An overview of potential mechanisms of the
depression-diabetes link
Khalida Ismail
Integration of Psychiatry into Primary Health Care
Kuwait
26-28 Jan 2014
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Depression-diabetes link
depression
type 2
diabetes
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Current evidence base
Depression is common in diabetes (10-30%)
Depression associated with worse biomedical
outcomes: 2-3 fold increase in mortality
Depression is under-detected yet highly treatable
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Bi directional association
depression
RR 1.10 (1.02-1.19)
RR 1.54 (1.13-2.09)
type 2
diabetes
Golden et al JAMA 2008
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Cause AND consequence= common
origins?
depression
type 2
diabetes
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The type 2 diabetes continuum
early
metabolic
programming
HPA axis
inflammation
insulin
resistance
impaired
glucose
tolerance
type 2
diabetes
Depression is associated with all stages of
the diabetes continuum
odds ratio
1.37-1.60
odds ratio
2.1
pre-diabetes
diabetes
effect size
0.17
odds ratio
3.1
complications
suboptimal
glycaemic control
hazards
ratio
2.0-5.0
mortality
Pre-diabetes: Mezuk Diabetes Care 2008
Diabetes: Anderson et al Diabetes Care 2001
Glyceamic control: Lustman et al Diabetes Care 2000
Complications: dr Groot et al Psychosom Med 2001
Mortality: Katon et al Diabetes Care 2005; Ismail et al Diabetes Care 2007
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Common mechanisms for the
depression-diabetes link
+/-
Psychological processes
Biological processes
Psychological mechanisms
•
•
•
•
diabetes specific distress
self-neglect of depression
impulse control
satiety
A cognitive behavioural model of the effect
of depression on the t2dm continuum
Altered cognitions
‘Im a failure if I can’t get blood sugars right’
‘Insulin is bad for me’
‘My life is not worth living’
Perception of
symptoms
blood glucose
medic side effects
fatigue/pain
Affect
Anxiety
low mood
Behaviour
reduced diabetes self care
unhealthy lifestyles
High blood sugar
Limitations of the psychological model
Glycaemic control
• Cross-sectional studies: pooled effect size 0.17
(Lustman, Diabetes Care 2000)
• Prospective studies: limited number and
unconvincing
Treatment of
depression in
diabetes
• Depression improves
• Inconsistent findings that glycaemic control
also improves (Katon et al Arch Gen Psychiatry
2004; Katon et al NEJM 2010)
Treatment of
depression in
cardiovascular
disease
• Depression improves
• No evidence from SADHEART (Glassman JAMA
2002) or ENRICHD (JAMA 2003) that cardiac
outcomes and mortality improves
Potential of the psychological model
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Biological mechanisms
•
•
•
•
•
•
•
•
•
HPA axis
innate inflammation
autonomic nervous system
early life programming
antidepressants
circadian clock
gut hormones and satiety
sleep apnoea
mitochondria
Brotman et al Lancet 2007
Multiple effects of the innate immune
response
ENVIRONMENTAL THREATS/TOXINS: excessive adiposity, chronic psychosocial
stressors eg smoking
MACROPHAGES: pro-inflammatory (IL-6, IL-1, TNF-) and anti-inflammatory cytokines
(adiponectin) ‘sickness behaviors’
ACUTE-PHASE RESPONSE: blood proteins (C-reactive protein (CRP), serum amyloid A)
and triglycerides
CELL DAMAGE: Pancreatic -cell apoptosis, insulin resistance, reduced insulin
secretion, endothelial dysfunction, central effects on neuroglia
DISEASE: type 2 diabetes, arthrosclerosis, depression, cognitive impairment
Innate inflammation as a common pathway
T2DM is an inflammatory condition (Pickup et al 1998)
Early
metabolic
programming
Innate
inflammatory
response
Insulin
resistance
T2DM
Macrophage theory of depression (Smith 1991)
Innate
inflammatory
response
Depression
Depression is associated with insulin resistance
1
2
3
4
5
6
7
8
9
10
Diagnostic Interview
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Self reported
0.46 (0.22, 0.71)
0.13 (0.08, 0.21)
Kan et al Diabetes Care
2012
Pooled effect size (95% confidence interval): 0.19 (0.11-0.27)
Childhood maltreatment is associated with
inflammatory markers in adults
30
20
10
0
hsCRP > 3 mg/L (%)
40
• High CRP risk group for cardiovascular disease
• (CDC, AHA): CRP>3mg/L
No
Moderate
Severe
Childhood maltreatment
Danese et al PNAS 2007
The SOUth London Diabetes Cohort Study
Setting of SOUL-D
Lambeth Southwark Lewisham
n= 96/139 surgeries
Baseline results from SOUL-D
Baseline characteristics by Patient Health Questionnaire-9 (≥10 represents
depression case)
No depression
(n=1278)
Depression
(n=182)
Mean age (SD), years
56.2 (11.5)
52.8 (9.5)*
Female (%)
557 (43.6)
94 (51.6)*
Mean body mass index (SD),
kg/m2
31.6 (6.3)
32.7 (7.1)*
Mean % HbA1c
7.00 (1.4)
7.10 (1.5)
Median hs C-reactive protein
(IQR), mg/l
2.6 (1.1-6.2)
3.4 (1.5-8.9)*
Median white cell count (IQR),
x109/L
6.5 (5.3-7.9)
7.1 (5.7-8.6)*
*p<0.05
adjusted for age, gender, marital status, smoking, ethnicity, BMI, antiinflammatory medication
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Innate inflammation as a common pathway
T2DM is an inflammatory condition (Pickup et al 1998)
Early
metabolic
programming
Innate
inflammatory
response
Insulin
resistance
T2DM
Macrophage theory of depression (Smith 1991)
Early
metabolic
programming
Innate
inflammatory
response
Insulin
resistance
Depression
Depression and type 2 diabetes:
the search for common origins
lifestyles
Depression is
common in
T2DM
Depression is
associated
increased
mortality
Treating
depression
alone does
not improve
glycaemic
control
foetal nutrition
innate inflammation
genomics
social
adversity
depression
type 2
diabetes
Ismail PoS 2013
Final conclusions
• Global epidemic of T2DM has led to increased absolute
burden of depression comorbidity
• The notion that depression and T2DM may share common
pathways offers new aetiological mechanisms for both
conditions
• There is a need for innovative models integrating
depression management with diabetes management
(similar to diabetes complications)
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