Paul  T.  Ingmundson,  PhD  South  Texas  Veterans  Health  Care  System  

University  of  Texas  Health  Science  Center  at  San  Antonio  Alamo  Sleep  Disorders  Center  

Course  Objec,ves    1)  Identify  changes  in  sleep  that  occur  after  exposure  to  psychological  trauma  

 2)  Identify  common  sleep  disorders  that  are  comorbid  with  PTSD  

 3)  Discuss  ways  in  which  effective  treatment  of  comorbid  sleep  disorders  may  facilitate  recovery  from  PTSD    

PTSD  Through  the  Past  100  Years  

PTSD:  A  Common  Problem  

Frequency  of  PTSD  and  TBI,  Iraq/Afghanistan  Veterans,  Rand  Study  

PTSD:    Triggered  byTrauma  

Traumas  differ,  and  Responses  to  Trauma  differ  

DSM-­‐V  Criteria  for  PTSD  Diagnosis  Criterion  A:  Stressor  Criterion  B:  Intrusion  Symptoms  Criterion  C:  Avoidance  Criterion  D:  Negative  Alterations  in  cognitions  and  mood  Criterion  E:  Alterations  in  Arousal  and  Reactivity  Criterion  F:  Duration  Criterion  G:  Functional  Significance  Criterion  H:  Exclusions  Dissociative  Features  

Criterion  A:  stressor  • The  person  was  exposed  to:  death,  threatened  death,  actual  or  threatened  serious  injury,  or  actual  or  threatened  sexual  violence,  as  follows:  (one  required)    • Direct  exposure.    • Witnessing,  in  person.  • Indirectly,  by  learning  that  a  close  relative  or  close  friend  was  exposed  to  trauma.  If  the  event  involved  actual  or  threatened  death,  it  must  have  been  violent  or  accidental.  • Repeated  or  extreme  indirect  exposure  to  aversive  details  of  the  event(s),  usually  in  the  course  of  professional  duties  (e.g.,  first  responders,  collecting  body  parts;  professionals  repeatedly  exposed  to  details  of  child  abuse).  This  does  not  include  indirect  non-­‐professional  exposure  through  electronic  media,  television,  movies,  or  pictures.    

       Criterion  B:  intrusion  symptoms      

• The  traumatic  event  is  persistently  re-­‐experienced  in  the  following  way(s):  (one  required)    • Recurrent,  involuntary,  and  intrusive  memories.  Note:  Children  older  than  six  may  express  this  symptom  in  repetitive  play.    • Traumatic  nightmares.  Note:  Children  may  have  frightening  dreams  without  content  related  to  the  trauma(s).    • Dissociative  reactions  (e.g.,  flashbacks)  which  may  occur  on  a  continuum  from  brief  episodes  to  complete  loss  of  consciousness.  Note:  Children  may  reenact  the  event  in  play.    • Intense  or  prolonged  distress  after  exposure  to  traumatic  reminders.    • Marked  physiologic  reactivity  after  exposure  to  trauma-­‐related  stimuli.    

Criterion  C:  avoidance      

• Persistent  effortful  avoidance  of  distressing  trauma-­‐related  stimuli  after  the  event:  (one  required)  • Trauma-­‐related  thoughts  or  feelings.  • Trauma-­‐related  external  reminders  (e.g.,  people,  places,  conversations,  activities,  objects,  or  situations).  

Criterion  D:  negaEve  alteraEons  in  cogniEons  and  mood    • Negative  alterations  in  cognitions  and  mood  that  began  or  worsened  after  the  traumatic  event:  (two  required)  • Inability  to  recall  key  features  of  the  traumatic  event  (usually  dissociative  amnesia;  not  due  to  head  injury,  alcohol,  or  drugs).  • Persistent  (and  often  distorted)  negative  beliefs  and  expectations  about  oneself  or  the  world  (e.g.,  "I  am  bad,"  "The  world  is  completely  dangerous").  • Persistent  distorted  blame  of  self  or  others  for  causing  the  traumatic  event  or  for  resulting  consequences.    • Persistent  negative  trauma-­‐related  emotions  (e.g.,  fear,  horror,  anger,  guilt,  or  shame).  • Markedly  diminished  interest  in  (pre-­‐traumatic)  significant  activities.  • Feeling  alienated  from  others  (e.g.,  detachment  or  estrangement).  • Constricted  affect:  persistent  inability  to  experience  positive  emotions.    

Criterion  E:  alteraEons  in  arousal  and  reacEvity       • Trauma-­‐related  alterations  in  arousal  and  reactivity  

that  began  or  worsened  after  the  traumatic  event:  (two  required)  • Irritable  or  aggressive  behavior  • Self-­‐destructive  or  reckless  behavior  • Hypervigilance  • Exaggerated  startle  response  • Problems  in  concentration  

• Sleep  disturbance  

Dura,on,  Func,onal  significance,  Exclusionary  criteria,  Dissocia,on  

Criterion  F:  duration    Persistence  of  symptoms  (in  Criteria  B,  C,  D,  and  E)  for  more  than  one  month.    Criterion  G:  functional  significance    Significant  symptom-­‐related  distress  or  functional  impairment  (e.g.,  social,  occupational).  Criterion  H:  exclusion    Disturbance  is  not  due  to  medication,  substance  use,  or  other  illness.    Specify  if:  With  dissociative  symptoms.    In  addition  to  meeting  criteria  for  diagnosis,  an  individual  experiences  high  levels  of  either  of  the  following  in  reaction  to  trauma-­‐related  stimuli:  Depersonalization:  experience  of  being  an  outside  observer  of  or  detached  from  oneself  (e.g.,  feeling  as  if  "this  is  not  happening  to  me"  or  one  were  in  a  dream).  Derealization:  experience  of  unreality,  distance,  or  distortion  (e.g.,  "things  are  not  real").    

PTSD  and  the  Comorbidity  Matrix  

Group  1:  low  comorbidity:  30%  have  lifetime  major  depression  (62.1%)  Group  2:  Substance  Dependent,  Depressed/Anxi0us,  high  suicidal  ideation  (14.1%)  Group  3:  Depressed/Anxious—high  suicidal  ideation  (23.7%)  

Sleep  Changes  in  PTSD:  Comorbidi,es  

� Insomnia:  Insomnia  complaints  >  PTSD  symptoms  

� Parasomnias:  Nightmares  vs.  REM  sleep  behavior  disorder  

� Sleep-­‐disordered  breathing  

Our  Sleep  Deprived  Culture  National  Sleep  Foundation  recommends  7-­‐9  hours  of  sleep  per  night  for  adults  50.2%  of  1249  soldiers  and  Marines  deployed  to  Afghanistan  reported  sleeping  <=  5  hours/night  Average  sleep  duration  for  deployed  personnel  6.  5  hours2  Sleep  disruption  has  been  correlated  medical  problems,  including:  •    Neurocognitive  deficits  •    Metabolic  dysregulation  •    Obesity  •    Cardiovascular  disease  And  mental  health  problems,  including:  •    PTSD  •    Substance  abuse  •    Suicidal  ideation  

Sleep  problems  in  PTSD  �  91%  of  Vietnam  Veterans  with  PTSD  report  sleep  problems,  compared  to  63%  of  Vietnam  Era  veterans,  and  53%  of  civilian  controls1.  

Neylan  TC  Marmar  CR  Metzler  TJ  et  al:  Sleep  disturbances  in  the  Vietnam  Generation:  findings  from  a  nationally  representative  sample  of  male  Vietnam  veterans.    Am  J  Psychiatry  1998  155  (7)  929-­‐33  

PTSD  and  the  Comorbidity  Matrix  

Sleep  Problems  (95%  of  PTSD  Patients)  

Sleep  Problems  in  Deployment  �  50.2%  of  1249  soldiers  and  Marines  deployed  to  Afghanistan  reported  sleeping  <=  5  hours/night  

�  Average  sleep  duration  for  deployed  personnel  6.  5  hours  to  6.7  hours  

�  Deployed  personnel  average  6.5  hours  sleep.      �  Postdeployed  personnel  report  more  sleep  problems.  �  Trouble  sleeping  correlated  with  mental  health  problems  

Peterson  AL  Goodie  JL,  Satterfield  WA,  Brim  WL:  Sleep  disturbance    during  military  deployment.    Mil  Med  2008;  173  (3):  230-­‐5  Seelig  AD,  Jacobson  IG,  Stimth  B,  et  al:  Sleep  patterns  before,  during  and  after  deployment  in  Iraq  and  Afghanistan.    Sleep  (2010,  33:12)  1615-­‐22  

Stress,  Chronodisrup,on,  and  PTSD:  a  Cascade    

Stress  •  Combat  Trauma,  Sexual  Trauma,  Disasters  

Sleep  Disruption  

•  Circadian  Dysrhythmia,  Sleep  Deficit,  Insomnia  

Disease  

•  Metabolic  disease,  cardiovascular  disease  •  Mental  health  problems  

Environmental  and  genetic  factors  are  modulated  concurrently  by  the  dual  actions  of  the  circadian  clock  and  the  stress  response  system,  which  interact  closely  to  regulate  brain  function.  Conversely,  the  psychiatric  phenotype  impacts  the  circadian  clock  and  the  stress  response  system      PTSD  

Adapted  fromLandgraf,  Dominic.    10/2014.    Circadian  clock  and  stress  interactions  in  the  molecular  biology  of  psychiatric  disorders    Current  psychiatry  reports    (ISSN:  1523-­‐3812),    16  (10),  p.  483.  

The circadian clock and the stress response system interact closely. During the day BMAL1 and CLOCK proteins are expressed at high levels to activate transcription of PERs, CRYs, RORα, REV-ERBα, and CCGs, as well as to promote the activity of GRs which, in turn, elevate transcription of GC-inducible genes like FKBP5. An accessory feedback loop consists of RORα, an activator of BMAL1 expression and REV-ERBα, an inhibitor of BMAL1 expression. GCs facilitate the expression of GC-responsive clock genes and clock controlled genes (CCGs) with GRE promoter elements. At night, PER and CRY protein levels are high and repress the activity of BMAL1/CLOCK and the GR. Through feedback inhibition, FKBP5 suppresses GR activity. Due to the tight connection between the circadian clock and the stress response system, manipulations of one system naturally lead to changes in the other  

Circadian  mechanisms  and  Stress    

Independent  Variable  

Wald  Statistic  (Wald  F)  

Significance  level  (Bonferroni  Correction)  

Odds  ratio  (95%  CI)  (OSA+Insomnia  vs  OSA-­‐Insomnia)*  

‘Essential  hypertension’   10.400   0.001   1.83  (1.27–2.65)  

‘Cerebrovascular  disease’   7.209   0.007   6.58  (1.66–26.08)  

‘Heart  failure’   0.937   0.333   0.42  (0.07–2.46)  

‘Cardiac  dysrhythmia’   0.007   0.934   0.93  (0.15–5.90)  

‘Ischemic  heart  disease’   0.896   0.344   0.39  (0.05–2.77)  

‘Depressive  disorders’   0.129   0.720   0.81  (0.26–2.51)  

‘Anxiety  disorders’   0.000   0.988   1.01  (0.27–3.75)  

‘Adjustment  Disorders’   0.704   0.402   0.40  (0.05–3.38)  

Sex  (male  vs.  female)   0.408   0.523   0.89  (0.62–1.28)  

Race  (White  vs.  Non-­‐White)   0.090   0.764   0.91  (0.47–1.74)  

‘Obesity’   25.434   0.000   0.08  (0.03–0.22)  

‘Diabetes’   0.887   0.347   0.55  (0.16–1.90)  

‘Hyperlipidemia’   0.010   0.921   1.07  (0.25–4.68)  

‘Medications’  (any  medication  vs  no  medication)   3.833   0.051   0.63  (0.39–1.00)  

‘Hypersomnia’   0.888   0.346   1.47  (0.66–3.29)  “Our  findings  that  hypertension  and  possibly  cerebrovascular  disease  are  more  common  in  those  with  OSA+Insomnia  are  consistent  with  theories  suggesting  that  a  possible  linking  mechanism  between  insomnia  and  OSA  is  the  hyperactivity  of  the  HPA  axis  [14],  [18],  [30]  and  the  sympathetic  nervous  system  [18].  OSA  leads  to  HPA  hyperactivity,  which  then  leads  to  hyperarousal  and  insomnia,  which  perpetuates  these  enhanced  cortisol  levels,  and  eventually  leads  to  the  development  of  other  diseases  associated  with  HPA  hyperactivity  like  cardiovascular  disease” PLoS  One.  2014;  9(3):  e90021.    Published  online  Mar  5,  2014.  doi:    10.1371/journal.pone.0090021  PMCID:  PMC3943798  Cardiovascular  and  Psychiatric  Morbidity  in  Obstructive  Sleep  Apnea  (OSA)  with  Insomnia  (Sleep  Apnea  Plus)  versus  Obstructive  Sleep  Apnea  without  Insomnia:  A  Case-­‐Control  Study  from  a  Nationally  Representative  US  Sample      Madhulika  A.  Gupta*  and  Katie  Knapp  

OSA  +  Insomnia:  A  potenEally  deadly  combinaEon  

Hypermetabolism  in  brain  regions  involved  in  arousal  regulaEon,  fear  responses,  and  reward  processing  persist  during  REM  sleep  in  combat  veterans  with  PTSD.  

During  wakefulness,  veterans  with  PTSD  showed  significantly  greater  relative  rCMRglc  in  a  large  cluster  of  70,326  contiguous  voxels  (MNI  coordinates  of  voxel  of  maximal  significance:  −8,  −34,  −6;  Z  =  4.70,  pFWE  <  0.001),  and  included  the  premotor  and  supplementary  motor  area,  medial  superior  and  inferior  frontal  gyri,  orbitofrontal  cortex,  gyrus  rectus,  and  pars  triangularis.  This  area  also  extended  bilaterally  into  the  anterior,  dorsal,  and  posterior  cingulate  cortex,  and  into  the  rolandic  operculum,  supramarginal  and  angular  gyri,  temporal  gyri,  and  fusiform  and  parahippocampal  gyri.  Limbic  structures  included  in  this  cluster  consisted  of  the  hippocampus,  amygdala,  and  insula,  as  well  of  the  basal  ganglia  (putamen,  caudate,  and  pallidum),  and  thalamus.  Parietal  regions  included  the  postcentral  gyrus,  and  precuneus,  extended  into  the  cuneus  and  occipital  gyri.  Finally,  this  region  included  brainstem  regions  involved  in  arousal  and  REM  sleep  regulation,  including  the  midbrain  reticular  formation,  left  and  right  locus  coeruleus,  raphe  nuclei  and  REM-­‐sleep  regulating  pedunculopontine  tegmentum  and  laterodorsal  tegmentum,  as  well  as  the  cerebellum.  Eigenvariate  values  were  extracted  from  for  each  veteran  and  group  means  were  calculated  for  selected  brain  regions  included  in  this  significant  cluster  

A  Window  into  the  invisible  wound  of  war:  Functional  neuroimaging  of  REM  sleep  in  returning  combat  veterans  with  PTSD  Anne  Germain,  Jeffrey  James,  Salvatore  Insana,  Ryan  J.  Herringa,  Oommen  Mammen,  Julie  Price,  Eric  Nofzinger  Psychiatry  Res.  2013  February  28;  211(2):  176–179.  

Fig. 1 Relative cerebral glucose metabolism (rCMRglc) associated with eveningness during wakefulness (A) and REM sleep (B) in combat-exposed military veterans with posttraumatic stress symptoms. Sagittal sections correspond to the x -coordinates of the pe...

Brant P. Hasler , Salvatore P. Insana , Jeffrey A. James , Anne Germain

Evening-type military veterans report worse lifetime posttraumatic stress symptoms and greater brainstem activity across wakefulness and REM sleep

Biological Psychology, Volume 94, Issue 2, 2013, 255 - 262

http://dx.doi.org/10.1016/j.biopsycho.2013.06.007

Eveningness  was  associated  with  greater  lifetime  PTSD  symptoms,  more  disturbed  sleep,  and  more  frequent  and  intense  nightmares.  Eveningness  was  also  associated  with  greater  brain  activity  in  posterior  cingulate/precuneus  and  brainstem  regions  across  wakefulness  and  REM  sleep,  overlapping  with  regions  related  to  arousal  and  REM  sleep  generation.  

Evening  chronotype  is  associated  with  more  PTSD  symptomatology  

Date of download: 9/11/2014

Copyright © American Psychiatric Association. All rights reserved.

From: Sleep Disturbances as the Hallmark of PTSD: Where Are We Now?

Am J Psychiatry. 2013;170(4):372-382. doi:10.1176/appi.ajp.2012.12040432

Hypnograms for Two Combat Veterans With and Without PTSDaa Both men served in Operation Iraqi Freedom; one was 25 years old, and the other was 26. Sleep characteristics were determined with polysomnography, and baseline measurements appear on the right. REM sleep periods are denoted by thicker horizontal bars. The asterisk on the left side of each graph denotes the latency between the beginning of the time in bed and the onset of sleep, and it is shorter in the veteran without PTSD. Vertical lines after sleep onset reflect awakenings from sleep. In these examples, the veteran without PTSD shows greater sleep efficiency (total sleep time divided by total time spent in bed) despite also showing more frequent brief nocturnal awakenings and a longer wake time after sleep onset than the veteran with PTSD. The percentage of N3 sleep (stages 3 and 4 in the figure) is rather high in both veterans and is higher in the veteran without PTSD. The percentage of REM sleep is slightly higher in the veteran with PTSD.

Figure Legend:

A  meta-­‐analysis  of  polysomnographic  studies  conducted  with  military  veterans  and  civilian  adults  with  PTSD  found  modest  indices  of  objective  sleep  disruption  in  PTSD  (28),  as  indicated  by  more  stage  1  (light)  sleep  (weighted  effect  size  d+=0.24,  95%  confidence  interval  [CI]:  0.02  to  0.46),  less  slow-­‐wave  sleep  (weighted  effect  size  d+=–0.28,  95%  CI:  –0.47  to  –0.09]),  and  greater  REM  density  than  in  subjects  without  PTSD  (weighted  effect  size  d+=0.43,  95%  CI:  0.13  to  0.73).  Examples  of  these  findings  are  depicted  in  Figure  3.  

PTSD  vs  No  PTSD:  differences  in  PSGs  

• Increased  Stage  N1  • Decreased  Stage  N3  • Increased  REM  density  

Acute  PTSD  is  associated  with  fragmented  sleep  and  decreased  REM  sleep,  while  REM  sleep  may  be  increased  in  chronic  PTSD  

“Thus,  our  findings  are  consistent  with  prior  literature  where  reduction  or  fragmentation  of  REM  sleep  has  been  observed  in  the  acute  aftermath  of  trauma  exposure,17,20  and  in  acutely  symptomatic  populations  within  several  years  of  the  onset  of  PTSD,21,22  and  the  observations  of  undisrupted  or  increased  REM  sleep  made  in  veterans  approximately  20  y  after  combat  exposure.25,26  Our  new  findings  and  those  from  the  literature  are  consistent  with  processes  where  reactions  to  trauma  among  those  in  whom  PTSD  develops  are  suppressive  or  disruptive  to  REM  sleep,  whereas  secondary  processes  over  time  promote  REM  sleep.”    

Sleep  as  a  predictor  of  suicidality  

MILITARY  MEDICINE,  179,  7:744,  2014  Prevalence  and  Mental  Health  Correlates  of  Sleep  Disruption  Among  Military  Members  Serving  in  a  Combat  Zone  Marcus  K.  Taylor,  PhD*f;  Susan  M.  Hilton,  MSf;  LCDR  Justin  S.  Campbell,  MSC  USN§;  Shiloh  E.  Beckerley,  PhD*;  CDR  Katharine  K.  Shobe,  MSC  USN/I;  Sean  P.A.  Drummond,  PhDJJ**;  For  the  Behavioral  Health  Needs  Assessment  Team  

Sleep  Deficit  increases  risk  for  GAD  X  9,  MDD  X  7.5,  PTSC  X  10.7  

Nondepressed  individuals  with  insomnia  have  a  two-­‐fold  increased  risk  for  developing  depression  

Cumula,ve  Incidence  of  Subsequent  Depression    Rela,ve  to  Sleep  Complaints  in  Early  Adulthood  

Chang  PP  et  al,  Am  J  Epidemiol.  1997;146:105-­‐114    

Cum

ulative  Incide

nce  (%

)  

Follow-­‐Up  Time  (Years)  0   5   10   15   20   25   30   35   40  

5  

10  

15  

20  

25  

30  

35  

40  

0  

Yes  No  

Insomnia   Total   Cases  

137   23  887   76  

P  =  0.0005  

(n=1,045)  

OSA  pa,ents  with  PTSD  sleep  less,  and  use  CPAP  less  

Treatments  for  Comorbid  Sleep  problems  in  PTSD  

Insomnia:  Cognitive  Behavioral  Treatment  of  Insomnia  (CBT-­‐I)  Parasomnias:    •   alpha  adrenergic  antagonist  (prazosin)  •   Imagery  Rehearsal  Therapy  (IRT)    

Prazosin:  an  alpha-­‐1  adrenergic  antagonist  for  treatment  of  PTSD-­‐related  nightmares  

�  Prazosin  in  the  Treatment  of  PTSD.  �  GREEN,  BEN;  FRCPsych,  MB  

�  Journal  of  Psychiatric  Prac,ce.  20(4):253-­‐259,  July  2014.  

�  DOI:  10.1097/01.pra.0000452561.98286.1e  

PTSD  and  Sleep:  Prac,ce  Points  for  Diagnosis  

�  Safe  environment:    Attend  to  patients’  concerns  about  lab  security,  preferences  concerning  technician  gender.    Hypervigilance,  perimeter  checking  may  be  associated  with  procedure  interruptions  

� Home  vs.  Lab  Testing:    Different  patients  may  have  different  needs/preferences  

�  Security  blankets/transitional  objects:    Patient  requests  for  service  animals/companions,  significant  others  present  

PTSD  and  Sleep:  Prac,ce  Points  for  Treatment  

� Address  the  comorbidities!  �  Insomnia:  CBT-­‐I  first,  sedating  antidepressants  may  be  appropriate  of  the  patient  also  has  depressive  symptoms.  

�  Insomnia:  possible  contraindications  for  benzodiazepines  and  BDZ  agonists  

� Nightmares:  �  Imagery  Rehearsal  Therapy  (IRT)      �  Prazosin  

1.  Sleep  disturbances  often  develop  into  independent,  comorbid  sleep  disorders  in  adults  with  PTSD.  2.  Sleep  disturbances  in  adults  with  PTSD  contribute  to  poorer  outcomes.    These  may  include  mental  health  consequences,  including  exacerbation  of  daytime  PTSD  symptom  severity,  anxiety,  depression,  irritability,  impaired  cognitive  functioning,  increased  suicidality,  and  and  more  functional  impairment  and  disability.  Physical  health  consequences  may  include  obesity,  metabolic  disturbances,  and  cardiovascular  disease.  3.  These  adverse  outcomes  may  be  ameliorated  by  with  sleep-­‐focused  treatment.  4.  A  thorough  evaluation  of  the  nature  and  adverse  impacts  of  sleep  disturbances  on  daytime  symptoms  and  overall  functioning  should  be  integral  to  PTSD  evaluation.    Assessment  and  treatment  of  sleep  disturbances  need  to  consider  the  impact  of  comorbid  PTSD.        

       

Conclusions:    Towards  an  Integrated  Treatment  of  Sleep  Disturbances  and  PTSD  

 

5.  Sleep  disturbances  comorbid  to  PTSD  require  targeted  interventions.  6.  Randomized  controlled  trials  indicate  that  prazosin  can  reduce  nightmares  and  insomnia  in  PTSD.  7.  Imagery  Rehearsal  Therapy  (IRT)  is  established  as  an  effective  behavioral  interventions  for  nightmares  and  may  relieve  PTSD-­‐related  sleep  disturbances.    8.  Other  pharmacological  interventions  such  as  cyproheptadine,  trazodone,  zaleplon,  and  zolpidem  may  also  reduce  nightmares  and  insomnia,  but  the  evidence  for  efficacy  in  treating  nightmares  is  weaker,  and  studies  on  patients  with  PTSD  are  lacking.      9.    Behavioral  insomnia  treatments  (CBT-­‐I)  have  received  robust  empirical  support,  and  may  have  better  long  term  outcomes  compared  to  pharmacotherapies  for  insomnia.      10.  There  is  some  evidence  that  treatment  of  comorbid  insomnia  may  ameliorate  symptoms  of  PTSD.    

Towards  an  Integrated  model-­‐-­‐ConEnued