Julio Licinio - An important role for SAHMRI

Julio Licinio, MD, FRANZCP South Australian Health and Medical Research Institute

Flinders University, Adelaide, Australia

Depression and obesity A neglected clinical interface

An important role for SAHMRI

Promote integration

Not only across institutions

But also across medical disciplines

Psychiatric patients are often physically ill

Fragmentation between mind and body

Research-wise

Clinically

Consumers are therefore often not well served

Wasted resources due to fragmentation

An example of mind – brain clinical and

research disconnect

Depression and obesity

10 good reasons to study

depression and obesity together

1. The two disorders frequently co-exist

in the same patient

2. Depression can cause obesity

3. Antidepressants cause weight gain

4. Obesity can cause depression

5. Obesity treatments can cause

depression and suiciality

10 good reasons to study

depression and obesity together

6. Chronic stress can cause both.

7. Brain circuits that regulate mood also

regulate food intake.

8. Both obesity and depression

contribute to cardiovascular disease

9. Both contribute to diabetes

10. Having one of these two disorders

makes treatment of the other

particularly challenging

Depression and obesity

Obesity is far more intertwined with depression than

appreciated

Is depression a cause or outcome of obesity?

Are both caused by a chronically dysregulated stress

response?

Is long-term obesity the outcome of antidepressant

treatment or exposure?

Obesity is tightly related to the medical outcomes of

depression

Diabetes

Cardiovascular disease

Cancer

What is the relationship?

Which way do the arrows go?

Stress Depression Obesity

Stress Obesity Depression

Stress Depression Obesity

Stress Obesity Depression

Obesity Stress Depression

Contributors to the obesity epidemic

Food marketing and consumption practices

Reduction in physical activity

Infections

Epigenetics/genetic variations

Maternal age

Reproductive fitness (greater fecundity among people with higher adiposity)

Positive assortative mating (mates are phenotypically more similar)

Sleep debt

Endocrine disrupters (such as industrial chemicals)

Reduction in ambient temperature variations

Intrauterine and intergenerational effects

Drug-induced weight gain

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Chronic stress may contribute to obesity

The rate of

obesity is

escalating in

recent years.

Obesity Trends* Among U.S. Adults

BRFSS, 1985 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14%



No Data <10% 10%–14%



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No Data <10% 10%–14% 15%–19%



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No Data <10% 10%–14% 15%–19%



No Data <10% 10%–14% 15%–19%



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No Data <10% 10%–14% 15%–19%



No Data <10% 10%–14% 15%–19% ≥20%



No Data <10% 10%–14% 15%–19% ≥20%



No Data <10% 10%–14% 15%–19% ≥20%



No Data <10% 10%–14% 15%–19% ≥20%



No Data <10% 10%–14% 15%–19% 20%–24% 25%–29%

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

Obesity Trends* Among U.S. Adults BRFSS, 2002

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29%



No Data <10% 10%–14% 15%–19% 20%–24% 25%–29%



No Data <10% 10%–14% 15%–19% 20%–24% 25%–29%



No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%



No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%



No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%



No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%



No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%



No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Prevalence* of Self-Reported Obesity Among U.S. Adults BRFSS, 2011

*Prevalence reflects BRFSS methodological changes in 2011, and these estimates should not be compared to previous years.

15%–<20% 20%–<25% 25%–<30% 30%–<35% ≥35%

The rate of obesity is

escalating in recent years.

Are chronic stress and,

other factors that act in

conjunction with stress

increasing in recent years

to facilitate obesity?

Are the rates of

stress increasing

over time?

Adrenals

Kidney

Posterior Pituitary Gland

Hypothalamus

Anterior Pituitary Gland

ACTH

Stress Circadian

rhythm

CRH

(-)

Glucocorticoids, Catecholamines, etc..

Glucocorticoids, Catecholamines, etc..

Muscle: Net loss of amino Acids (glucose)

Liver: Deamination of

proteins into amino acids,

gluconeogenesis (glucose)

Fat Cells: Free fatty

acid mobilization

Heart rate: Increased

Immune system: altered

Hypothalamopituitary adrenal (HPA) axis

Atrophy of apical dendritic branches in CA3 pyramidal

neurons cognitive impairments

Control Restraint (6 hr/day, 21 days)

• Repeated stress or chronically elevated glucocorticoids can

cause atrophy of apical dendrites in CA3, and reduce

production of new granule cells in dentate gyrus.

• Following repeated stress, there can be less inhibition of the

PVN by the hippocampus. Magarinos and McEwen. Neuroscience (1995) Vol 69, p89-98

Stress and Health Long term effects of stress

Obesity

Heart disease

Immune deficiency

Decreased sexual interest

Growth problems

Reduced bone density

Reduced muscle mass

Blood sugar imbalances

Cancer

Caused by chronically high cortisol levels

How do people cope with

increased chronic stress

and depression?

Antidepressant use has escalated

Milane MS, Marc A.

Suchard MA, Licinio

J, Wong M-L.

PLoS Medicine

2006;3:816-824

Antidepressant use has escalated

Antidepressants and weight gain 2 million fluoxetine (Prozac®) prescriptions in the USA in 1988

164 million antidepressant prescriptions in USA 2009

12.3 million antidepressant scripts for 1.6 million Australians 2008

56% of 7,525 started on antidepressants in Europe stopped by themselves within 4 months

Populations exposed to antidepressants shifts over time

Lifetime prevalence of exposure to antidepressants is very high

Critical to understand complex interactions among the factors associated with increased risk of obesity, such as MDD

Antidepressant use

Highly prevalent high-fat diets.

Major gaps in our understanding include: Interactions that occur with antidepressant exposure in an obesogenic environment

Whether obesity in the context of antidepressant exposure is different from obesity that is related to chronic imbalance between energy intake and expenditure

Whether various antidepressants affect body weight differently

Current situation

Baseline of obesogenic food environment

Chronic stress High cortisol

Depression

Widespread antidepressant use

What are the metabolic consequences of this combination?

Impossible and unethical to test experimentally in individual people

A new animal paradigm.

The SAD paradigm

stress – antidepressant – diet

The SAD paradigm

stress – antidepressant – diet

Chronic repeated stress elicits behavioral features of depression

Depression-like behaviors improve with short-term antidepressants

• Work of Suhyun Lee,

PhD student in our lab

• OP: Obesity prone animals

• Top tercile of weight gain

• Easier to see weight-related

outcome differences

• Exposure to antidepressants

leads to long-term weight

gain

• Provides materials for search

for mechanisms

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R-IM

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Comparison of average IGF-I/GAPDHgene expression between thetreatment. One tailed t-test: *, p<0.05;

**, p<0.01. NRCF: n=25, R-C: n=9,

R-FX: n=12, R-IM: n=13.

Treatment

Avg

.Rati

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F-I

/GA

PD

H

IGF-1

IGF-1

BDNF

NGF

GH

antidepressant

IGF-1 gene expression

There is a difference in IGF-1 in stressed versus non-stressed

Fat-diet weight gain: lower IGF-1 levels

Stress/antidepressant+fat diet: higher IGF-1 Note that stressed, non-antidepressant treated rats

were studied 10 months after stress (recovery period)

• Weight gain after termination of drug use

plus ongoing high fat diet

• Exposure to antidepressants leads to

long-term weight gain (with high fat diet)

• An epigenetic effect?

• Antidepressants are the second

bestselling drug class

• Lifetime antidepressant exposure:

A contributor to the obesity epidemic?

Antidepressants and weight gain

The spectrum of gene-environmental interactions

in the causation of obesity

Predominance of

nutritional

environment Predominance of

psychological

environment

Predominance of

genetic factors

Within SAHMRI’s Mind & Brain we will:

Foster new talent

Conduct groundbreaking research

Promote integration of efforts across academic,

clinical, and research groups in the city, state, as well

as nationally

Quarterly workshops for stakeholders

Closely collaborate in our research efforts with

those in other themes and areas

Translate results to improved healthcare in SA.

Healthcare

Julio Licinio - An important role for SAHMRI