1. An overview of potential mechanisms of the depression-diabetes link
Khalida Ismail
Id like to thank you to the organisers for inviting me. My main objective is to give you an overview of the potential mechanisms of the dd link. I will only have time to talk about t2dm today
Integration of Psychiatry into Primary Health Care Kuwait
26-28 Jan 2014

2. Depression-diabetes link
type 2 diabetes
At this conference we are interested in what way are the patients in the middle different to patients with depression alone or t2dm alone, or

3. 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
There are a number of statements we can be confident about. First that depression is common, it is increased 2 fold in people with diabetes compared to those without diabetes. Second that it is associated with worse biomedical outcomes, most notabiliy 2-5 fold increase in mortality depending on which studies and third, it is under detected and when detected under treated and yet amenable to treatment.

4. Bi directional association
depression
type 2 diabetes
RR 1.10 ( )
RR 1.54 ( )
Golden et al JAMA 2008

6. Cause AND consequence= common origins?
depression
type 2
diabetes
This suggests that it is not going to be so fruitful at the moment to answer which came first and a more productive line of research is to postulate that perhaps depression and t2dm have some pathways that are common to both

7. The type 2 diabetes continuum
early
metabolic
programming
HPA axis
inflammation
impaired
glucose
tolerance
insulin
resistance
when I think about t2dm, I think of it as the end point of a psychological and physiological journey that began in utero with genes from your parents and foetal nutriion, followed by factors in early childhood leading to being metabolically programmed and in the context of high fat diets and decreased physical activity going into adulthood, chronic activation of the innate inflammation and other metabolic processes.

8. Depression is associated with all stages of the diabetes continuum
odds ratio
odds ratio
3.1
hazards ratio
odds ratio
2.1
effect size
0.17
pre-diabetes
diabetes
suboptimal glycaemic control
complications
mortality
To make the task complicated, idepression is associated with t2dm at stages of its natural history, the depression phenotype is present before the diabetes phenotype and it increases its hold as the disease progresses from complications to mortality. So we have this situation where depression and diabetes seem to be interwoven with each other go hand in hand, interv
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

9. Psychological processes
Common mechanisms for the depression-diabetes link
+/-
So how do we search for mechanisms that are common to depression and t2dm? We can start making an albeit artificial distinguishing between pschological process and biological processes that might be common.
Psychological processes
Biological processes

10. Psychological mechanisms
diabetes specific distress
self-neglect of depression
impulse control
satiety
The most popular psychological explanation is that depressive state isleading self neglect anhedonia, poor conc but is this enough, other models currently been studied is the notion that diabetes specific distress is the driver for worse outcomes in t2dm. Yet again, there are two other psychological models from the field of addiction that have not been adequately studied.These are degree to which impaired impulse control-we know that impulse control disorders such as gambling, alcohol, drugs, bulimia and obesity tend to run in families. And there is a nother construct ‘satiety’ ie The condition of being full or gratified beyond the point of satisfaction; and this is under both higher cerebral control as well as capacity of our brains to know when we are full is also a concept that basic scientisits are studying.

11. Perception of symptoms
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
This is a standard cognitive behaviour model demonstrating how low mood is linked to changes in diabetes self care behaviours and ultimately poor glycaemic control.
Behaviour
reduced diabetes self care
unhealthy lifestyles
High blood sugar

12. 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
No evidence from SADHEART (Glassman JAMA 2002) or ENRICHD (JAMA 2003) that cardiac outcomes and mortality improves
Some further limitations of the psychological model are listed here. First if you remember my natural history slide, while depression is associated with worse glycemic control, the effect size is small ie 0.2 and there have been insufficient prospective studies of acceptable methodology. Second there have been many RCTs of the treatment of depression alone in diabetes. In these studies, depression always improves but improvement in glycaemic control is inconsistent. I will come back to this in my final section. There are similar observations in cardiovascular settings. Here, we know that depression increases risk of mortality following a myocardial infarct. Treatment of depression alone does not improve mortality following myocardial infarct.

13. Potential of the psychological model
Theoretical models for pschological interventions are still relatively simple. Basic CBT, problem solving and even my current favourite motivational intervieiwng.We are way behind the psychotherapists, variants of CBT,

14. Biological mechanisms
HPA axis
innate inflammation
autonomic nervous system
early life programming
antidepressants
circadian clock
gut hormones and satiety
sleep apnoea
mitochondria
What might be possible common biological pathways that could be shared with depression and t2dm-the dilemma for us are how many of these are mechanisms versus epiphenomon or collaterals

15. It has been argued that depression is a chronic flight fright or stress response. Chronic stress has a similar effect to acute stress response and the strongest evidence is for cardiovascular disease. End organ targets-encouraging
Brotman et al Lancet 2007

16. 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
There is increasing evidence that the Innate immune response has multi-system effect. The innate immunity is the body’s first line defence against environmental threats. Pro-inflammatory cytokines (interleukin (IL)-6, IL-1, tumour necrosis factor (TNF)-) are released by macrophages and other cells, and in turn stimulate the ‘acute-phase response’ =large changes in the concentration of blood proteins such as C-reactive protein (CRP), serum amyloid A, haptoglobulin and fibrinogen. Anti-inflammatory cytokines, such as adiponectin, are also released to counteregulate. If the pathological stressor continues, as with overeating, then over time, there is cell damage which leads to B islet cells destruction, reduced insulin secretion, increased insulin resistance, endothelial cells in the arteries damaged and in recent years, damage to brain cells. Finally perhaps over years this leads to manifest disease such as diabetes, heart disease and neuropsychological sequelae such as depression and cognitive impairment.

17. Innate inflammation as a common pathway
T2DM is an inflammatory condition (Pickup et al 1998)
Innate inflammatory response
Insulin resistance
T2DM
Early
metabolic programming
I am very lucky to be able to work with John Pickup who is professor of diabetes and metabolism at Kings College Hospital. He was the first person to test the hypothesis that activation of innate inflammation is linked to the pathogenesis of type 2 diabetes. Since then there have been thousands of studies to confirm this and it is now a well established observation but it was even earlier that the hypothesis that depression may also be an inflammatory response.
Innate inflammatory response
Depression
Macrophage theory of depression (Smith 1991)

18. Pooled effect size (95% confidence interval): 0.19 (0.11-0.27)
Depression is associated with insulin resistance 1 2 3 4 5 6 7 8 9 10
Diagnostic Interview 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
0.46 (0.22, 0.71)
Self reported
So is there any further evidence of activated innate inflammation in depression-this is a systematic review of observational studies of the association between depression and insulin resistance by my research fellow, Carol Kan and medical student, Naomi Silva. It is clearly a busy slide but the key findings are that while there is a small but highly significant association between depression and insulin resistance, in subgroup analysis, the effect size was greater, nearly 0.5 in those studies that had used diagnostic interview to detect depression
0.13 (0.08, 0.21)
Kan et al Diabetes Care 2012
Pooled effect size (95% confidence interval): 0.19 ( )

19. Childhood maltreatment is associated with inflammatory markers in adults
High CRP risk group for cardiovascular disease
(CDC, AHA): CRP>3mg/L 40 30
hsCRP > 3 mg/L (%) 20
If there is no evidence of in utero programming is there any evidence of early childhood programming.
Dunedin child to adult cohort in New Zealand-this is a large prospective cohort study
Measures objective and subjective of parenting and caregiving from emotional attention to discipline to abuse
Adjusted for lifestyle mediators, other stressors
People were defined according to whether they had levels of hs CRP associated with cardiovascuar disease and found a dose related positive association between degree of maltreatment and proportion who had CRP levels greater than 3
Considering they taking into account of multiple potential confounders, this does seem to suggest that early life experieces can programme the immune systems 10 No
Moderate
Severe
Childhood maltreatment
Danese et al PNAS 2007

20. The SOUth London Diabetes Cohort Study
For instance, screening for depression in diabetes is a problem. Just to illustrate, we are conducting a prospective cohort study of nearly 2000 newly diagbosed type 2 diabetes and following them up for 2 years to test whether depression at diagnosis is associated with worse glycaemic control.
The SOUth London Diabetes Cohort Study

21. Lambeth Southwark Lewisham n= 96/139 surgeries
Setting of SOUL-D
These are the primary care practices (n=96) where we recruited patients from. This is Kings College Hospital where I am based in the south of river Thames. I know Japanese people love the Queen and so we are not far from Buckingham Palace which is just north of the river from us!
Lambeth Southwark Lewisham n= 96/139 surgeries

22. 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 ( )
3.4 ( )*
Median white cell count (IQR), x109/L
6.5 ( )
7.1 ( )*
*p<0.05
adjusted for age, gender, marital status, smoking, ethnicity, BMI, antiinflammatory medication

23. Innate inflammation as a common pathway
T2DM is an inflammatory condition (Pickup et al 1998)
Innate inflammatory response
Insulin resistance
T2DM
Early
metabolic programming
Innate inflammatory response
Depression
Macrophage theory of depression (Smith 1991)
Early
metabolic programming
Insulin resistance

24. Depression and type 2 diabetes: the search for common origins
Depression is common in T2DM
Depression is associated increased mortality
Treating depression alone does not improve glycaemic control
lifestyles
depression
type 2 diabetes
foetal nutrition
Thank you. I am going to talk to you about my work on the depression and type 2 diabetes link. Based on our research and that of others, there are a number of statements we are confident of. First that depression is common, it is increased at least 2 fold in people with diabetes compared to those without diabetes. Second that it is associated with worse biomedical outcomes. In a south london diabetes foot cohort, we found a 3-fold increase in mortality. Third, when we treat just the depression, depression practically always improves but glycaemic control does not. This suggests that the psychological model of depression, which states that depressive cognitions and emotions interferes with diabetes selfcare, is insufficient to explain the adverse effects of depression on diabetes outcomes. Following John Pickup’s pioneering work here at Kings 20 years ago, it is well known that activation of innate inflammatory response is on the causal pathway for type 2 diabetes. My team is studying is whether the same activation of the innate inflammatory response is also on the causal pathway for depression or a subtype of depression. We are also studying risk factors for the depression and type 2 diabetes at different stages of the lifespan that includes genetics, early life adversity and lifestyle behaviours.
innate inflammation
genomics
social adversity
Ismail PoS 2013

25. 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)

26. SHUKRAN