DEPRESSIONE, DOLORE E
QUALITA’ DELLA VITA
Daniele La Barbera
CATTEDRA DI PSICHIATRIA
UNIVERSITA’ DI PALERMO
Overview
♦
Introduction: complexity of depression and
painful physical symptoms
♦
Prevalence of depression and associated
pain symptoms
♦
Biochemical evidence for role of serotonin
and norepinephrine in depression and pain
♦
Impact of pain symptoms on depression
outcomes
Una Patologia sociale
La depressione è un disturbo la cui incidenza, in
tutto il mondo, è segnalata in costante e rapido
aumento
Nel 2020, secondo l’Organizzazione Mondiale della
Sanità, la Depressione rappresenterà la seconda
causa di malattia e di invalidità
Si tratta di uno dei Disturbi più sottostimati e
sottodiagnosticati di tutta la Medicina, con una
difficoltà, specialmente nell’ambito della Medicina
generale, a diagnosticare correttamente l’esordio
I sintomi funzionali
Per queste ragioni il Disturbo spesso progredisce
per anni, prima che venga riconosciuto e trattato
correttamente.
I pazienti che richiedono il trattamento di sintomi
fisici funzionali al MMG presentano molto
frequentemente una depressione sub-clinica.
Il dolore fisico spesso complica la diagnosi di
depressione, in fase d’esordio.
Multidimensional Aspects
of Depression
Change in
Sleep
Suicidal
Lack of Energy
Lack of
Interest
Tearfulness
Sadness
Change in
Appetite
Irritability
Depression
Anxiety or
Phobias
Obsessive
Rumination
Decreased
Concentration
Pain
Feelings of Guilt
Change in
Psychomotor Skills
Physical Symptoms
Emotional Symptoms
Excessive
Worry over Physical
Health
Associated Symptoms
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 2000:352.
Ohayon MM, et al. Arch Gen Psychiatry. 2003;60(1):39-47.
Depression: Consider
Mind and Body
♦
Painful symptoms associated with depression have
generally been a neglected area of research and
have received little clinical attention1
♦ Confusion exists in terminology in describing
physical symptoms and pain associated with
depression2,3
•
•
•
♦
Chronic painful physical conditions
Medically unexplained symptoms
Somatized symptoms
Depression should be high on a list of possible
diagnoses if a patient presents with multiple
unexplained physical symptoms including general
aches and pains
1. Kroenke K, et al. American J of Med. 1989;86:262-266.
3. Bair MJ, et al. Arch Intern Med. 2003;163:2433-2445.
2. Tylee A, et al. J Clin Psych. 2005;7:167-176.
Prevalence of Depression and
Comorbid Pain Symptoms
♦
La prevalenza del
dolore in pz. depressi e
di depressione in pz.
con sindromi dolorose
é più elevata della
prevalenza di queste
condizioni esaminate
singolarmente
♦
La presenza di
dolore influenza
negativamente il
riconoscimento e il
trattamento della
depressione
Prevalence of Painful Conditions and Organic
Conditions in Patients With Major Depression
32.7%†
Medical Condition
(Organic and
functional diseases)
18.2%
(n=136)
43.4%‡
14.4%
(n=108)
38.5%
(n=288)
†
‡
28.9%
(n=216)
(Pain ≥6 months)
Without a Medical
Condition or Painful
Physical Condition
Total percentage of MDD patients with a medical condition.
Total percentage of MDD patients with a painful physical condition.
Ohayon MM, et al. Arch Gen Psychiatry. 2003;60(1):39-47.
Painful Physical
Condition
Chronic Painful Physical Conditions Are
Highly Correlated With Major Depression
MDD (n=748)
Without MDD (n=18,232)
100
50
***
43.4%
***p<0.001
**p<0.01
% of Cases
40
30
***
24.5%
***
16.3%
20
16.1%
***
12.8%
***
6.9%
10
2.7%
0
≥ 1 CPPC
Backache
**
3.0%
1.5%
6.9%
3.1%
Gastrointestinal
Joint/
Headache
Disease Articular Disease
• CPPC=Chronic Painful Physical Condition
Ohayon MM, et al. Arch Gen Psychiatry. 2003;60(1):39-47.
5.4%
Limb Pain
Prevalence of Depression and Pain Symptoms
in Newly Referred Neurology Outpatients
Neuropathy/NM* (109)
Pain Syndrome (40)
Headache (101)
Symptomatic** (61)
Others (30)
Movement (53)
Cerebrovascular (37)
MDD Alone
Pain Alone
MDD with Pain
Cognitive (20)
Seizure (24)
0
10
20
30
40
50
% With Condition (N=483)
*NM: neuromuscular
**Symptomatic: dizziness, numbness
Williams LS, et al. JNNP. 2003;74:1587-1589.
60
70
100
Persistence of Symptoms by Baseline Status
in Newly Referred Neurology Outpatients
100
Depression Symptom
Persistence
100
80
% of Patients
% of Patients
80
Pain Symptom
Persistence
60
40
60
40
20
20
0
0
3 months
12 months
Follow-up Waves
Williams L, et al. Neurology. 2004;63:674-677.
3 months
MDD Alone
Pain Alone
MDD with Pain
12 months
Follow-up Waves
Pain Is Common in Patients With
Depression Across Studies
♦
Data from 3 studies:
•
•
Naturalistic randomized trial (ARTIST) (n=573): 69%
rate of pain in primary care patients with depression1
International telephone survey (n=18,980):
43.4% of patients with
MDD present with
chronic painful physical
MDD Without
Pain
conditions2
MDD With
35%
Pain
Literature review: the
65%
mean prevalence of pain
was 65% in a meta-analysis
of 14 studies3
US telephone survey (n=5808) 65.6% prevalence
of depression with chronic pain4
3
•
•
3
1. Bair MJ, et al. Psychosom Med. 2004;66(1):17-22.
2. Ohayon MM. J Clin Psychiatry. 2004;65(suppl 12):5-9.
3. Bair MJ, et al. Arch Intern Med. 2003;163(20):2433-2445. 4.Arnow BA, et al. Psycho Med; In Press
Pain Is a Common Physical
Symptom in Psychiatric Patients*
%
Psychiatric
%
Healthy
Tired, lack of energy
85
40
Headache, head pains
64
48
Dizzy or faint
60
14
Parts of body felt weak
57
23
Muscle pains, aches, rheumatism
53
27
Stomach pains
51
20
Chest pains
46
14
Symptom
* Psychiatric patients not limited to MDD.
Adapted from: Kellner R, et al. Am J Psychiatry. 1973;130:102-105.
Serotonin and Norepinephrine:
The Connection Between
Pain and Depression
Serotonin (5HT) and Norepinephrine
(NE) Pathways in the Human Brain
Thalamus
Corpus Callosum
Hypothalamus
Cingulate
Gyrus
Hippocampus
Ascending tracts
for 5HT and NE
Prefrontal Cortex
(Orbitofrontal Cortex)
Locus Coeruleus
Amygdala
Raphe Nuclei
Descending tracts
for 5HT and NE
• Most serotonin tracts originate in the raphe nuclei located in the midbrain.
• Most norepinephrine tracts originate in the nuclei of the locus coeruleus located in the midbrain.
Guyton AC, et al. Textbook of Medical Physiology, 10th ed.2000:663-688. Mega MS, et al.J Neuropsychiatry Clin Neurosci 1997;9:315-330.
Hales RE, et al. Textbook of Clinical Psychiatry, 4th ed.2003:479-486.
Evidence implicating serotonin (5-HT)
and norepinephrine (NE) systems in MDD
Depression successfully treated by activation of serotonin (5-HT)
systems or norepinephrine (NE) systems
Selective serotonin reuptake inhibitors
(SSRI) may treat depression
Norepinephrine reuptake inhibitors
(NRI) may treat depression
Evidence of dysfunctional 5-HT or NE systems in depressed
patients
Depressogenic effects of depletion of 5HT or NE synthesis in SSRI or NRI
treated patients respectively
Blunted neuroendocrine responses to 5-HT
or α2-adrenergic agonists
Reduced CSF levels of 5-HT metabolite in
depressed patients
Bymaster FP, et al. Current Pharmaceutical Design. 2005;11:1475-1493.
Pain Modulation–Serotonin
and Norepinephrine
Descending Modulation → PAG indirectly controls
♦
Neuropathic pain is
associated with increased
excitation and decreased
inhibition of ascending
pain pathways
♦ Descending pathways
modulate ascending signals
♦ NE and 5-HT are key
neurotransmitters in
descending inhibitory
pain pathways
♦ Increasing the availability of
NE and 5-HT may promote
pain inhibition centrally
Fields HL, et al. Ann Rev Neuro. 1991; 14:219-245.
Fields HL, et al. Textbook of Pain. 4th ed.1999; 310.
pain transmission in the dorsal horn
ACC
T
H
PAG
Amygdala
DLPT
Pain facilitation
Pain inhibition
RVM
Dorsal
Horn
Pain
Transmission
Neuron
ACC: anterior cingulate cortex
PAG: periaqueductal gray (5-HT)
DLPT: dorsolateral pontine tegmentum (NE)
RVM: rostroventral medulla (5-HT)
T: Thalamus
H: Hypothalamus
Serotonin and Norepinephrine Modulate
the Neurotransmission of Pain
Aβ
β Fiber
(Touch)
Aβ
β Fiber
I
II
C Fiber
(Nociception)
III
DLPT
NE
IV
5-HT
V
Norepinephrine
RVM
5-HT
Dorsal
horn
Fields HL, et al. Annu Rev Neurosci. 1991;14: 219-245.
Studies have shown that the activity of the anterior cingulate
gyrus increases with peripheral pain stimuli,such as heat applied
to the skin, but it also has increased activity when warm stimuli
are applied if the patientis expecting hot stimuli
Impact of pain symptoms on
depression outcomes
♦ Quando
il dolore è da moderato a
severo, danneggia il funzionamento e/o
è refrattario al trattamento, è associato
a più sintomi depressivi e a un peggior
esito della depressione (più bassa
qualità della vita, diminuzione della
capacità di lavoro, aumentata
utilizzazione delle risorse sanitarie)
Depression and Painful Symptoms Increase
the Burden of Depression
♦
Strong correlation with pain and psychiatric
distress reporting1
♦ Depression and painful physical symptoms
increase cost
•
•
Increase/overutilization of healthcare services2
2.8- and 4-fold expenditure elevations in depressed
patients with backache and migraine, respectively3
♦
Outcome of treatment for unexplained symptoms
may be poor4
♦ Associated risk of failure to achieve remission5
•
Greater risk of relapse, suicide, and
substance abuse6,7
1. Bao Y, et al. Psychiatr Serv. 2003;54:693-697.
3. Sheehan DV. Manag Care 2002;11:7-10.
5. Fava M, et al. J Clin Psych. 2004;65:521-530.
7. Paykel ES, et al. Psychol Med. 1995;25:1171-1180.
2. Greenberg PE, et al. J Clin Psych. 2003;64(Suppl 7):17-23.
4. Kroenke K, et al. Am J Med. 1989; 86:262-266.
6. Hirschfeld RM, et al. JAMA. 1997;277:333-340.
Remission in Major Depressive Disorder
Remission
Minimal to No
Symptoms
Minimize
Relapse
HAM-D ≤71
MADRS ≤102
1. Frank E, et al. Arch Gen Psych. 1991;48(9):851-855.
3. Judd LL, et al. J Affect Disord. 1998;50:97-108.
Function
Restored
2. Montgomery SA, et al. Br J Psych. 1979;134:382-389.
4. Keller MB. J Clin Psych. 2004;65(S4):53-59
Residual Symptoms Predict Relapse
Median Time to Relapse
(Weeks)
300
250
231 Weeks
200
150
100
68 Weeks
50
0
Asymptomatic
Residual Symptoms
• Strongest predictor of relapse is presence of residual depressive symptoms.
Judd LL, et al. J Affect Disord. 1998;50:97-108.
Pain Predicts Time to Remission During
Treatment of Recurrent Depression
Median Time
to Remission
100
20
80
15
12.3
10
% of Patients
25
17
Weeks
Remission
68%
60
40
5
20
0
0
No Pain
Pain
79%
No Pain
• Higher levels of pain but not somatization predicted longer time to remission.
Karp JF, et al. J Clin Psychiatr. 2005;66:591-597.
Pain
Improvement in Painful Physical Symptoms
Is Associated With Higher Remission Rates
% of Patients Achieving
Remission (9-Week Study)
60100
50
p<0.001
40
36.2%
30
17.8%
20
10
0
≥50% Improvement in PPS
(n=77)
<50% Improvement in PPS
(n=49)
• Remission was defined as a HAM-D17 Total Score ≤7
• Painful physical symptom(PPS) improvement was measured by Visual Analog Scale for overall pain
Fava M, et al. J Clin Psychiatry. 2004;65(4):521-530.
Conclusions
♦
Unexplained physical symptoms (particularly
pain) are common in depressed patients
and may complicate and increase the time
to diagnose depression
•
♦
Remission of depression is correlated with
improvement in pain
•
♦
In both primary care and psychiatric settings
Resolution of emotional and painful physical
symptoms may be responsible for the higher
remission rates
Remission should be the goal of treatment
for depression
Depression Guideline Panel. Depression in Primary Care. 1993;23(2).
Hamilton M. Jneurol Neurosurg Psychiatry. 1960;23:56-62.