Sleep, a Governor of Morbidity in PTSD: A Systematic Review of Biological Markers in PTSD-Related Sleep Disturbances

Figures & data

Table 1 Literature Search Strategy, Consisting of Medical Subject Headings (MeSH) and Keywords. OVID Online Platform Was to Search EMBASE, Medline, AMED, PsychINFO Databases

Component	1	2	3
MeSH Heading	Stress Disorders, Post Traumatic (All Fields)	Sleep Initiation and Maintenance disorders (All Fields)	Biomarkers (All Fields)
Function	“OR”
Keywords	PTSD Post-traumatic Stress Disorder	Insomnia Chronically disrupted sleep Sleep initiation disorder Nightmares	Biomarker* Neuroendocrine Neurotransmitter Hormone Inflammatory Cytokine Blood pressure Hypotension Hypertension Heart Rate Bradycardia Tachycardia
Search	“1” AND “2” AND “3”
Filter	“Published 2005 – Current Date”

Note: *All Suffix Search.

Figure 1 Summary of literature screening method employed. A total of 513 articles were identified using the search strategy developed. After removal of duplicates, 471 articles were retained for title and abstract screening, following which 38 were retained for full-text eligibility assessment. Sixteen studies were deemed to meet all the inclusion criteria and were subject to analyses.

Table 2 Summary of Data Extraction from Included Studies

Study	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16
Reference	^Citation117	^Citation118	^Citation119	^Citation120	^Citation121	^Citation122	^Citation123	^Citation124	^Citation125	^Citation126	^Citation127	^Citation128	^Citation129	^Citation130	^Citation131	132
Population	Military	Military	Military	Urban	Urban	NS Civilian	NS Female	Military	Military	NS	Military	Military + EMS	Kidney Transplant	Military	Military	Japanese Female
Population Size	44	61	68	38	38	47	53	66	18	66	1855	35	268	45	31	105
Males	NR	0	66	21	12	8	0	64	17	30	1477	34	138	45	31	0
Females	NR	61	2	17	26	39	53	2	1	36	378	1	129	0	0	105
Age	33.3	38.3	22.8	NR	22.8	47.0	41.3	34.9	40.9	30.0	37.4	43.3	49.9	36.5	41.2	37.4
Study Design	Case-controlled	Cohort	Case-controlled	RCT	Cohort	RCT	Cohort	Cohort	Cohort	Cohort	Prospective	Cohort	Cohort	Cohort	Cohort	Cohort
Sleep Measures	PSG, ESS, PSQI	PSQI	PSQI	ISI	Actigraphy, Sleep diary	PSQI	Actigraphy	PSG, PSQI	ISI	PSG, Actigraphy, Sleep diary	Sleep items from SC-90	PSG, sleep diary	AIS	Sleep diary, PSQI	Actigraphy, NR	AIS
Intervention	CBTI or CBTI + PAP	N/A	CBTI or CBTI + PAP	RSA Biofeedback	N/A	ERRT	N/A	SOC	CAN	Metyrapone	N/A	N/A	N/A	N/A	Canine presence	N/A
PTSD assessments	PCL-M	CAPS + DTS	PCL-M	PCL-C + PTS-T	CAPS	CAPS	CAPS	PCL-M	PCL-M	CAPS	SCID + DTS	CAPS + PCL-5	DTS	CAPS + SCID	CAPS	PDS DSM-IV, Japanese IES-R
Physiological Measures	Hypertension	BP	N/A	BPM, HRV	HR, HRV	HR, SCL	BRS	N/A	HRV, BRS, BP	N/A	BP	SPO2, HR	BP	HR	HR, REI, RSA	N/A
Biochemical Measures	BDNF, IGF-1	N/A	mRNA	N/A	N/A	N/A	N/A	IL-6, CRP	Ag-II, Ag1/7, Epinephrine, Norepinephrine, CRP, vasopressin, IL-1, IL-6, IL-10, Cortisol, alpha-amylase, DNA methylation	ACTH, Cortisol, 11-deoxycortisol	N/A	N/A	Ht, Hb, WBC, PLT, CRP, Glucose, Urea, creatinine, proteins, albumin, Na, K, Ca, P, Fe, ferritin, TSAT, PTH, 25(OH) D3, HbcA1c	Cortisol, ACTH, Melatonin	N/A	IL-6, IL-1β, TNF-α, CRP, sIL-6R
Sample Matrix	Plasma	N/A	Peripheral Blood	N/A	N/A	N/A	N/A	Peripheral Blood	Peripheral Blood, Saliva (Cortisol & Alpha-amylase)	Peripheral Blood	N/A	N/A	Peripheral Blood, Urine	Peripheral Blood	N/A	Serum
Additional Measures	N/A	BDI-II	QIDS	BDI-II	PHQ-9	TRNS, TSI, PILL, PTCSS	N/A	QIDS, RAND HRQOL	CES-D, GAD-7, Grip strength	N/A	BDI	Nightmare questionnaire, AUDIT, HADS	JH-RLSSS, HADA	N/A	Prior mood, kinetocardiogram	IES-R, CTQ, SAI, BDI-II, JRBAN S

Abbreviations: NR, not reported; N/A, not applicable; RCT, randomized control trial; PSG, polysomnography; ESS, Epworth Sleepiness Scale; PSQI, Pittsburgh Sleep Quality Index; ISI, Insomnia Severity Index; AIS, Athens Insomnia Scale; CBTI, cognitive behavior therapy for insomnia; PAP, positive airway pressure; RSA, respiratory sinus arrhythmia; SOC, standard of care; CAN, closed-loop allostatic neurotechnology intervention; PCL, PTSD checklist; CAPS, Clinician Administered PTSD Scale; SCID, Structured Clinical Interview for DSM-IV; DTS, Davidson Trauma Scale; TSI, Trauma Symptom Inventory; PILL, Pennebaker Inventory of Limbic Languidness; PTCSS, Post Treatment Clinical Significance Survey; NR, nightmare recall; SCL, skin conductance level; BP, blood pressure; HRV, heart rate variability; BRS, baroreceptor sensitivity; HR, heart rate; BPM, breaths per minute; REI, Respiratory Event Index; RSA, respiratory sinus arrhythmia; IES-R, Impact of Event Scale-Revised; CTQ, Childhood Trauma Questionnaire; SAI, State-Trait Anxiety Inventory; BDI-II, Beck Depression Inventory-II; JRBANS, Japanese version of the Repeatable Battery for the Assessment of Neuropsychological Status.

Table 3 Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) Assessment of Evidence Quality. Final GRADE Quality Assessment Possibilities; High, Moderate, Low, Very Low

Certainty Assessment
No of Studies	Risk of	Inconsistency	Indirectness	Imprecision	Publication Bias	Overall Certainty of Evidence
SDs regulate BP in PTSD (assessed with: BP, BRS)
5 studies	Not serious	Not serious	Serious	Not serious	All plausible residual confounding would reduce the demonstrated effect, dose response gradient	⨁⨁⨁◯ MODERATE
Sympathetic dominance in PTSD is mediated by sleep (assessed with: HR, nHF, nHF/LF, RSA, SC)
7 studies	Not serious	Not serious	Not serious	Not serious	Dose response gradient	⨁⨁⨁◯ MODERATE
Sleep regulates global inflammatory status (assessed with: Peripheral blood cytokines, mRNA expression)
4 studies	Not serious	Serious	Not serious	Not serious	All plausible residual confounding would reduce the demonstrated effect	⨁⨁◯◯ LOW
Protection from glucocorticoid over exposure in PTSD is at the expense of sleep (assessed with: Cortisol, 11-Deoxycortisol, ACTH)
3 studies	Not serious	Not serious	Not serious	Not serious	All plausible residual confounding would reduce the demonstrated effect	⨁⨁⨁◯ MODERATE
Trophic factor regulation improved with improved sleep (assessed with: IGF-1, BDNF)
1 study	Serious	Not serious	Not serious	Not serious	Strong association, all plausible residual confounding would reduce the demonstrated effect, dose response gradient	⨁⨁⨁⨁ HIGH

Abbreviations: SDs, sleep disturbances; PTSD, post-traumatic stress disorder; BP, blood pressure; BRS, baroreceptor sensitivity; HR, heart rate; HRV, heart rate variability; nHF, normalized high frequency; LF, low frequency; RSA, respiratory sinus arrhythmia; SC, skin conductance; ACTH, adrenocorticotrophic hormone; IGF-1, insulin like growth factor 1; BDNF, brain derived neurotrophic factor.

Figure 2 Graphic showing the different sleep assessment methods employed across the included studies, as a percentage of the total number methods. Pittsburgh Sleep Quality Index (21.7%), Polysomnography (21.7%), Sleep diary (17.4%), Actigraphy (13%), Trauma-related nightmare survey (4.3%), Symptom checklist 90 (4.3%), Insomnia Severity Inventory (4.3%), Epworth Sleepiness Scale (4.3%), Athens Insomnia Scale (4.3%), dichotomous nightmare recall (4.3%).

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