Depression & Somatic Symptoms:

A shifting paradigm

Dr. Santanu Ghosh, MD, Ph.D, FPSM

Sexual Wellbeing Specialist
Associate Professor, Psychiatry
Tripura Medical College, Agartala
Case vignette
 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 Now a days she remains withdrawn.
 PAIN AND MIND BODY DUALISM

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 defeat significant guilt

• Unsatisfied aggressive impulses
• A history of real or imagined loss

http://bjp.rcpsych.org/content/188/1/91.full
 Somatoform Disorders
Three central features:

Physical complaints
without organic basis

Psychological factors
and conflicts seem
important

Symptoms or magnified
health concerns are not
under conscious control
(Guggenheim2000)
 Persistent severe and distressing pain that
cannot be explained fully by a physiological
process of physical illness

Association with emotional conflicts

Somatoform or psychosocial problems.
pain disorders Chronic pain - a way of seeking
human relationship, attention and
support
Sometimes dissipate when an
accompanying psychiatric disorder is
treated.
 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.
 DEPRESSION AND PAIN cont.

Dysfunction at the level of the Neurotransmitters may Adrenergic and serotoninergic

serotoninergic and noradrenergic open or close the ‘gate’ pathways from the brainstem to the
neurons causes psychological and on perception of painful spinal cord will inhibit incoming
physically painful symptoms of stimuli painful stimuli
depression

Bair MJ, Robinson LR, Katon W, Kroenke K. Depression and pain comorbidity. A literature review. Arch Intern
Med. 2003; 163: 2433-2445.
Theories of Pain
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.

 Pattern theory
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.
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.
The interplay among these connections determines when painful
stimuli go to the brain

1. When no input comes in, the

inhibitory, neuron prevents the projection
neuron from sending signals to the brain
(gate is closed).

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).
 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
 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.
 Comparison of different classes

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.

 Comparison of different classes

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

Is Vortioxetine is next option to
deal depression with pain?
How Vortioxetine works?
Key feature of vortioxetine is “MULTIMODALITY”
Inhibition of a
SERT
Targets 3 Modes of Action transporter

5HT1A receptors

5HT1B receptors
Actions at several G-
protein linked receptors
5HT1D receptors

5HT7 receptors

Inhibition of a ligand-
5HT3 receptor
gated ion channel

CNS Spectr. 2015 Apr;20(2):93-7 19

Expert Opin Pharmacother. 2021 Jun;22(9):1167-1177
SERTONIN REUPTAKE INHIBITION SERTONIN RECEPTOR BINDING

5-HT1A
Agonist

5-HT1B
Partial
Agonist

5-HT1D
SERT Vortioxetine Antagonist

5-HT3
Antagonist

5-HT7
Antagonist
20
 Enhancing 5-HT release by combining 5HT transporter inhibition with
actions at 5HT receptors (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors)
SERT inhibition
When SERTs are inhibited, this causes 5HT to rise everywhere there are
presynaptic 5HT nerve terminals. However, the amount of 5HT release is
limited due to the multiple negative feedback mechanisms that inhibit
further 5HT release. Specifically, presynaptic somatodendritic 5HT1A
receptors inhibit 5HT release, especially immediately after administration,
but eventually downregulate to allow enhanced release by SERT inhibition
with chronic administration. Simultaneous stimulation of 5HT1A
presynaptic autoreceptors while blocking SERT may lead to more rapid
desensitization of the 5HT1A presynaptic receptors, and make the enhanced
release of 5HT occur faster. However, 5HT release is also importantly
regulated by 5HT1B, 5HT1D, and 5HT7 receptors, which act long-term to
limit the amount of 5HT that is released by SERT inhibition.
CNS Spectr. 2015 Apr;20(2):93-7
Actions at 5HT receptors
SERT inhibition combined with stimulating 5HT1A
receptors and partially or fully blocking 5HT1B/D
and 5HT7 receptors. Shown here are the
combination of vortioxetine’s actions that lead to
enhanced release of 5HT. In addition to blocking
SERT, vortioxetine simultaneously stimulates
5HT1A receptors and blocks 5HT1B, 5HT1D, and
5HT7 receptors. The negative feedback of 5HT1B,
5HT1D, and 5HT7 receptors is blocked, thereby
enhancing 5HT release compared to blocking SERT
alone.
21
 Action at 5-HT3 Receptors
Vortioxetine enhances the
release of ACh and
NE by blocking 5HT3 receptors.
By contrast with SSRI actions,
vortioxetine blocks the 5HT3
receptor so that GABA is not
released by 5HT, and therefore
both NE and ACh are
disinhibited—ie, their levels are
enhanced.

5HT3 antagonism enhances not

only the release of 5HT,
but also of norepinephrine (NE)
and acetylcholine (ACh), which
may be linked to its
antidepressant and procognitive
properties.
CNS Spectr. 2015 Oct;20(5):455-9. 22
 Effects on glutamate and GABA
(gamma amino butyric acid) release
Vortioxetine enhances glutamate release. Not
only does vortioxetine block SERTs the same as
SSRIs, but it also has numerous direct receptor
actions that diminish GABA inhibition at both
populations of GABA interneurons.

At the top, agonist actions at 5HT1A receptors

inhibit GABA release; also, antagonist actions at
5HT3 receptors inhibit GABA release. At the
second GABA neuron below, agonist actions at
5HT1A receptors and possibly partial agonist
actions at 5HT1B receptors inhibit GABA release
from this interneuron.

Combining what happens at both GABA neurons,

glutamate release downstream is disinhibited.
Perhaps the most robust of these actions is the
blockade of 5HT3 receptors. When glutamate
release is enhanced, it can lead to the enhanced
downstream release of numerous
neurotransmitters including DA, NE, ACh, HA,
and 5HT. 23
CNS Spectr. 2015 Aug;20(4):331-6
 Pharmacokinetics
• 66 hours
Half-life
• 7-11 hrs.
Tmax
• 75%
Bioavailability
• 98 % bound to plasma proteins
Distribution
• Extensively metabolized by cytochrome
Metabolism P450 (CYP) 2D6
• 59 % urine
Excretion • 26 % faeces
Food has no effect on bioavailability can be taken without any regards to food
24
Innovator’s Prescribing Information
 Indication and Dosage

Treatment of Major depressive disorder (MDD) in adults

Innovator’s PI
 How to dose?

• Recommended starting dose – 10 mg once daily

• Dose should then be increased to 20 mg/day, as tolerated

• Consider 5 mg/day for patients who do not tolerate higher doses

• Once-daily dosing with OR without food

• Can be discontinued abruptly

 Use in Special Population
• No adequate data • No data are • Safety and • No dose
on the available effectiveness of adjustment is
developmental regarding the vortioxetine recommended on
risks associated presence of tablets has not the basis of age
with use of vortioxetine in been established
vortioxetine in human milk, the in pediatric
pregnant women. effects on the patients for MDD
Pediatrics
Pregnancy Lactation Geriatrics
breastfed infant, treatment
or the effects of
the drug on milk
production.
• Dose adjustment • Dose adjustment
is not required in is not required in
this patient this patient
population. population.

Hepatic Renal
Impairment Impairment

Innovator PI
Clin Pharmacokinet. 2018; 57(6): 673–686.
 Side effects
Notable:

• Nausea
• Diarrhea
• Dry mouth, and
• Headaches

Life threatening:

• Activation of suicidal ideation

• Abnormal bleeding
Contraindications

Hypersensitivity


Abnormal bleeding


 Hyponatremia

Angle closure Glaucoma


 Vortioxetine

Pros
• Reduced risk of weight gain compared to other antidepressants.

• Reduced risk of sexual dysfunction compared to other antidepressants.

Cons
• Risk of increased suicidal thoughts in users under the age of 18 as well as risk
for serotonin syndrome not limited to any age groups.

• During pregnancy can result in withdrawals in the newborn.

• Risk for bleeding issues, hyponatremia especially in the elderly, and emerging
mania or hypomania in all age groups.

• Can cause both psychological dependence and physical withdrawals .

How long does it take for vortioxetine to start working?

• Sleep, energy, or appetite may show some improvement within the

first 1-2 weeks.

• Depressed mood and lack of interest in activities may need up to 6-8

weeks to fully improve.
Impact on Cognition in Working Professionals

Key Highlights
• Depression has a substantial negative impact on workplace productivity,
and cognitive difficulties may play a key role
• Vortioxetine has shown to improve cognitive functioning among MDD
patients
• Vortioxetine improves executive functioning, speed of processing, verbal
learning & memory aspects of cognition
• Patients in managerial or professional positions reported the greatest
improvement of cognitive function.
• Vortioxetine has more pronounced cognitive effect in working adults
• Cognitive improvement with vortioxetine is independent of it’s impact on
mood symptoms

1. J Clin Psychiatry. 2017 Jan;78(1):115-121. 32

 Switch from SSRI/SNRI – Impact on Emotional
Blunting & Overall Functioning (Contd…)

Key Highlights
• About 50% of MDD patients treated with SSRIs or SNRIs suffer
emotional blunting
• Emotional blunting has important functional consequences for
patients’ daily life
• In this study vortioxetine was effective for treating emotional blunting
• Improved emotional blunting also correlated with greater motivation
and energy
• Improvement in emotional blunting correlated with improved overall
functioning
Vortioxetine 10-20 mg effective in patients with MDD with partial
response to SSRI/SNRI therapy and emotional blunting

J Affect Disord. 2021 Mar 15;283:472-479.

 Switch from SSRI/SNRI – Impact on Emotional
Blunting & Overall Functioning (Contd…)
Overall
Depressive
Symptoms
Reduction

Overall Improved
Functionin Emotional
g Switch to Blunting
Vortioxetine
in MDD
patients

Cognitive
Motivation
Performan
& Energy
ce

J Affect Disord. 2021 Mar 15;283:472-479.

Drug interaction

SSRI, SNRI

TCA

MAO Inhibitors 

Tramadol & Antipsychotics 

Antiplatelet agents
 Summary
Likely be used in
CANMAT
Novel mechanism – Approved for patients who do not
recommends as 1st
1st multimodal treatment of MDD respond/tolerate to
line in 10-20
serotonergic agent in adults an SSRI or an
mg/day dose range
SNRI

Level I evidence for

Reduces risk of Improves cognitive use in MDD with
No effect on sexual
relapse in remitted functioning among cognitive
function
patients MDD patients symptoms
(CANMAT)
Especially useful if the
Improved TESD in patient develops sexual
MDD patients who No QTc dysfunction, weight No dose titration
switched from prolongation gain, increased blood required
certain SSRIs pressure, or cognitive
dysfunction

Can be stopped
Convenient Once abruptly without
daily usage discontinuation
symptoms
Thank you