ANTIDEPRESSANT TREATMENT TO ADDRESS SYNDEMIC DEPRESSION AMONG PERSONS WITH HIV David J. Grelotti, MD June 10, 2016 UCSD HIV & Global Health Rounds

2. ANTIDEPRESSANT TREATMENT
TO ADDRESS SYNDEMIC
DEPRESSION AMONG
PERSONS WITH HIV
David J. Grelotti, MD
Director of Mental Health Services, Owen Clinic
Assistant Professor, Department of Psychiatry
University of California, San Diego

3. Disclosure
• Pharmaceutical industry: Travel support (2014) from
unrestricted educational grant to Kocaeli University
School of Medicine from Novo Nordisk Saglik Urunleri Tic.
Ltd. Sti.
• Government grants: NIMH; NIDA; NIAID/Harvard
University Center for AIDS Research

4. Outline
• Depression and HIV
• Syndemics
• Antidepressant treatment

5. Diagnoses of HIV-infected patients referred for mental
health services at London clinic
Adams et al. 2016
Depression: Relevance to HIV
Numberofpatients
Year

6. Question 1: Which of these symptoms are
required to diagnose depression?
A. Depressed mood most of the day, nearly every day
B. Markedly diminished interest or pleasure in activities
C. Feelings of worthlessness or excessive or inappropriate
guilt
D. Significant distress or impairment in social,
occupational, or other important areas of functioning.

7. Depression: Symptoms and signs
The ABCs of Depression
• Affect: Look sad, feel sad
• Behavior: Psychomotor
slowing, lack of interest in
engaging in pleasurable
activities, lack of energy,
insomnia or hypersomnia
• Cognition: Difficulty
concentrating, persistent
guilty ruminations, feelings of
worthlessness, thoughts of
suicide

8. Major Depression: Diagnosis
5 or more during the same 2-week period:
1. Depressed mood most of the day, nearly every day
2. Markedly diminished interest or pleasure in activities
3. Significant weight loss or decrease or increase in appetite
4. Insomnia or hypersomnia
5. Psychomotor agitation or retardation nearly
6. Fatigue or loss of energy
7. Feelings of worthlessness or excessive or inappropriate guilt
8. Diminished ability to think or concentrate or indecisiveness
9. Recurrent thoughts of death, recurrent suicidal ideation
without a specific plan, or a suicide attempt or a specific plan
for committing suicide
DSM5 2014

9. Major Depression: Diagnosis
• Not due to a substance (e.g., a drug of abuse, a
medication) or a medical condition (e.g., hypothyroidism)
• Not due to Bereavement
• Not Schizoaffective Disorder or other form of psychosis
• Not Bipolar Disorder: No history of a Manic Episode, a
Mixed Episode, or a Hypomanic Episode
• Significant distress or impairment in social, occupational,
or other important areas of functioning.
DSM5 2014

10. Depression: Burden of disease
Global Burden of
Disease Study 2010
• YLL – Years of Life
Lost due to premature
mortality
• YLD – Years of Life
lived with Disability
• DALYs – Disability
Adjusted Life Years
Lozano et al. 2012; Murray et al. 2012; Vos et al. 2012

11. Rankings of leading causes of disease burden
*Self-harm / Suicide
Depression: Burden of disease
Global US and Canada
HIV Depression HIV Depression
YLL # 6 # 13* # 26 # 6*
YLD # 36 # 2 # 50 # 2
DALYs # 5 # 11 # 37 # 5
Lozano et al. 2012; Murray et al. 2012; Vos et al. 2012

12. Depression: Prevalence in the US
Hall et al. 2015; Bing et al. 2001
0%
1%
2%
3%
4%
5%
6%
7%
8%
HIV in the US general
population
Depression in the US
general population
Prevalence

13. Depression: Prevalence in HIV
Bing et al. 2001; Mimiaga et al. 2015
0%
10%
20%
30%
40%
50%
Depression in the US
general population
Depression in HIV-
infected men and
women in the US
Depression in HIV-
uninfected MSM in
the US
Prevalence

14. Comorbidity: Prevalence
General
populationa
HIV-infected
men and
womena
HIV-uninfected
MSMb
Depression 7.6% 36.0% 47.3%
Heavy
alcohol use
4.7% 18.5% 10.5%
Illicit drug
use
10.3% (any
illicit drug)
50.1% (any
illicit drug)
25.1%
(stimulants)
13.7% (≥3 other
illicit drugs)
a. US samples b. Urban US sample of RCT participants
Grant et al. 2004; Bynum et al. 2010; Bing et al. 2001; Mimiaga et al. 2015

15. Rankings of disease burden in the US and Canada
*Self-harm / Suicide
Comorbidity: Burden of illness
HIV Depression Alcohol Drugs
YLLa # 26 # 6* # 32 # 15
YLD # 50 # 2 # 16 # 7
DALYs # 37 # 5 # 19 # 11
Lozano et al. 2012; Murray et al. 2012; Vos et al. 2012

16. Comorbidity: HIV outcomes
Depression and substance use:
• Increase risk of HIV infection
• Act as barriers to accessing treatment services and delay
in initiating ART
• Are associated with suboptimal adherence to ART,
treatment failure, poorer viral suppression
• Are associated with greater HIV-related morbidity and
mortality
Tegger et al. 2008; Celantano et al. 2001; Kalichman et al. 2007; Malta et al. 2010; Obel et al. 2011; Boarts et al. 2006

17. Comorbidity
• Health disparities,
social and historical
influences on HIV risk
• “Multimorbidity,” “dual
diagnosis,” and other
notions of disease
concentration
• Syndemics
Farmer 1999; Tsai & Burns 2015

18. Depression and HIV: Syndemics
“A syndemic is a set of
intertwined and mutually
enhancing epidemics
involving disease
interactions at the
biological level that
develop and are
sustained in a
community/population
because of harmful social
conditions and injurious
social connections.”
- Singer & Clair 2003
• Disease concentration:
Co-occurrence of
disease due to harmful
conditions
• Disease interaction:
Mutually reinforcing
harmful effects on health
Singer & Clair 2003; Tsai & Burns 2015

19. Syndemics theory
Syndemic conditions
• Depression and other
mental health problems
• Substance use
• Intimate partner violence
• Childhood sexual abuse
• Sexual compulsivity
• High-risk sexual behavior
Populations studied
• MSM
• MSMW
• MSW
• Lesbian women
• Bisexual women
• Transgender women
Stall et al. 2003; Brennan et al. 20013; Friedman et al. 2014; Mustanski et al. 2014; Coulter et al. 2015

20. Syndemics model for HIV
Early life adversity
• Bullying
• Physical or sexual
abuse
• Harassment
Psychosocial
epidemics
• Violence victimization
• Depression
• Substance use
• Sexual compulsivity
HIV vulnerability
Stall et al. 2015

21. Syndemics: HIV
transmission
METHODS:
EXPLORE Study
4395 uninfected MSM
Longitudinal 4-year
study
SYNDEMICS:
Depression, Alcohol,
Stimulant, Other
polysubstance use,
Childhood sexual abuse
FINDINGS:
Seroconversion in 3.3%
of those with no
syndemics vs. 15.2% of
those with 4 or 5
syndemics;
Adjusted hazard of 8.59
of HIV-infection with 4 or
5 syndemic conditions
Mimiaga et al. 2015

22. Syndemics:
Adherence
METHODS:
Primary care HIV clinic
333 HIV+ men and
women
MEMS cap monitoring of
adherence
SYNDEMICS:
Childhood abuse;
Current violence;
Alcohol or substance
abuse/ dependence;
PTSD, Mood, and other
psychiatric disorders
FINDINGS:
Increased risk of <80%
adherence in persons
with syndemics (p =
.01);
8.5 times greater odds
of <80% adherence with
5+ syndemics
Blashill et al. 2015

23. Syndemics:
Detectable viral
load
METHODS:
Multicenter AIDS Cohort
Study
766 HIV+ MSM
Prospective /
longitudinal
SYNDEMICS:
Depression,
Polysubstance use,
Unprotected anal
intercourse
FINDINGS:
Syndemics count was
associated with viral
load (p<.01), detectable
viral load (p<.05), and
adherence (p<.001)
Black MSM greater rates
of syndemics (p<.0001)
Friedman et al. 2015
34%
38%
45%
66%
0%
10%
20%
30%
40%
50%
60%
70%
Detectable viral load (%)

24. Syndemics: Summary
• Clustering of psychosocial conditions with HIV infection
and HIV risk
• Varying methodologies used to measure syndemic conditions
• Additive risk of HIV transmission and poorer HIV-related
treatment outcomes
• Future steps:
• Longitudinal studies focusing on syndemic conditions to
demonstrate disease interaction

25. Syndemics: What to do?
• Prevention of early life adversity through structural
interventions (e.g., community mobilization, service
integration, economic interventions, funding reform)
• Promoting resilience (e.g., education)
• Targeted prevention efforts (e.g., encourage condom use)
• Treat the syndemics
• Single component, Multicomponent, or transdiagnostic
• Psychosocial (e.g., community, family, group, individual) or
biomedical
Gilbert et al. 2015; O’Leary et al. 2014; Pitpitan et al. 2015; Pachankis 2015; Blank et al. 2013;
Operario and Nemoto 2010; Rotheram-Borus et al. 2009

26. Diagnoses of HIV-infected patients referred for mental
health services at London clinic
Adams et al. 2016
Depression and HIV: Treatment
Numberofpatients
Year

27. Question 2: Which of the following is NOT
a treatment for depression?
A. Sertraline
B. Trazodone
C. Bupropion
D. Alprazolam
E. Electroconvulsive therapy
F. Cognitive behavioral therapy
G. Amitriptyline
H. Venlafaxine
I. Interpersonal therapy

28. Depression and HIV: Antidepressants
Himelhoch & Madoff 2005

29. Depression and HIV: Antidepressants
Directly Observed Antidepressant Medication Treatment
Study (PI: David Bangsberg, MD, MPH)
• Non-blinded, randomized controlled trial among HIV-
infected, homeless or marginally-housed adults in San
Francisco
• Treatment group: Directly observed once-weekly
fluoxetine for 6 months followed by self-administered
once-weekly fluoxetine for 3 months
• Control group: Referral to a nearby community clinic for
psychiatric care
R01MH054907 PI: David Bangsberg, MD, MPH

30. Directly observed fluoxetine
Tsai et al. 2013
Significant benefit of fluoxetine comparable to other
antidepressant trials

31. Directly
observed
fluoxetine:
Alcohol use
METHODS:
Multilevel mixed-effects
linear regression
• Hamilton Rating
Scale for Depression
(HAMD)
• Beck Depression
Inventory-II (BDI)
• Self-report of any
alcohol use in the
past 90 days
FINDINGS:
Significant effect of
fluoxetine on depressive
symptoms
No evidence of a
moderating or mediating
role of alcohol
Study month
Grelotti et al. under review

32. Directly
observed
fluoxetine:
Drug use
Study month
Grelotti et al. under review
METHODS:
Multilevel mixed-effects
linear regression
• Hamilton Rating
Scale for Depression
(HAMD)
• Beck Depression
Inventory-II (BDI)
• Self-report of any
drug (crack, cocaine,
heroin, or meth) use
in the past 90 days
FINDINGS:
Significant effect of
fluoxetine on depressive
symptoms for non-users
only
No evidence of a
moderating or mediating
role of drug use

33. Directly observed fluoxetine: Results
Stratification
Group
HAMD BDI
Effect of treatment
(95% CI)
p Effect of treatment
(95% CI)
p
Alcohol users -1.76 (-3.42 to -
0.10)
.038 -3.95 (-7.36 to -0.54) .023
Alcohol nonusers -2.34 (-4.10 to -
5.84)
.009 -6.45 (-10.1 to -2.78) .001
[Alcohol use x
fluoxetine treatment
interaction]
-0.62 (-3.03 to 1.80) .618 -2.49 (-7.49 to 2.52) .330
Drug users -1.51 (-3.47 to 0.46) .133 -4.32 (-9.48 to 0.81) .099
Drug nonusers -2.22 (-3.72 to -
0.73)
.004 -5.47 (-8.31 to -2.62) <.001
[Drug use x
fluoxetine treatment
interaction]
-0.74 (-3.41 to 1.94) .591 -1.15 (-6.72 to 4.41) .685

34. Depression and HIV: Antidepressants
• Antidepressants effectively treat depression among
persons infected with HIV
• Syndemic conditions (social marginalization, substance
use) should not deter providers from prescribing
antidepressants for depression
What’s the impact of depression treatment on HIV-
related outcomes?

35. Depression treatment: HIV outcomes
• Antidepressant studies are mixed
• Directly observed antidepressant medication treatment study – no
effect on viral suppression or adherence
• Research on Access to Care in the Homeless (REACH) Study –
2.03 (95% CI 1.15; 3.58; p = .025) greater odds of viral suppression
among persons with depression treated with antidepressants
• Kaiser Permanente – depressed persons adherent to SSRI
treatment had ART adherence and viral load similar to non-
depressed patients
• Limited by lack of power, duration of treatment,
depression symptom severity, and/or ability to adjust for
access to psychosocial interventions
Horberg et al. 2008, Tsai et al. 2010; Tsai et al. 2013

36. Depression treatment: HIV outcomes
• Meta-analysis of 12,243 persons from 29 studies
• Antidepressant studies targeting depression (10)
• Psychosocial interventions targeting depression (6)
• Psychosocial interventions targeting other issues (13)
• 1.83 (95% CI: 1.27, 2.55) greater odds of adherence with
depression treatment
• Studies targeting depression (predominantly
antidepressant trials) showed a greater impact on
adherence than those targeting other issues
Sin & DiMatteo 2014

37. Question 3: True or false? Most HIV care
providers believe treating depression is
part of their role.
A. True
B. False

38. Depression:
Role of
providers
Provider routine practices and beliefs %
Belief that treating depression is part of their
role
77%
How depression is assessed:
• Screening 32%
• Observation or patient discloses 61%
Confidence in prescribing:
• Prescribing an initial antidepressant 59%
• Use of full dose ranges 45%
• Changing or augmenting antidepressants 14%
Follow up within 4 weeks 37%
Survey of 72 HIV
providers (Attending,
fellow, “mid-level”
providers)
Bess et al. 2013

39. Depression: Treatment barriers
• Perception of providers that on average only 50% of their
patients with recognized depression were receiving
treatments.
• Depression went undiagnosed in 54% of HIV-infected
patients with depression
• National sample of HIV-infected persons from 1996-1998
• Persons with less perceived need, less than high school education,
and private insurance were less likely to be diagnosed
Bess et al. 2013; Asch et al. 2003; Taylor et al. 2004

40. Depression: Treatment barriers
• Community factors
• Availability of providers
• Stigma of mental illness
• Patient factors
• Syndemics
• Provider factors
• Lack of familiarity with psychiatric prescribing:
General medical providers are less likely to prescribe psychiatric
meds than mental health specialists (31% vs. 61%, p<.0001)
• Report not enough time in appointments
• Base treatment decisions on subjective “perception of need”
• Under-recognition of depression
Bess et al. 2013; Asch et al. 2003; Taylor et al. 2004

41. Depression:
Treatment
strategies
DEPRESSION
• Depression (uncomplicated)
• Depression and smoking cigarettes
• Depression and pain
• Depression and difficulty sleeping
and/or weight loss
ANXIETY
• Anxiety disorders
• As needed medication
INSOMNIA
BENZODIAZEPINES
ADHD
NIGHTMARES IN SETTING OF PTSD
Prescribing “Smartset”:
1. Recommended first-
line therapy
2. Dosing and titrating
3. Side effects to warn
people about
4. Interactions with HIV
medications

42. Depression Treatment: SLAM-DUNC
• “Measurement-Based Care” (MBC)
• Captures best practice:
• Treatment algorithms
• Defined windows for follow up
• Systematic screening for depressive symptoms and side effects
• Uses a Depression Care Manager to provide data and
recommendations to providers
Pence et al. 2012

43. MBC Haiti: RCT
• SLAM DUNC was adapted for Haiti and used at
GHESKIO (Groupe Haïtien d'Etude du Sarcome de
Kaposi et des Infections Opportunistes) using non-
specialist health workers
• Participants were randomized to MBC or “enhanced care”
• 482 patients were screened
• 21% had confirmed major depression
• 43 received MBC, 35 received enhanced care
• Participants were 61% female
• Mean age was 34.7 years
• Preliminary findings are available for depression symptom
severity.
R21MH103054 PI: Jessy Dévieux, PhD

44. MBC Haiti: Depression outcomes
0
2
4
6
8
10
12
14
16
0 3
MBC
Control
Study Month
PHQ9score
P=.023
Jean-Gilles et al. 2016

45. Summary
• Depression is a highly disabling syndemic that magnifies
HIV risks
• Antidepressant treatment works in populations with HIV
and active substance use, and when guided by non-
specialist health workers employing measurement-based
care
• Antidepressant treatment treats depression and likely
improves HIV treatment outcomes

46. Future steps
• Scalable interventions to decrease syndemics and
improve treatment outcomes among HIV-infected persons
• Interventions to address syndemics in HIV-uninfected
persons and improve success of PrEP and other HIV
prevention efforts

47. Recommendations
1. Ask your patients about depression and other syndemic
conditions
2. Give patients hope that depression, like HIV, can also
be treated
3. Start treatment and refer if necessary

48. Acknowledgments:
• David Bangsberg
Alexander Tsai
HOME Study Team
• Jessy Dévieux
Michele Jean-Gilles
GHESKIO Study Team
Contact information:
David Grelotti, MD
UC San Diego
200 West Arbor Dr. #8681
San Diego, CA 92106
dgrelotti@ucsd.edu