Physical and Mental Health Impacts of Depression

Psychiatry Below the Neck: The Physical
Consequences of Depression, Stress and
Anxiety

Richard G Petty MD, MSc, MRCP(UK), MRCPsych,
Promedica Research Center,
Georgia State University College of Health
Sciences,
Loganville, Georgia,
USA
rpettyus@aol.com
RichardGPettyMD.com

Sunday, July 26, 2009

Disclosure
Richard G. Petty, MD, MSc, MRCP(UK), MRCPsych
 Consultant
• AstraZeneca; Eli Lilly and Company; Janssen Pharmaceuticals
 Speaker’s Bureau
• Abbott Pharmaceuticals, Astra Zeneca; Janssen Pharmaceuticals
 Grant Support
• British Diabetic Association; Bristol Meyers Squibb; British Heart
Foundation; Du Pont Merck, Inc.; Eli Lilly and Company; Janssen;
Medical Research Council (UK); National Institute of Mental
Health; Pfizer


Objectives

 1. Attendees will be able to list the main
cardiovascular, endocrine, metabolic,
immunological and oncological associations of
depression, stress and anxiety
 2. Participants will be able to describe the impact of
depression, stress and anxiety on pre-existing
physical illnesses
 3. Attendees will be able to screen for the physical
problems associated with depression, stress and
anxiety


There Is a Serious Lack of Physical Well-being in Individuals
With Major Mental Illness: Not Only Schizophrenia, But Also
Bipolar Disorder and Major Depressive Disorder


 Mortality rates: people die on average 10-20 years earlier than the
general population1-3


 Mortality rates: people die on average 10-20 years earlier than the
general population1-3
 In part because of suicide, but also:
 Cardiovascular diseases
 Coronary artery disease 4
 Arrhythmias
 Diabetes mellitus - Type II5
 Obesity6
 Some forms of cancer
 Respiratory illness
 Substance abuse7

1. Harris, E.C. and Barraclough, B. Br J Psychiatry 1998; 173: 11-53
2. Newman and Bland Can J Psychiatry 1991; 36: 239-245
3. Tabbane, K., R. Joober, et al. 1993; Encephale 19: 23-8
4. Allebeck, Schizophr Bull 1989; 15: 81-89
5. Dixon et al, J Nerv Ment Dis 1999; 187: 495-502
6. Allison, D., et al. J Clin Psychiatry 1999; 60: 215-220
7. Herran et al, Schizophr Res 2000; 41: 373-381


Depression, Anxiety and Stress
 Each may be associated with an array of
similar physical problems
 These physical complications may have an
enormous impact on the health and well-
being of the patient
 Depression, anxiety and stress may each
complicate physical illnesses and modulate
their course, severity and outcome


The Physical Complications of
Depressive Disorders


Somatic Symptoms in People with Major Depressive
Disorder
 Fatigue 86%*  Chest pain 27%
 Insomnia 79%*  Sexual symptoms 23%
 Nausea 51%*  Pain in extremities 20%
 Dyspnea 38%  Dizziness 19%
 Palpitations 38%  Abdominal pain 18%
 Back pain 36%*  Tinnitus 18%
 Diarrhea 29%  Joint or limb pain 16%
 Headache 28%

Patients presenting in a Psychosomatic Clinic assessed with Cornell Medical Index Questionnaire
*Significantly higher % in those with MDD
Nakao, M. et al, Psychopathology 2001: 34, 230-5


Common Complicating Problems in
Depression
 Smoking
 Poor physical activity
 Adherence to medical advice
 Sleep disturbances


Depressive Disorders in the
Physically Ill: Key Points
 Depressive disorders are common in the
physically ill

 Depressive disorders co-occurring with
physical illness complicate treatment of both
disorders

 Depressive disorders and physical
illnesses must be treated in parallel


Comorbid Depression Alters the
Outcome of Physical Illness
 Depressed post-stroke patients
 Less compliant with treatment, more irritable
and demanding1
 Depressed patients following myocardial
infarction
 Less compliant with rehabilitation programs,
longer recoveries and slower return to normal
functioning2
 Are 2.7 times more likely to die3
 Depressed diabetic patients
 Poorer glucose control4

1. Ross, E.D. and Rush, A.J. Arch Gen Psychiatry 1981: 38, 1344-1354
2. Guiry, E., et al. Clin Cardiol 1987: 10, 256-260
3. Surtees, P.G. et al. Am J Psychiatry 2008: 165, 515-523
4. Lustman, PJ, et al. Diabetes Care 1988: 11, 605-612


Increased Mortality Associated With
Depression and Physical Illness
 Depressed patients have a significantly higher 4-
year mortality than non-depressed controls after
controlling for severity of physical illness1
 Depression increased mortality in 211
hospitalized patients with a life-threatening illness
 Depressed patients had significantly poorer outcome
over the 28 days following admission — 47% died or had
life-threatening complications vs 10% of the non-
depressed patients2

Murphy E, et al. Brit J Psych, 1988, 152:347-353.
Silverstone PH, J Psychosomatic Res. 1990, 34:6;651-657.


Depressive Disorders and
Physical Illness: Possible Associations
 Common cause for both
 Physical illness “causing” depressive
disorder
 Depressive disorder “causing” physical
illness


The Major Physical Consequences of
Depression
 Fatigue
 Sleep disturbances
 Inflammation
 Carbohydrate and fat metabolism
 Hypothalamic-pituitary-adrenal axis
 Cardiovascular disease
 Osteoporosis
 The immune system


Inflammation 1
 A Missing Link Between:
 Sleep deprivation1
 Circadian rhythm disorders2-5
 Stress6
 Insulin resistance7-8
 Abdominal obesity9
 Diabetes mellitus10

1. Liu, H., Wang, G., Luan, G., and Liu, Q. J Thromb Thrombolysis 2008: July
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18597046
2. Shephard, R. J., and Shek, P. N. Can J Appl Physiol 1997; 22, 95-116
3. Dickerson, F., Stallings, C., Origoni, A., Boronow, J., and Yolken, R. Prog Neuropsychopharmacol Biol Psychiatry 2007: 31, 952-5
4. Huang, T. L., and Lin, F. C. Prog Neuropsychopharmacol Biol Psychiatry 2007: 31, 370-2
5. O'Brien, S. M., Scully, P., Scott, L. V., and Dinan, T. G. J Affect Disord 2006: 90, 263-7.
6. Hamer, M., and Stamatakis, E. Physiol Behav 2008: 94, 536-9
7. de Luca, C., and Olefsky, J. M. FEBS Lett 2008: 582, 97-105
8. Heilbronn, L. K., and Campbell, L. V. Curr Pharm Des 2008: 14, 1225-30
9. Nathan, C. Epidemic inflammation: pondering obesity. Mol Med 2008: 14, 485-92
10. Savoia, C., and Schiffrin, E. L. Clin Sci (Lond) 2007: 112, 375-84


Inflammation 2
 Chronic inflammation affects the photic response of the
suprachiasmatic nucleus1
 Cox-2 inhibition appears promising in the treatment of
depression and schizophrenia2
 Particulate air pollution is associated with systemic
inflammation3
 Inflammation is associated with a reduction in heart rate
variability, a marker of depression and a major predictor of
death after myocardial infarction4
 Physical exercise reduces inflammation and improves
heart rate variability and mood5

1. Palomba, M., and Bentivoglio, M. J Neuroimmunol 2008: 193, 24-
2. Muller, N., and Schwarz, M. J. Curr Pharm Des 2008: 14, 1452-65 7
3. Liu, L., Ruddy, T. D., Dalipaj, M., Szyszkowicz, M., You, H., Poon, R., Wheeler, A., and Dales, R. J Occup Environ Med 2007: 49, 258-65
4. von Kanel, R., Nelesen, R. A., Mills, P. J., Ziegler, M. G., and Dimsdale, J. E. Brain Behav Immun 2008: 22, 461-8
5. Thompson, A. M., Mikus, C. R., Rodarte, R. Q., Distefano, B., Priest, E. L., Sinclair, E., Earnest, C. P., Blair, S. N., and Church, T. S. Contemp Clin Trials 2008: 29, 418-27


Inflammation, Sickness Behavior and
Depression
 Inflammation and cytokines
 Cytokine-induced sickness behavior:1
 Weakness
 Malaise
 Listlessness
 Disinterest
 Poor concentration
 Anorexia

Myers, J. S. Oncol Nurs Forum 2008: 35, 802-7


The Physical Consequences of
Depression: Insulin Resistance


What is Insulin Resistance?


 Insulin resistance is defined as an impaired biological response to
insulin1

 Insulin resistance is a primary defect in the majority of patients with
Type 2 diabetes2

 In non-diabetic individuals, insulin resistance, in combination with
hyperinsulinemia, has a strong predictive value for the future
development of Type 2 diabetes3

1. American Diabetes Association. Diabetes Care 1998;21(2):310–314
2. Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721
3. Bloomgarden ZT. Clin Ther 1998;20(2):216–231


 Insulin resistance is defined as an impaired biological response to
insulin1

 Insulin resistance is a primary defect in the majority of patients with
Type 2 diabetes2

 In non-diabetic individuals, insulin resistance, in combination with
hyperinsulinemia, has a strong predictive value for the future
development of Type 2 diabetes3

Present in ~30-33% of the general population of the USA, but
with marked ethnic differences

1. American Diabetes Association. Diabetes Care 1998;21(2):310–314
2. Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721
3. Bloomgarden ZT. Clin Ther 1998;20(2):216–231


Insulin Resistance Syndrome

Synonyms
 Metabolic syndrome
 (Metabolic) Syndrome X
 Dysmetabolic syndrome
 Reaven’s syndrome
 Multiple metabolic syndrome


The Metabolic Syndrome and the Insulin
Resistance Syndromes
 Several sets of criteria
 Most usually defined in the USA as the
presence of 3 or more of the following:
 Abdominal obesity
 (Waist circumference >40 inches in men; >35 inches in
women
 Glucose intolerance (fasting glucose ≥110 mg/dL)
 Blood pressure ≥130/85 mmHg
 Triglycerides >150 mg/dL
 Low HDL(Men: <40 mg/dL; women: <50 mg/dL)

NCEP ATP III. Circulation. 2002;106;3143.


The Metabolic Syndrome and the Insulin
Resistance Syndromes
 Several sets of criteria
 Most usually defined in the USA as the
presence of 3 or more of the following:
 Abdominal obesity
 (Waist circumference >40 inches in men; >35 inches in
women
 Glucose intolerance (fasting glucose ≥110 mg/dL)
 Blood pressure ≥130/85 mmHg
 Triglycerides >150 mg/dL
 Low HDL(Men: <40 mg/dL; women: <50 mg/dL)

Present in ~22% of the general population of the USA, but with marked ethnic
variations

NCEP ATP III. Circulation. 2002;106;3143.


Insulin
Resistance


Intra-Abdominal Inactivity Glucose
Genetics Medications
Obesity Intolerance

Cigarette
Smoking
Aging

Fetal
Malnutrition

Insulin
Resistance


Obesity Intolerance

Cigarette
Smoking
Aging

Fetal
Malnutrition

Insulin
Resistance

Type 2
Diabetes


Obesity Intolerance

Cigarette
Smoking
Aging

Fetal
Polycystic Malnutrition
Ovary
Syndrome
Dyslipidemias
Insulin
Microalbuminuria
Resistance Endothelial
Dysfunction

QTc
Prolongation Dysfibrinolysis

?Certain Macrovascular
Malignancies Disease

Other Type 2 Non Alcoholic Hypertension
Metabolic Effects: e.g. Fatty Liver
Hyperuricemia Diabetes
Disease


Homeostatis Model Assessment (HOMA)

Normal: 100% β-cell function: Insulin resistance (R) =1

β-cell function (%): 20 x Insulin (µU/ml
glucose (mmol) - 3.5

Insulin resistance: Insulin (µU/ml) x glucose (mmol)
22.5

Hafner et al. Diabetes Care 1996; 1138-1141
Mathews DR, Hoskeer JP, et al. Diabetologia, 1985; 28:412-419


Differentiation Between Insulin Resistance Syndrome and
Type 2 Diabetes


Type 2 Diabetes
Insulin Resistance

CVD= Coronary vascular disease; PCOS = Polycystic ovarian syndrome; NAFLD = Non-alcoholic fatty liver disease
Adapted from: ACE Position Statement on the Insulin Resistance Syndrome, Endocr Pract. 2003; 9, 240-252;
Reaven GM. Diabetes 1988;37:1595–1607; Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721

Type 2 Diabetes
Insulin Resistance

Compensatory
Hyperinsulinemia

Insulin Resistance
Syndrome

CVD

Hypertension
Stroke
PCOS
NAFLD


Type 2 Diabetes
Insulin Resistance

Inadequate Insulin Response + β-cell Compensatory
failure Hyperinsulinemia

Impaired Glucose Tolerance
Insulin Resistance
Syndrome

Type 2 Diabetes Mellitus CVD

Hypertension
Retinopathy Stroke
Nephropathy PCOS
Neuropathy NAFLD


The Physical Consequences of Depression:
Insulin Resistance
 Insulin resistance is common in depression1 and anxiety2
 Insulin resistance is associated with obesity, depression,
and chronic low-grade inflammation in women with
polycystic ovary syndrome3
 Insulin resistance syndrome predisposes to the development
of depressive symptoms4
 There is a complex relationship between antidepressants
and insulin resistance5,6

1. Timonen, M., Salmenkaita, I., Jokelainen, J., Laakso, M., Harkonen, P., Koskela, P., Meyer-Rochow, V. B., Peitso, A., and Keinanen-Kiukaanniemi, S.
Psychosom Med 2007: 69, 723-8
2. Narita, K., Murata, T., Hamada, T., Kosaka, H., Sudo, S., Mizukami, K., Yoshida, H., and Wada, Y. Psychoneuroendocrinology 2008: 33, 305-12
3. Benson, S., Janssen, O. E., Hahn, S., Tan, S., Dietz, T., Mann, K., Pleger, K., Schedlowski, M., Arck, P. C., and Elsenbruch, S. Brain Behav Immun 2008: 22,
177-84
4. Koponen, H., Jokelainen, J., Keinanen-Kiukaanniemi, S., Kumpusalo, E., and Vanhala, M. J Clin Psychiatry 2008: 69, 178-82
5. Chen, Y. C., Shen, Y. C., Hung, Y. J., Chou, C. H., Yeh, C. B., and Perng, C. H. J Affect Disord 2007: 103, 257-615.
6. Levkovitz, Y., Ben-Shushan, G., Hershkovitz, A., Isaac, R., Gil-Ad, I., Shvartsman, D., Ronen, D., Weizman, A., and Zick, Y. Mol Cell Neurosci 2007: 36, 305-12


Intrapsychic or Environmental Stress Can Lead
to Increased Insulin Resistance

Basal Intra- Peripheral
Corticosteroid Abdominal Insulin
Insulin
Release Fat Levels
Resistance



Stress

Insulin
Release Fat Levels
Resistance



Stimulation
Release of Pancreatic
of FFA Insulin
and TG Release
+
Stress Reduced
Insulin
Breakdown

Insulin
Release Fat Levels
Resistance


Depression With
Comorbid Diabetes
 15% to 20% of patients with Type I or Type II
diabetes have major depression
 Depression in diabetic patients is associated with
 Poor compliance with diabetes regimen
 Poor glycemic control
 Increased risk for microvascular and macrovascular
complications

Lustman, P. J., Penckofer, S. M., and Clouse, R. E. Curr Diab Rep 2007: 7, 114-22


Depression With Comorbid Diabetes
 Fluoxetine, citalopram and nortriptyline are effective in
major depression with comorbid diabetes
 Improvement in depression has an independent and
clinically relevant beneficial effect on glycemic control
 There is increasing evidence that antidepressants
may worsen metabolic control1

1. Derijks, H. J., Meyboom, R. H., Heerdink, E. R., De Koning, F. H., Janknegt, R., Lindquist, M.,
and Egberts, A. C. Eur J Clin Pharmacol 2008: 64, 531-8


Cardiovascular Disease
 Coronary artery disease is more common in
depression, anxiety and stress disorders


Depression and Physical Dysfunction from
Coronary Artery Disease (CAD)
 Physical dysfunction secondary to CAD linked
with:
 Number of main coronary vessels stenosed >70%
(p<0.03)
 Depression (p=0.001)
 After 1 year, physical function no longer
associated with number of arteries stenosed, but
still significantly associated with depression
(p<0.001)

Sullivan et al. Am J Med. 1997


Depression and Myocardial Infarction


Patients with depression have 5-fold
increased risk of cardiac mortality1

 New-onset depression after myocardial
infarction doubles mortality over eight
years2
 The risk is reduced by:
 Cardiac rehabilitation3
 Some antidepressant medications4

1. Frasure-Smith, N. JAMA 1992: 268, 195
2. Dickens, C., McGowan, L., Percival, C., Tomenson, B., Cotter, L., Heagerty, A., and Creed, F. Psychosom Med 2008: 70, 450-5
3. Milani, R. V., and Lavie, C. J. Am J Med 2007: 120, 799-806
4. Jiang, W. Cleve Clin J Med 2008: 75 Suppl 2, S20-5


Depression in the Medically Ill:
Cerebrovascular Accident
 Multiple studies have shown an increased risk of
stroke in people with chronic depression1

 Depression appears to be an independent risk
factor for stroke, though metabolic disturbances
and cerebral microvascular disease may yet prove
to be the “cause” of both

Surtees, P. G., Wainwright, N. W., Luben, R. N., Wareham, N. J., Bingham, S. A., and Khaw, K. T.
Neurology 2008 70, 788-94

Depression and Stroke:
Fluoxetine vs. Maprotiline vs. Placebo
 52 severely disabled hemiplegic subjects were
followed during 2 months of physical therapy1
 Greatest improvements in functioning were observed in the
fluoxetine group
 Fluoxetine yielded significantly larger number of patients with good
recovery compared to maprotiline and placebo

 Subsequent studies have shown that successful
treatment with most SSRIs improve recovery after
stroke2

1. Dam M. Stroke. 1996;27:1211-1214
2. Bilge, C., Kocer, E., Kocer, A., and Turk Boru, U. Eur J Phys Rehabil Med 2008: 44, 13-8


Osteoporosis
 In depression:1
 Reduced bone mineral density
 Increased risk of fractures

 It is unknown if anxiety or chronic stress decrease
bone mineral density

1. Mezuk, B., Eaton, W. W., and Golden, S. H. Osteoporos Int 2008: 19, 1-12


Cancer
 Clinical depression is the most common
psychiatric disorder among cancer patients and is
associated with significant functional impairment1

1. Hopko, D. R., Bell, J. L., Armento, M. E., Robertson, S. M., Hunt, M. K., Wolf, N. J., and Mullane, C. J
Psychosoc Oncol 2008: 26, 31-51

Depression and Cancer
16
Fluoxetine Desipramine †
†
* *
Mean Change**

12
† †
* *
8 †
†

4 *
† *
†
0
HAM-D-17 HAM-A CGI-Severity FLIC

**Positive values are used to indicate improvement; *p<0.05 for analysis of change within drug treatment group
using Wilcoxon’s signed rank statistic with no allowance for investigator effects; †p<0.05 for analysis of change
within drug treatment group using Wilcoxon’s signed rank statistic after adjusting for investigator effects using
weighted means. Holland JC et al. Psycho-Oncology. 1998;7(4):291-300


Effect of Psychosocial Treatment on Survival of
Patients with Metastatic Breast Cancer
1.0 Treatment (N=50)

Control (N=36)
0.8 Overlapping control and
treatment probabilities of survival
Probability of Survival

0.6 Some points represent more than 1 case

0.4

0.2

0.0
0 20 40 60 80 100 120 140
Months from Study Entry to Death

Spiegel et al. Lancet, 1989, II, 888-891


Treating Depression in Cancer

 Intervention-Depression Care for People with
Cancer:
 Scotland, UK
 Nurse-delivered complex intervention
 200 patients, mean age 56.1 years
 Reduced:
 Depression
 Anxiety
 Fatigue
 Cost-effective

Strong, V., Waters, R., Hibberd, C., Murray, G., Wall, L., Walker, J., McHugh, G., Walker, A., and Sharpe, M. Lancet 2008: 372,
40-8


Major Depression and Medical Comorbidity
Evaluation
 Consider all symptoms of major depression
despite another possible physical cause
 Probe for loss of interest or pleasure or
psychological symptoms such as guilt or loss
of self-esteem
 Evaluate medication regimen for drugs that
may cause depression


Depressive Disorders In The Physically Ill:
Obstacles To Recognition
 Attributing depressive symptoms to somatic illness

 Denial of depressive experience

 Similarity between depressive symptoms and
symptoms of other illnesses


Risk Factors For Depressive
Disorders In Physical Illness
 Female gender
 Being unmarried
 Living alone
 Previous depressive episodes
 Certain medical treatments
 Severe forms of physical illness


Diagnosing Depressive Disorders In
The Physically Ill: Patient’s And
Family’s Psychiatric History
 Family history of depressive disorders/mania/
hypomania
 Family history of suicide/suicide attempt(s)
 Previous depressive episodes
 Good response to antidepressants in past episodes
of mental disorder


Diagnosing Depressive Disorders In The Physically
Ill: Patient’s And Family’s
Psychiatric History (cont’d)
 Previous manic or hypomanic episodes
 Previous suicide attempt(s)
 History of alcoholism or alcohol abuse and/or
substance abuse disorders
 Seasonal variation and/or diurnal variation of
depressive symptoms


Treatment of Depression and Anxiety in
Physical Illness
 Antidepressants cause improvement in
depression in patients with a wide range of
physical diseases significantly more frequently
than either placebo or no treatment
 Antidepressants are reasonably well-tolerated
in patients with physical illness
 Increasing evidence suggests that non-
pharmacological approaches to treatment are
also important

Gill D, Hatcher S. In: The Cochrane Library, Issue 2, 1999.


Conclusions
 Depression, anxiety and stress are all best
seen as systemic disorders with psychiatric
symptoms
 It is essential to be alert to the possible
physical associations of each of these
disorders, and to screen and manage them
appropriately


Suggested Evaluations and Investigations of People
with Depression, Stress and Anxiety Disorders
 Evaluations:
 Weight and height -> BMI
 Measure waist and hips
 Blood pressure and pulse - lying and standing
 Signs of EPS or tardive dyskinesia
 Investigations:
 Fasting electrolytes, creatinine, glucose and lipids + measure insulin
resistance in high-risk patients
 Liver function tests
 Thyroid stimulating hormone: if equivocal consider free T3 and CK
 Prolactin
 Electrocardiogram
 (Bone density measurement only if there are other high risk factors)
 Despite the evident resource implications, suggest doing these at least
annually, and more often if:
 Abnormal
 There are clinical changes
 There are other risk factors present


Health Promotion Interventions
Female patients Male patients
Reinforce the need for: Reinforce the need for:
 Breast self-exam  Annual prostate exam
 Does the patient know  When, if ever, has he had
how to do a breast exam? a prostate exam?
 Annual pap test  Testicular self-exam
 When was the last pap
smear?  Does the patient know
how to do a self-exam?
 Mammography
 Has she ever had a
 PSA, if indicated
mammogram?  Has the patient ever had a
PSA?


Useful Addresses


Healia.com


www.richardgpettymd.com


rpettyus@aol.com


Additional Data


Concept of the Immune System

Adoptive IS Innate IS

AP-Cells Monocytes, ...

Complement
System

Th0-Cells

IFN-γ IL-4
IL-2 IL-10
IL-6 IL-6

Antibodies

Th1-Cells Th2-Cells B-Cells


The Balance of Humoral and Cellular
Immune Response

Th1 cells Th2 cells

cellular immune response humoral


Th1/Th2 in Major Depression

Markers of Th1/Th2 Responses in Major Depression
Site of cytokine Th1 Th2
expression
In-vitro production IFN-γ ↑ IL-6 ↑↑

Peripheral sIL-2R ↑↑ IL-6 ↑↑
IFN-γ ↑
IFN-γ ↑⇒ TRP↓
CSF sIL-2R ↑ IL-6↓
sIL-6R ↓
Hypothesis A Th1-serotonin-link in A Th2-dominance or an overactivation
suicidal MD? of monocyte/macrophage system in
non-suicidal MD?


Immune Changes in Depression

T-cell Macrophage
activation activation

IFN-γ IL-1 TNF-α IL-6

IL-1ra IL-6R
Autoimmune
response PGE2
Leucocyte
number
Cortisol
Acute phase
proteins
Adapted from: Song, Leonard, 2000


Interleukine 6 (IL6)

 Marker of monocyte activation
 Modulation of HPA axis
 Elevation in depression


Immune-Neurotransmitter Interaction in
Depression
T-cell Macrophage
activation activation

IFN-γ IL-1 TNF-α IL-6

Tryptophan
degradation 5-HT transporter 5-HT NE
?
PGE2
5-HT
Cortisol


The Relationship Between the Th1 Cytokine
IFN-g and Serotonin Metabolism

Tryptophan
IFN-g + IDO

+
Kynurenine Serotonin

KYN-Hydrox.

Quinolinate 5-Hydroxyindole acetic acid

(IDO = indoleamine 2,3-dioxygenase;
KYN-Hydrox. = kynurenine hydroxylase)

Possible Ways For Pro-inﬂammatory

Wichers & Maes, 2001


Cytokine-Neurotransmitter Interaction of
Antidepressants

IL-10 IFN-γ IL-1 TNF-α IL-6

Antidepressants

5-HT transporter 5-HT NE

PGE2
Cortisol


Inflammation, Prostaglandin E2 and Depression

 IL-6 (PGE2↑) and TNF-α (COX-2 expression↑)
increased in a subgroup of depressive patients
 Salivary concentration of PGE2 increased in major
depression (Ohishi et al, 1987; Nishino et al, 1988)
 Increased PGE2 production in lymphocytes of major
depression (Song et al, 1998)
 PGE2 reduces noradrenaline-release and stimulates
the HPA-axis in the CNS (Song & Leonard, 2000)
 Antidepressants inhibit PGE2-synthesis (Mtabaji et al,
1977)

Physical and Mental Health Impacts of Depression

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