National Adaptive Trial for PTSD Related Insomnia

Inclusion Criteria:

1. Ability to comprehend and provision of signed and dated informed consent form

2. Stated willingness to comply with all study procedures and availability for theduration of the study (approximately 17 weeks from the date of being randomized)

3. Individuals, between the ages of 18 and 75 years

4. Allow digital recording of phone interviews

5. PTSD related to military service

6. Primary DSM-5 diagnosis of PTSD, assessed by structured interview using the CAPS-5

7. Total CAPS-5 score 23

8. ISI >15

9. Screening clinical laboratory tests without clinically significant abnormalitiesthat would make study participation inappropriate, as determined by the siteinvestigator with input, if needed, from the study chair

10. Electrocardiogram (ECG) at baseline without clinically significant abnormalitiesthat would make study participation inappropriate, as determined by the siteinvestigator with input, if needed, from the study chair and/or contingent uponapproval by consulting medical physician.

11. Females of childbearing potential:

12. Must have a negative pregnancy test during screening

13. Must agree not to become pregnant or breastfeed during the course of the study

14. Must be willing to use a reliable form of contraception for 16 weeks (duringstudy treatment and for 2 weeks after taking the last dose) which includes:barrier contraceptives (male or female condoms with or without a spermicide,diaphragm or cervical cap with spermicide, or intrauterine device) andhormone-based therapy (contraceptive pills, intrauterine devices, orDepo-Provera®)

15. Birth control for female participants is not necessary if surgically sterile orif with a partner with whom they are not capable of conceiving children (defined as a surgically sterile female by hysterectomy, bilateraloophorectomy, or bilateral tubal ligation; surgically sterile male who hasundergone a complete orchiectomy or successful vasectomy; or a same sexpartner)

16. Agree to secure firearms while receiving study treatment

17. If individuals are undergoing evidence-based psychotherapy (EBT), which includescognitive behavioral therapy (CBT), cognitive processing therapy (CPT), prolongedexposure therapy (PE), and/or stress inoculation therapy (SIT), they must havestarted these therapies at least 60 days prior to starting screening. If screeningis started, and it is then discovered that EBT was started within 60 days prior toscreening, participants must wait at least 60 days since staring the new EBT beforethey can complete the screening ISI, the screening PCL, and the Phone Assessment. (Supportive individual and group therapy is allowed)

18. Agreement to adhere to Lifestyle Considerations (see Section 5.3) throughout studyparticipation

19. Clinical evidence of adequately treated sleep apnea or absence of sleep apnea havinga severity that would make study participation problematic, established by meetingone of the criteria below:

20. Clinical evidence of adequately treated sleep apnea with a continuous positiveairway pressure (CPAP) or alternative treatment device (as defined in Section 8.1) (Participants can be reevaluated at least 30 days after screen failure.)

21. If clinically tested, sleep study negative for sleep apnea or resultsindicating an Apnea-Hypopnea Index (AHI) < 23 within the past 6 months

22. If tested for study eligibility, ApneaLink (or equivalent alternative device)result or other sleep study shows AHI < 23.

Exclusion Criteria:

1. Currently enrolled in any other interventional study unless prior approval isprovided by the study team (It is a CSP policy that exemptions will be assessed forindividual patients on a case-by-case basis. Exemptions require the agreement inwriting of the following individuals or groups: (1) the SIs of both studies; (2) theStudy Chairs of the involved studies; (3) the appropriate CSP Center Director(s);and (4) the VA Central IRB.)

2. Allergy and/or history of intolerance to trazodone hydrochloride and/or eszopiclone,or history of experiencing complex sleep behaviors (i.e., sleep walking, sleepdriving, and/or engaging in other activities while not fully awake) while taking anysleep medication

3. A comorbid current or lifetime diagnosis of bipolar I disorder, bipolar II disorder,schizoaffective disorder, schizophrenia or delusional disorder, or current comorbiddiagnosis of schizophreniform disorder, brief psychotic disorder, psychotic disorderdue to a general medical condition, substance-induced psychotic disorder orpsychotic disorder not otherwise specified (NOS) according to Structured ClinicalInterview for DSM-5 (SCID)-I-RV/P

4. History of moderate or severe traumatic brain injury (TBI) or history of grossstructural damage as shown on MRI.

5. Positive urine test for an illicit substance, excluding cannabis, within the past 90days prior to screening

6. Substance use meeting DSM-5 criteria for moderate or severe dependence (excludingnicotine) within the past 12 months prior to screening. (Note: Current milddependence for alcohol and cannabis use is acceptable, but current mild dependenceof any other substances is exclusionary.)

7. Inpatient psychiatric hospitalization within 30 days prior to screening

8. Suicidal or homicidal ideation with intent or plan to harm themselves or otherswithin 90 days prior to screening

9. Chronic liver disease with two or more of the following occurring within the pastsix months: international normalized ratio (INR) greater than or equal to 1.7 (noton warfarin therapy), bilirubin greater than or equal to 2 mg/dL, serum albumin lessthan or equal to 3.5 g/dL, ascites, or encephalopathy (Participants can bereevaluated in 30 days)

10. Clinical and laboratory evidence of untreated hypothyroidism or hyperthyroidism

11. A corrected QT (QTc) interval greater than 470 ms

12. Unstable, serious medical condition or one requiring acute medical treatment, orplanned hospitalization for extended care

13. Dementia, epilepsy, stroke, or current treatment with warfarin for anticoagulation

14. Taking any of the exclusionary medications listed in Appendix A. Note- an individualtaking one of these medications for the sole purpose of improving sleep that electsto undergo an adequate wash-out period of at least 5 half-lives of the parentcompound or active metabolite (e.g., for medications like diazepam), under the careof the individual's clinical provider, would not be excluded by this criterion.

15. Under criminal investigation or pending legal charges with potential incarceration

16. Individuals who lack stable contact information (including lack of a telephonenumber)

17. Participants who anticipate working during the hours of midnight to 6am during thecourse of study trial

18. Participants with narcolepsy