1.
Depression & Somatic Symptoms:
A shifting paradigm
Dr. Santanu Ghosh, MD
Associate Professor, Psychiatry
Tripura Medical College, Agartala

2.
Case vignette

3.
A 27 years old, educated house wife presented in
Psychiatry outpatient Department, TMC with difficulty in falling
asleep, pain abdomen, low backache, burning sensation in the
feet, tingling and numbness in lower extremities for last 2 years.
On further enquiry it was found that she already had
several consultations from Medicine and Surgery OPD and all
types of organic causes have been ruled out. It was also found that
she is married for last 5 years without having any issue. She had
marital disharmony for not being able to conceive. She was also
having low mood. Due to these physical ailments, she avoids
social and family functions. Now a days she remains withdrawn.

4.
PAIN AND MIND BODY DUALISM
Although pain may originally develop from an external
source, it often becomes a psychological phenomenon (Engel,
1959).
Risk factors for developing chronic pain:
• A history of significant guilt
• Unsatisfied aggressive impulses
• A history of real or imagined loss
http://bjp.rcpsych.org/content/188/1/91.full

5.
Somatoform Disorders
Three central features:
Physical complaints without organic basis.
Psychological factors and conflicts seem important in
initiating, exacerbating, and maintaining the symptoms
Symptoms or magnified health concerns are not under
conscious control(Guggenheim2000)

6.
• Somatization disorder has been recognized since the time of ancient
Egypt. An early name for somatization disorder was hysteria, a
condition incorrectly thought to affect only women. (The word
hysteria is derived from the Greek word for uterus, hystera.)
• In the 17th century, Thomas Sydenham recognized that
psychological factors, which he called antecedent sorrows, were
involved in the pathogenesis of the symptoms.

7.
• In 1859, Paul Briquet, a French physician, observed the
multiplicity of the symptoms and the affected organ systems and
commented on the usually chronic course of the disorder.
• Because of these clinical observations, the disorder was called
Briquet's syndrome for a time, although the term somatization
disorder became the standard in the United States when the third
edition of DSM (DSM-III) was introduced in 1980.

8.
Somatoform pain disorders
• Persistent severe and distressing pain that cannot be explained fully
by a physiological process of physical illness.
• It occurs in association with emotional conflicts or psychosocial
problems.
• Chronic pain - a way of seeking human relationship, attention and
support .
• Sometimes dissipate when an accompanying psychiatric disorder is
treated.

9.
Somatoform pain disorders cont..
• It has been always difficult to specify to which extend the chronic
pain is associated with a given lesion.
• The expression of chronic pain may vary with different personalities
and cultures.
• It has been clinically accepted that the patient is not malingering and
the complaints about the extend of the pain are to be believed.

10.
DEPRESSION AND PAIN
• Depression is often a chronic disorder and though its symptoms may
be alleviated by appropriate medication and other therapies, physical
complaints tend to be more intractable.
For example, fibromyalgia (FM), a syndrome characterized by
widespread muscle pain and generalized tender points, is often
associated with major depressive disorder.
Dunne F, Dunne C. Fibromyalgia syndrome and psychiatric disorder. Br J Hosp Med. 1995; 54: 194-197.

11.
DEPRESSION AND PAIN cont.
• Dysfunction at the level of the serotoninergic and noradrenergic
neurons could affect both ascending and descending pathways
resulting in the psychological and physically painful symptoms of
depression.
• Neurotransmitters may open or close the ‘gate’ on perception of
painful stimuli.
• Therefore adrenergic and serotoninergic pathways from the brainstem
to the spinal cord will inhibit incoming painful stimuli
Bair MJ, Robinson LR, Katon W, Kroenke K. Depression and pain comorbidity. A literature review.
Arch Intern Med. 2003; 163: 2433-2445.

12.
Theories of Pain

13.
Specificity theory.
Von Frey (1895) argued that the body has a separate sensory
system for perceiving pain—just as it does for hearing and
vision—and this system contains its own special receptors for
detecting pain stimuli, its own peripheral nerves and pathway to
the brain, and its own area of the brain for processing pain
signals. But this structure is not correct.

14.
Goldschneider(1920):
There is no separate system for perceiving pain, and the
receptors for pain are shared with other senses, such as of
touch. According to this view, people feel pain when
certain patterns of neural activity occur, such as when
appropriate types of activity reach excessively high levels
in the brain. These patterns occur only with intense
stimulation. Because strong and mild stimuli of the same
sense modality produce different patterns of neural activity,
being hit hard feels painful, but being caressed does not.
Pattern theory

15.
Gate Control Theory of Pain
Ronald Melzack and Patrick Wall
proposed that a gating mechanism exists
within the dorsal horn of the spinal cord.
Small nerve fibers (pain receptors) and
large nerve fibers ("normal" receptors)
synapse on projection cells (P), which go
up the spino-thalamic tract to the brain,
and inhibitory interneurons (I) within the
dorsal horn.

16.
1. When no input comes in, the
inhibitory, neuron prevents the projection
neuron from sending signals to the brain
(gate is closed).
The interplay among these connections determines when painful
stimuli go to the brain
2. Normal somatosensory input
happens when there is more large-fiber
stimulation (or only large-fiber stimulation).
Both the inhibitory neuron and the projection
neuron are stimulated, but the inhibitory
neuron prevents the projection neuron from
sending signals to the brain (gate is closed).
3. Nociception (pain reception) happens
when there is more small-fiber stimulation or
only small-fiber stimulation. This inactivates the
inhibitory neuron, and the projection neuron
sends signals to the brain informing it of pain
(gate is open).

17.
ASSESSMENT OF CHRONIC PAIN AND DEPRESSION
• Patient Health Questionnaire
• Zung self report depression scale
• Beck Depression Inventory

18.
TREATMENT OPTIONS
• TCA
• MAO inhibitors
• SSRI
• SNRI
Antidepressants which increase the levels of serotonin and
NA are the ones which have beneficial effects on pain.
Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci
2001; 26: 30-6

19.
Comparison of different classes
• TCAs inhibit both serotonin and norepinephrine uptake in vitro to variable
degrees, indicating their potential being serotonin-norepinephrine dual
uptake inhibitors.
• In vivo amines that are potent and selective NRIs for which they
substantially lose the practical effects of . In addition, TCAs are rapidly
metabolized to secondary As are notorious their inherent side effects stem
by inhibition of multiple receptors such as muscarinic, α-adrenergic and
histamine H1 receptors.
• SNRIs have been shown to be more efficacious than monoamine oxidase
inhibitors in producing analgesia, with the analgesic effects of the
antidepressants beginning before the antidepressant effects

20.
Is Desvenlafexine is next option to
deal depression with pain?

21.
Commonly used for:
• Major Depressive Disorder
• Vasomotor Symptoms
• Fibromyalgia
• GAD
• Social anxiety disorder
• Panic Disorder
• Post traumatic stress disorder
• Premenstrual dysphoric syndrome

22.
How Desvenlafexine works?
1.Boosts serotonine, norepinephrine and dopamine.
2. Blocks serotonine reuptake pump.
3. Blocks norepinephrine uptake.
4. Presumably desensitizes both serotonine 1A
receptor and beta adrenergic receptor.

23.
DESVENLAFAXINE
Pros
• Minimal drug interactions
• Short half life and fast renal clearance avoids build-up (good
for geriatric populations)
Cons
• GI distress in 10%+.
• Very high Dose related increase in total cholesterol, LDL and
triglycerides.
• Very high Dose related increase in BP.

24.
DESVENLAFAXINE cont.
 It is O-desmethylvenlafaxine
 Hydroxylation increases water solubility, thereby facilitating renal
excretion.

25.
PHARMACODYNAMICS
 DV blocks the reuptake of 5HT and NE.
 DV is more noradrenergic than venlafaxine.
 5HT: NE = 11:1 (Deecher et al, J Pharmacol Exptl Ther 2006).]
 DV only weakly inhibits DA reuptake (may not be clinically
significant at therapeutic doses).
 Low affinity for ACh, histamine, 5HT, alpha-1, and other receptors.

26.
PHARMACOKINETICS
• Food minimally affects absorption of the OD pill.
• Bioavailability, 80% (partly because of XR technology).
• Tmax, 6-8 h with the OD preparation.
• Half-life, 9-11 h.
• Steady state, 4-5 days with the OD preparation.
• Only 30% protein-bound.
• <5% metabolized by CYP 3A4 to (inactive)
O,N-didesmethylvenlafaxinE
(Oganesian et al, Psychopharmacol Bull 2009).

27.
How to dose?
• Initial dose 50 mg once daily.
• Maximum recommended dose is 100 mg/day
• Dose up to 400 mg once daily have been shown to be
effective but with increased side effects.

28.
How long until Desvenlafexine works?
• Onset of therapeutic action: 2-4 weeks
• If it is not working within 6-8 weeks then consider dose
escalation.

29.
Best Augmenting combination for
partial response:
• Mirtazepine
• Bupropion
• Reboxetine
• Atomoxetine

30.
Side effects
Notable:
• Insomnia, sedation, anxiety and dizziness
• Nausea, vomiting, constipation and decreased appetite
• Sexual dysfunction
• SIADH
• Hyponatremia
• Hypertension
Life threatening:
• Rare seizure
• Induction of hypomania
• Activation of suicidal ideation

31.
Summary
• DV is the principal active metabolite of venlafaxine.
• It is slightly more noradrenergic an SNRI than venlafaxine.
• It does not block any neurotransmitter receptors.
• It is effective against depression and against the vasomotor
symptoms of menopause.
• It attenuates physical pain symptoms associated with depression.

32.
Summary
• A common serotonergic adverse effect is nausea (transient, self-
limiting).
• Common noradrenergic adverse effects include constipation, dry
mouth, sweating, [weight loss].
• Dysuria not reported.
• Low risk of CVS adverse effects.
• Minimal hepatic metabolism (CYP 3A4).
• Minimal inhibition of CYP2D6.
• Starting dose is the usual target dose (50 mg/day).