in  the  SD  +  SGB  group, 
 indicating  that  a  right-sided  SGB  can  alleviate  the  decrease  in  serum  MT 
 secretion  secondary  to  sleep  deprivation.  The  elevated  IL-6  and  IL-1β  levels 
 caused  by  sleep  deprivation  are  pro-in�ammatory  cytokines,  indicating  that 
 right-sided  SGBs  can  inhibit  the  initial  in�ammatory  reaction  after  trauma 
 exposure  19  .  They  can  also  be  used  to  inhibit  the  excessive  in�ammatory 
 reaction after TBI, preserving brain function. 

 The  Caspase-3  protein  that  was  found  in  elevated  levels  in  SD  rats  was 
 reduced  after  SGB,  further  indicating  that  the  excessive  apoptosis  can  be 
 alleviated  as  evidenced  by  the  fact  that  CA3  protein  levels  were  reduced  in 
 the  SD  +  SGB  group  19  .  Furthermore,  the  degree  of  stress  damage  on 
 hippocampal  neurons  was  signi�cantly  reduced  in  the  SD  group.  Though 
 these  are  all  post-injury  alleviating  factors,  the  behavioral  platform  used  in 
 this  experiment  showed  that  prophylactic  administration  of  SGB  can 
 provide  preventative  treatment  for  spatial  learning  and  memory 
 dysfunction  19  . 

 The  results  of  this  experiment  make  it  highly  evident  that  SGB  injections 
 produce  several  signi�cant  bene�ts  such  as  increased  melatonin  production 
 and  secretion,  alleviation  of  hippocampal  apoptosis  due  to  decreased 
 Caspase-3  protein  levels,  spatial  learning  and  memory  dysfunction 
 improvement,  and  hippocampal  neuron  regeneration  after  damage.  Given 
 that  this  is  a  non-invasive,  generally  safe  treatment,  SGBs  should  be  further 
 investigated and utilized based on this experiment done in the rat model. 

 In  addition  to  these  studies,  a  cohort  of  behavioral  clinicians  was 
 interviewed  about  their  thoughts  on  the  e�cacy  of  SGB  for  trauma-related 
 disorders  20  .  Approximately  50  mental  health  providers  were  sent  an  18-item 
 survey  to  assess  their  experiences  with  SGB  as  a  treatment  for  trauma-related 

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 conditions.  Of  the  27  clinicians  that  responded,  23  had  input  that  was  used 
 in  this  study  (10  psychologists,  7  psychiatrists,  4  licensed  clinical  social 
 workers,  and  2  psychiatric  nurse  practitioners).  Experience  with  SGB  varied 
 between  providers.  The  survey  showed  that  95%  (22  out  of  23)  of  providers 
 would  recommend  the  use  of  SGB  to  a  colleague  while  65%  said  this 
 procedure  is  very  bene�cial  20  .  30%  indicated  SGB  as  somewhat  helpful  and 
 over  80%  were  likely  or  very  likely  to  refer  a  patient  to  get  an  SGB  procedure. 
 96%  of  the  providers  also  responded  that  SGB  is  most  helpful  for  arousal 
 and reactivity compared to other symptoms  20  . 

 This  cohort  responded  that  SGB  is  at  least  as  bene�cial  as  other  heavily  used 
 interventions,  with  100%  responding  that  SGB  is  very  bene�cial  or 
 somewhat  bene�cial.  None  of  the  respondents  said  that  SGB  is  harmful  or 
 not  helpful  20  .  Furthermore,  SGB  was  overall  favored  over  each  of  the  8 
 interventions endorsed for PTSD in the Clinical Practice Guideline  20  . 

 Both  qualitatively  and  quantitatively,  the  overall  results  of  studies  assessing 
 the  e�cacy  of  SGB  as  an  intervention  for  PTSD  support  their  use  for 
 widespread  treatment.  SGBs  are  highly  bene�cial  with  minimal  risks  and 
 side  e�ects.  The  main  side  e�ect  is  Horner’s  syndrome  which  subsides  a 
 couple  of  hours  post-procedure  when  the  local  anesthetic  has  worn  o�  and 
 also  acts  as  an  indicator  to  clinicians  that  the  injection  was  successful  16  .  This, 
 in  addition  to  the  fact  that  this  is  non-invasive,  quick,  and  has  immediate 
 bene�cial  e�ects,  can  help  increase  treatment  adherence  rates,  thereby  also 
 improving  the  number  of  those  with  PTSD  who  can  bene�t  from  this 
 treatment over others. 

 Because  of  the  sheer  number  of  veterans  and  active  military  personnel  that 
 su�er  from  this  disorder,  all  of  the  conducted  studies  have  been  limited  to 
 veterans,  mainly  Caucasian  men  aged  18-65.  This  limits  generalizability  for 
 others  that  PTSD  a�ects  including  sexual  assault  victims,  those  who  have 
 experienced  natural  disasters  or  other  non-combat-related  trauma,  women, 
 children,  and  people  of  other  ethnicities.  Furthermore,  the  Department  of 
 Defense  is  the  main  source  of  funds  for  these  clinical  trials.  This  forces  the 
 trials  to  only  include  those  who  are  serving  or  who  have  served  in  combat. 
 Due  to  this,  funding  outside  of  the  DoD  needs  to  be  identi�ed  to  carry  out 
 trials on non-military civilians who su�er from PTSD. 

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 Future  applications  of  SGBs  are  limited  given  these  trials.  In  order  to  make 
 this  treatment  more  mainstream  and  widespread,  there  can  be  increased  and 
 more  diverse  populations  in  clinical  trials,  more  in-depth  research,  training 
 of  physicians  outside  of  military  hospitals  and  clinics  to  perform  this 
 procedure,  and  better  analysis  of  complete  data  sets.  Overall,  this  is  a  highly 
 e�ective  treatment  that  is  limited  by  its  research  and  the  training  of 
 physicians  as  well  as  funding  for  trials  and  insurance  coverage  for  patients.  It 
 has  been  shown  to  increase  melatonin  levels  to  combat  insomnia,  regulate 
 gene  expression,  decrease  hippocampal  apoptosis,  reverse  hippocampal 
 damage,  improve  spatial  learning  and  memory,  and  decrease  depression, 
 anxiety,  hyperarousal,  and  hypervigilance  [5,  16,  18,  19,  20]  ,  making  this  a  target  for 
 further  application.  The  numerous  bene�cial  e�ects  of  SGBs  warrant 
 further research and application, especially for those outside of the military. 

 SGB  can  be  used  to  target  the  expression  of  Caspase-3  protein,  IL-1β,  and 
 IL-6.  Targeting  these  proteins  can  aim  to  reduce  highly  damaging 
 hippocampal  tissue  reduction  and  neuronal  degeneration,  along  with 
 reducing  in�ammation  in  the  brain  and  body  immediately  following  a 
 traumatic  event  because  of  the  pro-in�ammatory  properties  of  IL-1β  and 
 IL-6  genes.  Further  research  on  the  e�ects  of  SGB  on  gene  expression  is 
 warranted  because  of  these  proteins’  roles  in  PTSD  symptom  severity. 
 Western  blot  assays  should  be  utilized  in  further  studies  to  assess  this  as  this 
 has only been done in a rat model. 

 2.3.  Topiramate 

 Topiramate,  a  medication  commonly  used  to  treat  migraines  and  epilepsy,  is 
 a  second-generation  anti-epileptic  drug  21  .  Though  the  precise  mechanism  is 
 unknown,  it  is  known  that  the  drug  blocks  voltage-gated  sodium  channels, 
 which  are  thought  to  control  depolarization  during  seizures.  It  reduces 
 membrane  depolarization  with  AMPA  and  kainate  receptors  [10,  11]  while  also 
 enhancing  GABA  receptor  activity.  Additionally,  it  is  known  to  be  an 
 inhibitor  of  carbonic  anhydrase  and  NMDA  receptor  activity,  allowing  for 
 partial regulation of seizures in the brain  21  . 

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 An  in  vivo  study  was  conducted  with  30  veteran  patients  su�ering  from 
 PTSD  and  alcohol  use  disorder,  in  which  patients  were  placed  in  two 
 groups,  treatment  or  placebo  (negative)  9  .  There  was  a  12-week  double-blind 
 treatment  administered  in  which  half  the  patients  (randomized)  were  given 
 increasing  doses  of  topiramate  from  25  mg  on  day  1  up  to  300  mg  a  day  by 
 week  6,  and  constant  doses  through  week  12.  Participants  in  the  negative 
 control group were given a placebo treatment. 

 The  primary  hypothesis  of  the  di�erence  between  the  tested  topiramate 
 group  and  placebo  group  was  tested  using  a  statistical  t-test,  which 
 produced  a  p-value=0.019  that  indicated  statistically  signi�cant  results  in 
 the  di�erence  between  these  two  groups  and  their  drinking  days  per  week  9  . 
 The  main  e�ect  of  the  treatment  for  those  who  received  it  was  reduced 
 standard  drinks  per  week,  which  decreased  by  55%  for  the  topiramate  group 
 along with a 61% reduction in drinks per day  9  . 

 An  additional  in  vivo  study  analyzed  e�ciency  of  topiramate  treatment  on 
 post-traumatic  stress  disorder  patients  from  the  clinic  of  the  violence 
 program  of  Federal  University  São  Paulo  City  22  .  This  was  another  12-week 
 double-blind  treatment  test  where  35  patients  were  randomly  assigned  to 
 the  treatment  group  or  negative  control  group.  The  Clinician  Administered 

 Berkeley Pharma Tech Journal of Medicine |  47 



 Post-traumatic  Stress  Scale  (CAPS)  and  Beck  Depression  Inventory  (BDI) 
 were  used  as  primary  indicators  of  results  22  .  The  mean  topiramate  dose 
 administered was 102.95 mg a day. 

 The  study  yielded  82.35%  of  patients  with  signi�cant  improvements  in  their 
 CAPS-B  score,  seen  with  improvements  in  re-experiencing  symptoms  such 
 as  �ashbacks,  intrusive  memories,  and  nightmares  of  the  trauma  (p  = 
 0.04)  22  .  There  was  also  a  signi�cant  improvement  in  avoidance/numbing 
 symptoms  associated  with  trauma,  social  isolation,  and  emotional  numbing 
 in  CAPS-C  scores  (p  =  0.0001).  Additionally,  there  was  a  signi�cant 
 decrease  in  CAPS  total  score  for  the  experimental  group  when  compared 
 with the placebo group (p = 0.0076)  22  . 

 The  �rst  study  analyzed  a  high  ratio  of  male  participants  with  barely  any 
 female  subjects.  This  made  results  highly  biased  towards  male  patients,  and 
 further  research  may  have  to  be  done  to  gauge  if  the  results  can  be 
 generalized  to  female  patients  due  to  di�erences  in  PTSD  manifestation 
 between  genders.  However,  the  second  study  saw  similar  improvements  in 
 CAPS  scores  with  a  majority  of  the  participants  being  women,  at  21  out  of 
 35 patients. 

 Additionally,  the  study  focused  on  PTSD  patients  that  were  veterans.  We 
 cannot  generalize  these  e�ects  to  other  populations  struggling  with 
 post-traumatic  stress  disorder  since  the  studies  were  concentrated  on 
 veterans  su�ering  from  symptoms.  Furthermore,  the  majority  of 
 participants  in  the  �rst  study  were  white.  More  research  concentrating  on 
 di�erent  races  can  help  broaden  the  spectrum  of  participants  that  gain 
 positive results following the treatment of topiramate. 

 For  both  studies,  only  30-40  patients  were  observed,  and  with  such  a  small 
 sample  size,  the  results  are  less  accurate.  More  studies  conducted  with 
 greater sample sizes will increase the signi�cance of the results. 

 Though  already  being  widely  used  as  a  drug  to  treat  neurological  illnesses 
 such  as  epilepsy  or  migraines,  further  studies  regarding  the  dosage  of 
 topiramate  to  treat  post-traumatic  stress  disorder  are  proven  to  produce 
 positive  results.  The  main  risk  is  topiramate  may  also  produce  adverse  e�ects 
 when  taken  in  larger  doses,  with  the  most  common  side  e�ects  in  migraine 

 Berkeley Pharma Tech Journal of Medicine |  48 



 patients  being  insomnia  and  drowsiness.  However,  it  is  known  as  a  relatively 
 safe  drug.  It  should  be  avoided  in  patients  prone  to  experiencing  metabolic 
 acidosis  due  to  being  a  carbonic  anhydrase  inhibitor  21  .  With  the  already 
 signi�cant  results  seen  in  topiramate  decreasing  post-traumatic  stress 
 disorder  indicative  diagnosis,  including  CAPS  score,  BDI  score,  and  PTSD 
 Symptom  Severity  scores,  further  studies  conducted  on  a  larger  and  more 
 diverse  sample  group  can  give  support  in  popularizing  this  method  for 
 post-traumatic stress disorder patients. 

 2.4.  Stem Cell Therapy 

 Stem  cell  therapy  and  transplantation  have  been  used  widely  since  their  �rst 
 application  in  1957  23  .  Stem  cell  transplants  are  mainly  used  to  target 
 damaged  cells  from  chemotherapy  or  diseases  usually  related  to  cancer.  Stem 
 cell  therapies  are  of  particular  interest  because  of  the  vast  results  they  have 
 the  potential  to  produce.  The  application  of  stem  cell  therapy  for 
 trauma-related  disorders  such  as  PTSD  has  not  yet  been  explored  in 
 humans.  The  only  research  done  on  this  topic  consists  of  a  single  in  vivo 
 study published in 2021  6  . 

 The  2021  study  used  induced  pluripotent  stem  cells  (iPSCs),  generated  by 
 reprogramming  somatic  cells  by  inserting  certain  genes.  iPSCs  can  be 
 di�erentiated  into  any  cell  type  6  .  Among  the  various  types  of  cells,  induced 
 pluripotent  stem  cell-derived  neural  progenitor  cells  (iPSC-NPCs)  can 
 replace  lost  neurons  that  have  degenerated  in  a  highly  speci�c  region  of  the 
 brain.  They  can  replace  the  loss  of  neurons  in  the  hippocampus  and 
 regenerate  impaired  hippocampal  structure,  and  there  is  accumulating 
 evidence  that  iPSC-NPCs  can  support  tissue  repair  and  functional  recovery 
 after neurogenic injuries  6  . 

 In  this  study,  male  Sprague  Dawley  rats  were  used  as  subjects.  Cell  culturing 
 of  iPSCs  was  done  in  an  embryonic  stem  cell  medium  until  typical  human 
 embryonic  stem  cell  morphology  was  present.  The  stem  cell  colonies  were 
 then  dissociated.  The  rats  were  randomized  to  six  groups  (n=8)  on  days  7, 
 14,  and  21.  On  day  7,  the  groups  included  control,  PTSD,  PTSD  +  PBS, 
 and  PTSD  +  iPSC-NPCs.  On  days  14  and  21,  the  group  was  PTSD  + 
 iPSC-NPCs.  14  days  after  the  initial  injury,  iPSC-NPCs  were  transplanted 

 Berkeley Pharma Tech Journal of Medicine |  49 



 into  the  hippocampal  site  6  .  At  di�erent  points  in  time,  the  rats’  brains  were 
 dissected for analysis. 

 The  open  �eld  test  was  used  to  evaluate  outcomes  related  to  locomotor 
 activities.  The  fear  conditions  test  was  used  to  subject  the  rats  to  a 
 tone-foot-shock  pairing.  The  induced  pluripotent  stem  cells  were  allowed  to 
 develop  for  24  days  in  the  laboratory  to  ensure  di�erentiation.  Seven  days 
 after  transplantation,  there  was  no  signi�cant  di�erence  between  the  control 
 and  transplant  groups  in  residence  time  and  behavior  modi�cation  6  .  This 
 indicates  that  short-term  transplantation  does  not  a�ect  locomotor  activity 
 or  anxiety.  Long-term  treatment  was  shown  to  be  e�ective  14  and  21  days 
 after  treatments,  with  increased  residence  time  and  behavior  modi�cations 
 indicating  lowered  levels  of  anxiety  and  depression  6  .  This  also  supports  that 
 long-term treatment improves and regulates cognitive dysfunction. 

 

 Furthermore,  neuronal  nuclear  protein  (NeuN)  was  used  as  a  marker  of 
 mature  neurons  in  immuno�uorescence  assay.  This  suggested  that 
 iPSC-NPC  transplantation  can  increase  neurogenesis  in  the  damaged 
 hippocampus  found  in  PTSD  6  .  In  addition,  immunostaining  indicated  that 
 transplantation  can  increase  astrogliosis,  thereby  minimizing  damage  to 
 CNS  injuries.  In  another  Western  blot  analysis,  there  was  a  reduction  in 
 BDNF  expression  which  was  reversed  after  14  and  21  days  in  the  transplant 
 group.  This  suggests  that  transplantation  supports  functional  recovery 
 through upregulating BDNF  6  . 

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 The  results  of  this  study  indicate  that  iPSC-NPC  transplantation  after 
 NPC  treatment  in  vitro  can  promote  neurogenesis  and  functional  recovery, 
 reduce  anxiety  and  depression,  and  repair  damaged  hippocampal  tissue  and 
 neurons  6  .  The  limitations  of  stem  cell  transplantation  as  an  intervention  for 
 PTSD  are  numerous.  This  is  the  only  study  that  has  been  done  on  this 
 intervention  for  PTSD,  and  it  is  only  in  a  rat  model,  not  in  humans.  The 
 results  of  long-term  transplantation  indicate  that  further  research  is  needed 
 before  it  can  be  considered  a  viable  treatment  option.  Stem  cell  transplants 
 are  also  limited  because  of  the  high  risk  of  developing  neoplasms,  so  the  cells 
 must  be  treated  carefully  before  transplant.  Though  this  may  seem  like  an 
 intense  treatment  for  PTSD,  there  is  promise  that  it  can  be  bene�cial  in 
 reducing symptoms and physiological damage. 

 2.5  Immunotherapy 

 PTSD  is  often  comorbid  with  a  number  of  in�ammatory  diseases  and 
 autoimmune  disorders  7.  Though  many  factors  can  play  a  role  in 
 in�ammation  unrelated  to  trauma,  there  are  elevated  rates  of 
 immune-related  conditions  in  those  with  PTSD.  A  review  published  in 
 2022  assessed  the  use  of  anti-in�ammatory  drugs  for  reducing  PTSD 
 symptoms  and  their  mechanism  within  the  disorder  7  .  Though  the 
 directional  relationship  between  PTSD  and  in�ammation  is  unknown, 
 accumulating  evidence  points  to  the  adaptive  and  innate  immune  systems’ 
 roles  in  the  pathophysiology  of  PTSD.  There  are  often  variations  in 
 peripheral  in�ammatory  markers  in  those  with  PTSD  including  C-reactive 
 protein,  IL-6,  IL-10,  and  tumor  necrosis  factor-alpha  (TNF-α)  7  .  There  have 
 also  been  several  genomic  studies  that  have  identi�ed  multiple  genes  related 
 to  the  immune  system  that  are  altered  in  those  with  PTSD.  More 
 speci�cally,  transcriptomic  studies  performed  on  US  marines  showed  the 
 upregulation  of  immune-related  genes  and  the  overexpression  of  genes 
 related  to  the  innate  immune  response.  Interferon  signaling  pre-deployment 
 was able to predict post-deployment PTSD  7  . 

 Berkeley Pharma Tech Journal of Medicine |  51 



 PTSD  is  associated  with  variations  in  regions  of  the  brain  that  regulate  fear, 
 anxiety,  and  threat  detection.  These  regions  mainly  consist  of  the  amygdala, 
 hippocampus,  and  hypothalamus.  Upon  stress,  people  with  PTSD  have 
 heightened  amygdala  activation  and  increased  pro-in�ammatory  cytokine 
 levels  7  .  This  is  associated  with  depression,  social  disconnection,  fatigue,  and 
 cognitive  disturbance,  which  often  come  with  PTSD.  The  hippocampus, 
 which  is  involved  in  fear  and  memory  processing,  is  often  found  in  smaller 
 volumes  in  those  with  PTSD.  A  smaller  hippocampus  is  associated  with 
 increased  in�ammation.  In  a  rat  model,  it  was  found  that  in�ammation  of 
 the  hippocampus  suppresses  neurogenesis  and  stimulates  apoptosis  of 
 neuronal  progenitor  cells,  indicating  that  in�ammation  of  the  hippocampus 
 may  greatly  contribute  to  cognitive  and  emotional  issues  that  come  with 
 PTSD.  Several  more  peripheral  structures  are  a�ected  by  in�ammation  and 
 PTSD,  which  a�ect  neurotransmitter  release  and  reuptake,  again  correlating 
 the emotional issues of PTSD and in�ammation  7  . 

 Of  the  two  FDA-approved  SSRIs,  none  target  in�ammation.  There  are 
 several  proposed  potential  treatments  in  this  review  that  target  the 
 in�ammation  associated  with  PTSD,  though  none  are  FDA  approved  for 
 PTSD  treatment.  Monoclonal  antibodies  are  approved  for  the  treatment  of 

 Berkeley Pharma Tech Journal of Medicine |  52 



 autoimmune  disorders  and  cancers  7  ,  and  the  elevated  levels  of  IL-1β,  IL-6, 
 and  TNF-α  give  reason  to  believe  that  blocking  these  pro-in�ammatory 
 cytokines  using  monoclonal  antibodies  could  better  regulate  gene 
 expression  and  reduce  in�ammation.  Though  there  are  no  studies  on  this 
 intervention  for  PTSD,  several  TNF  inhibitors  have  been  reported  to  reduce 
 anxiety  and  depression  in  people  with  psoriasis,  indicating  the  potential 
 application of TNF inhibitors for other diseases that cause in�ammation  7  . 

 Non-steroidal  anti-in�ammatory  drugs  (NSAIDs)  and  cyclooxygenase  2 
 (COX-2)  inhibitors  can  regulate  the  pro-in�ammatory  cytokine  production 
 in  the  body,  thereby  directly  reducing  in�ammation  7  .  Celecoxib,  a  COX-2 
 inhibitor,  was  able  to  reduce  depression  symptoms  in  people  with  major 
 depressive  disorder,  meaning  it  potentially  reduced  IL-6  levels,  one  of  the 
 upregulated  genes  in  people  with  PTSD.  Ibuprofen,  an  NSAID,  reduced 
 anxiety  in  a  rat  model  of  PTSD  and  decreased  expression  of  IL-1β  and 
 TNF-α  while  increasing  BDNF  expression  in  the  hippocampus  7  .  This 
 indicates  that  the  e�ect  of  ibuprofen  on  PTSD  was  moderated  by  decreased 
 anti-in�ammatory activity and increased expression of BDNF in the brain. 

 Glucocorticoids  are  another  class  of  drugs  that  can  be  employed  to  treat  the 
 symptoms  of  PTSD.  Glucocorticoids  work  to  suppress  the  in�ammatory 
 response  following  exposure  to  stress  by  promoting  the  production  of 
 anti-in�ammatory  cytokines  and  suppressing  the  production  of 
 pro-in�ammatory  cytokines.  Clinical  trials  have  shown  that  glucocorticoid 
 treatment  combined  with  psychotherapy  can  improve  PTSD  symptoms. 
 Glucocorticoid  administration  after  prolonged  exposure,  however,  has  been 
 shown  to  not  have  signi�cant  e�ects  on  eliminating  PTSD  symptoms  alone. 
 Studies  investigating  the  prophylactic  e�ects  of  glucocorticoids  following 
 trauma  exposure  found  that  glucocorticoid  treatment  following  an  acute 
 traumatic  event  was  able  to  signi�cantly  reduce  stress  symptoms  and  the 
 incidence of PTSD  7  . 

 In  addition  to  these  approaches,  angiotensin-converting  enzyme  inhibitors, 
 noradrenergic  beta-receptor  blockers,  angiotensin  receptor  blockers,  and 
 cannabinoids  also  have  bene�cial  e�ects  when  used  to  treat  PTSD.  There 
 are  several  mechanisms  by  which  they  do  this  through  suppressing 
 in�ammation  7  .  There  is  a  growing  body  of  strong  evidence  that  supports 

 Berkeley Pharma Tech Journal of Medicine |  53 



 the  use  of  immunotherapy  to  reduce  PTSD  symptoms,  including 
 in�ammation.  The  drugs  in  this  review  are  generally  safe  with  proper 
 oversight  and  are  underutilized  for  PTSD.  Given  that  glucocorticoids  and 
 noradrenergic  beta-receptor  blockers  can  work  prophylactically  to  reduce 
 the  incidence  of  PTSD  following  a  traumatic  event,  further  research  and 
 applications  are  warranted  for  trauma-related  conditions.  If  there  is  further 
 evidence  that  glucocorticoids  can  work  prophylactically,  they  can  be  a 
 supplement  to  other  treatments,  such  as  stellate  ganglion  blocks,  for 
 individuals  who  arrive  at  the  hospital  after  an  intensely  traumatic  event, 
 possibly  blocking  the  development  of  PTSD.  The  link  between  PTSD,  the 
 brain,  and  in�ammation  produces  the  potential  for  anti-in�ammatory 
 treatment  as  a  prophylactic  intervention  after  an  acute  traumatic  event,  but 
 before the onset of PTSD. 

 Discussion 

 This  qualitative  systematic  review  aims  to  highlight  several  novel  therapies 
 for  PTSD  as  well  as  the  limitations  of  their  current  studies.  Some  common 
 limitations  in  novel  research  for  PTSD  include  low  adherence  rates, 
 funding/participant  bias  at  military  hospitals  funded  by  the  Department  of 
 Defense,  and  low  generalizability  rates  given  the  limited  demographics  of 
 study  participants.  These  issues,  in  combination  with  a  disorder  that  is  not 
 yet  fully  understood,  greatly  hinder  widespread  access  to  groundbreaking 
 treatments for PTSD. 

 The  identi�cation  of  pressure-sensitive  and  oxygen-sensitive  genes  through 
 hyperbaric  oxygen  therapy  can  possibly  be  used  in  combination  with  gene 
 therapy  to  upregulate  these  genes.  This  could  potentially  be  used  to  enhance 
 the  e�ects  of  hyperbaric  oxygen  therapy  under  normal  atmospheric 
 conditions.  Hyperbaric  oxygen  therapy  is  commonly  used  to  assist  in  neural 
 regeneration  after  brain  injuries  or  ischemic  strokes,  heal  large  wounds,  and 
 restore  hearing  after  sudden  deafness.  HBOT  exhibits  several  di�erent 
 mechanisms  in  which  it  has  proven  to  be  e�ective,  but  induced  hyperoxia  is 
 ultimately  the  objective  of  the  treatment.  Forcing  extra  oxygen  to  perfuse 
 throughout  the  body  has  many  e�ects,  and  the  oxygen  works  directly  to 

 Berkeley Pharma Tech Journal of Medicine |  54 



 �ght  bacterial  infections  by  releasing  stem  cells  and  various  growth  factors4. 
 This  in  turn  helps  regulate  the  immune  system  and  e�ectively  reverse 
 hippocampal  tissue  damage.  Immune  disorders  are  very  commonly 
 comorbid  with  PTSD,  indicated  by  elevated  levels  of  in�ammatory  markers 
 in  individuals  with  PTSD.  These  novel  therapies  have  the  potential  to  be 
 administered in unison to maximize the e�ects of treatment  7  . 

 Stellate  ganglion  blocks  take  an  interesting  approach  to  PTSD  in  that  they 
 utilize  local  anesthetic  to  block  signal  transmission  to  the  brain.  Stellate 
 ganglion  blocks  are  used  for  a  wide  variety  of  disorders,  and  the  studies 
 reviewed  in  this  paper  indicate  that  these  injections  can  provide  immediate 
 relief  to  individuals  with  PTSD.  These  injections  are  safe  when  performed 
 correctly,  and  more  than  one  can  be  administered  if  one’s  symptoms  return 
 after  an  initial  injection.  Though  there  isn’t  relevant  longitudinal  research,  it 
 has  shown  to  be  safe  to  intermittently  administer  more  anesthetic, 
 indicating  potential  long-term  relief  with  the  use  of  several  injections.  The 
 main  side  e�ect  of  SGBs,  Horner’s  syndrome  16  ,  is  a  temporary  condition 
 that  causes  minor  neurological  symptoms.  Stellate  ganglion  blocks  are 
 low-risk  treatments  that  are  supported  by  several  in  vivo  studies  and  clinical 
 trials.  The  available  data  warrants  their  use  as  therapy  for  PTSD  to  provide 
 immediate relief of physical, cognitive, and emotional symptoms. 

 Topiramate  is  another  low-risk  treatment  that  aims  to  reduce  alcoholism  in 
 individuals  with  PTSD  8  .  Topiramate  is  a  widely  accepted  anticonvulsant 
 that  is  now  being  used  in  other  ways.  Two  clinical  trials  have  yielded 
 statistically  signi�cant  results  in  di�erent  areas  [9,22]  ,  indicating  that 
 topiramate  can  be  an  e�ective  medication  for  alcohol  use  disorder  comorbid 
 with PTSD. 

 Some  of  these  interventions  have  produced  great  results,  assessed  by  a 
 decrease  in  total  symptom  severity.  Aside  from  stem  cell  therapy,  these 
 treatments  are  safe  and  e�ective  for  many  individuals  with  PTSD  and  other 
 disorders,  and  the  qualitative  evidence  supports  the  mainstreaming  of  these 
 therapies when administered in concert with psychotherapy. 

 Berkeley Pharma Tech Journal of Medicine |  55 



 Conclusion 

 With  the  limitations  seen  in  the  discussed  studies,  further  in-depth 
 investigation  of  all  methods  would  increase  the  strength  of  statistical 
 evidence,  expand  on  PTSD-speci�c  e�ects  of  each  treatment,  and  generalize 
 the  outcomes  to  more  diverse  groups  of  patients.  O�ering  di�erent  and 
 more  feasible  approaches  to  these  treatments  would  also  popularize  the 
 e�ective  treatment  of  PTSD  symptoms  according  to  their  speci�c 
 mechanism  and  signi�cance  in  terms  of  the  bene�ts,  risks,  and  limitations 
 they provide. 

 Berkeley Pharma Tech Journal of Medicine |  56 



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