antidep

2. Novel Antidepressants
Prof. Hani Hamed Dessoki, M.D.Psychiatry
Acting Dean, Faculty of Nursing
Prof. Psychiatry
Founder of Psychiatry Depart., Beni Suef University
Supervisor of Psychiatry Depart., El-Fayoum University
Treasurer of Egyptian Psychiatric Association
APA member
2019

3. Size of the Problem
• Major depressive disorder (MDD) is a
major public health concern with
significant impairment in psychological,
occupational, and social functioning.
• The prevalence rates for depression are
estimated to be around 3.2% in patients
without comorbid physical illnesses and
9.3% to 23.0% in patients with chronic
conditions.

4. • It affects around 300 million individuals
regardless of gender, ethnicity,
geographical location, and socioeconomic
status, contributing to the overall global
burden of disease.

5. • (SSRIs) are the appropriate first-line options
for the treatment of depression along with
psychotherapeutic interventions, but many
patients either do not respond to different
options or intolerant to the undesired effects
of medications.
• Despite multiple treatment regimen, about
60% of patients with MDD continue to report
residual impairments even after treatment

6. • This residual symptoms and functional
impairment have a higher risk of relapse
into the future episodes of MDD

7. • Depression may not be caused by the simple
deficiency of serotonin in the brain, but rather a
complex interplay of various neurotransmitters
including serotonin, norepinephrine, glutamate,
and histamine at certain brain areas.
• The novel antidepressants exert their
therapeutic benefits by acting on multiple
neurotransmitters.
• The complexity of underlying the neurobiological
mechanism should be considered while
formulating a plan of care.

9. Vilazodone
• Vilazodone. It is approved for the
treatment of MDD.
• Vilazodone inhibits serotonin uptake with
minimal or no effect on reuptake of
norepinephrine or dopamine.
• The pharmacokinetics of vilazodone (5 to
80 mg) are dose proportional.
• Steady-state plasma levels are achieved
in about 3 days.

10. 1- What is the Mechanism of
Action of Vilazodone ?
Vilazodone has 3 Site of actions:
1- Presynaptic 5-HT1A in Raphe Nuclei causing Rapid
Desensitization.
2- Postsynaptic 5-HT1A in Limbic System causing
Increased Dopamine level in Prefrontal Cortex (PFC)
3- SERT as any SSRI with Higher Inhibitory Power
than Other SSRIs (IC 50 = 1.6 nM).

11. Benefits of Rapid 5-HT1A Desensitization
1) Rapid Anti-Depressant Effect (1st W)
2) Rapid Anxiolytic Effect (Prevent Initial Agitation)
3) 5-HT release From 5-HT Pump from Raphe N
5-HT Pump in
Raphe N
Benefits of High Affinity to SERT (IC 50 =
1.6 nM)
Increases Extracellular 5-HT in Limbic
System (Double Effect) >>> More High
Efficacy in 5-HT Related Disorders
Benefits of High Affinity to Post synaptic 5-
HT1A
Increasing Dopamine in PFC:
1- Preventing Emotional Blunting,
Sexual Dysfunction & Weight Gain
2- Improving Cognition &
Anhedonia.

12. 2- What is the Place of Vilazodone
in Therapy ?
1- As a 1st Line agent as its combined action on SERT
& 5-HT1A offer a Unique Initial Rapid Antidepressant
effect.
2- In Patients who DO NOT respond to SSRI/SNRI or
Do Not Tolerate SSRI/SNRI
3- In Patients who Developed Sexual Dysfunction,
Weight Gain or Increased Blood Pressure on
SSRI/SNRI
4- In Patients who cannot Tolerate Antipsychotic Augmentation
Trial due to Weight Gain, Sedation, Extrapyramidal symptoms or
Dyslipidemia.

13. 3- What is Inhibitory Power To SERT of
Vilazodone Compared with Other SSRIs ?
The Inhibitory Power To SERT is a measure tool for
inhibitory potency, which is defined as:
The half maximal Inhibitory Concentration (IC 50) = the
concentration needed to reduce the SERT activity to
50%.
The smaller the IC 50, the potent the inhibitory power
to SERT, The Higher Efficacy.
Among All SSRIs, Vilazodone is the 2nd Potent
Inhibitory Power To SERT after Paroxetine.

14. 4- What are Symptoms Improved in 1st Week ?
And Why ?
In the Main Clinical Trial, By which FDA Approved Vilazodone
For Depression, 4 Symptoms of 10 of MDRS were improved in
the 1st week which are:
[1] Inner Tension
[3] Concentration difficulties
[2] Lassitude
[4] Suicidal Thoughts
2 Symptoms in 2nd W, And the Rest 4 Symptoms in 6th W

15. WHY This 4 Symptoms Improved in 1st Week?
Due to Increased DA
Release in PFC by
5-HT1A Agonism
Due to Direct
5-HT1A Agonism
(Suicidal attempters
have decreased
5-HT1A activity)
[Proved by PM &
Biology of
Suicidality]

16. The Role of Direct 5-HT1A Agonism in the
Biology in Suicidal Behavior

17. • Elimination of vilazodone is primarily by
hepatic metabolism with a terminal half-life
of approximately 25 hours.
• Dose should be reduced to 20 mg when
co administered with CYP 3A4 strong
inhibitors.
• Concomitant use with inducers of CYP
3A4 may require dose adjustment.

18. • The effect of CYP 3A4 inducers on
systemic exposure of vilazodone has not
been evaluated.
• Vilazodone is available as 10-, 20-, and
40-mg tablets.
• The recommended therapeutic dose of
vilazodone is 40 mg once daily. Treatment
should be titrated, starting with an initial

19. • Dose of 10 mg once daily for 7 days,
followed by 20 mg once daily for
an additional 7 days, and then an increase
to 40 mg once daily.
• Vilazodone should be taken with food. If
vilazodone is taken withoutfood,
inadequate drug concentrations may result
and the drug’seffectiveness may be
diminished.

20. Vortioxetine
Vortioxetine works mainly as an inhibitor of
serotonin (5- HT) reuptake, but it has a more
complex pharmacologic profile than
other SSRIs. It also acts as an agonist at 5-
HT1A receptors, a partial
agonist at 5-HT1B receptors and an
antagonist at 5-HT3, 5-HT1D, and 5- HT7
receptors.

21. Vortioxetine
• Side effects include nausea, constipation,
and vomiting.
The recommended starting dose is 10 mg
administered orally once
The maximum recommended
dose is 10 mg/day in CYP 2D6 poor
metabolizers. Reduction of the dose
by one-half is suggested when receiving a
CYP 2D6 strong inhibitor
(e.g., bupropion, fluoxetine, paroxetine, or
quinidine) concomitantly.

22. Ratios of Serotonin to
Norepinephrine Reuptake Inhibition
• Below are different ratios of serotonin to norepinephrine reuptake
inhibition. As you can see, Effexor has the most lop-sided ratio. Newer
drugs like Cymbalta and Pristiq slightly bridged the gap, but still focus more
on serotonin than norepinephrine. The latest SNRI approved for depression
called Fetzima favors the norepinephrine, but has almost an equally
balanced ratio.
Venlafaxine – (30:1)
Duloxetine – (10:1)
Desvenlafvaxine – (10:1)
Fetzima – (1:2)
Fetzima (Levomilnacipran)
• Approved in 2013, this is an antidepressant that works as a serotonin-
norepinephrine reuptake inhibitor (SNRI). It contains the “levo” enantiomer
of the drug milnacipran and has similar effects. In comparison to other
drugs, this drug provides a more balanced reuptake of both serotonin and
norepinephrine. What makes this drug different from other SNRIs is that its
ratio of reuptake inhibition is almost even (1:2).

23. Non-Antidepressant SNRIs
Sibutramine
• Approved 1998, is an appetite suppressant drug that was initially prescribed
to help treat obesity. Due to the fact that it’s been associated with increased
risk of strokes and cardiovascular problems, it was pulled from the
market in 2010. This drug acted centrally as an SNRI with a distinct
mechanism of action, closely resembling amphetamines.
• It differs from other appetite suppressants (e.g. amphetamines) because it
doesn’t force the release of neurotransmitters, it only prevents their
reuptake.
Savella (Milnacipran)
• Approved 2009, this drug is utilized for the treatment of fibromyalgia. It has
also been approved to treat major depression in countries outside the
United States. This drug inhibits the reuptake of serotonin and
norepinephrine at a ratio of 1:3. The drug Fetzima (Levomilnacipran) which
was approved in 2013 in the United States is very similar to this drug and it
inhibits reuptake at a 1:2 ratio – which is slightly more balanced.

24. Desvenlafvaxine

25. Levomilnacipran ER
• Levomilnacipran ER, 1S, 2R- milnacipran,
is an SNRI approved by the FDA for the
treatment of MDD in adults

26. • All SNRIs inhibit the reuptake of 5-HT and NE
with a difference in their potencies for the
respective transporters, resulting in clinical
implications.
• Levomilnacipran ER is a relatively more active
enantiomer of racemic milnacipran. It has two-
folds higher potency for norepinephrine
compared to serotonin reuptake inhibition and
preferentially inhibits norepinephrine reuptake
compared to duloxetine, venlafaxine, and
desvenlafaxine.

27. • It lacks effect on other receptors, ion channels or
transporters tested in vitro, including
serotonergic (5HT1-7), α- and β- adrenergic,
muscarinic, or histaminergic receptors and
Ca2+, Na+, K+ or Cl- channels.
• Levomilnacipran is an ER formulation, allowing
once-daily dosing. The recommended dose
range for levomilnacipran is 40-120 mg/day.
• The starting dose is 20 mg /day and then it can
be increased to 40 mg/day after two days.

29. Ketamine
• Ketamine has been in use since 1970,
used as an anesthetic agent. It also
became a drug of abuse as a psychedelic
club drug. In 2006, a study by Zarate CA
Jr at the National Institute of Mental Health
(NIMH) concluded that Ketamine produced
a robust and rapid antidepressant effect
after a single IV infusion with an onset
within 2 hours postinfusion and remained
significant for a week.

30. Ketamine
• It is a nonbarbiturate anesthetic chemically
designated dl 2-(0-
chlorophenyl)-2-(methylamino)
cyclohexanone hydrochloride.
• Ketamine hydrochloride injection should
be used by or under the direction and
supervision of physicians who are
experienced in administering general
anesthetics and in maintenance of an
airway and in the control of respiration.

31. • Since the landmark study thousands of
depressed patients have
received off-label Ketamine infusions even
though the FDA has not
approved it. The benefits are transitory for
1 to 2 weeks and require
ongoing regular infusions.

32. • Alternate modes of administration
including intranasal and PO formulations
are being explored but oral
bioavailability is only 8% to 17%.
• As of now this treatment modality is being
practiced by a few psychiatrists as an off-
label use for patients who have failed to
show response to conventional
antidepressant therapy or ECT.

33. Psilocybin
• . Psilocybin, the active ingredient in
mushrooms, is being investigated in the
treatment of anxiety and depression
particularly in the end-of-life situations like
patients with terminal cancer. Numerous
studies across the country are looking at
this mysterious and magical product that
has been used since ancient times in
various cultures.

34. • A single dose of Psilocybin ha been shown
to reduce anxiety and
depression by altering perception and
producing mystical-type
experiences with effects lasting up to 6
months. At this time, Psilocybin remains
confined as a potential treatment for
anxiety and depression in
controlled research setting under the
guidance of well-trained personnel.

35. • Antidepressants in development.
Numerous new antidepressants are
currently in development but are years
from any regulatory approval. Theses
agents have newer and novel mechanisms
of action including: Triple reuptake
inhibitors that block serotonin,
norepinephrine and dopamine reuptake.
NK receptor antagonists that block
substance P receptor, and also offers
anxiolytic properties.

36. CRF1 antagonists
• CRF1 antagonists that block
corticotrophin-releasing receptors, and
regulate HPA axis. Glutamate-acting drugs
that block N-methyl-D-aspartate receptors
(NMDA).

37. Opioid for depression
• Opioid for depression. Recent studies
show opioid dysregulation in
major depression. The combination of
buprenorphine and samidorphan show
promising results in treatment-resistant
depression equivalent to adjunct treatment
with antipsychotics.
• Obvious concerns for abuse exist but
combination of buprenorphine with mu-
opioid receptor antagonist may block

38. New Receptors

39. Transcranial Magnetic Stimulation
• TMS induces electrical fields in the brain
without an electrode through the
application of alternating magnetic fields
via a coil held on the scalp. It is a
noninvasive stimulation of focal regions of
the brain without the need for
anesthesia.

40. Transcranial Magnetic
Stimulation
A. Indications. It is approved by the FDA for
the treatment of MDD in
adult patients who have failed to achieve
satisfactory improvement from
one prior antidepressant medication at or
above the minimal effective
dose and duration in the current episode.

41. • B. Side effects, interactions with
medications, and other risks.
Administration of TMS is a noninvasive,
relatively benign procedure but
it is not entirely without risk, the most
serious being an unintended
seizure.

42. C. Patient selection. Patients who have
failed a trial of one or more
antidepressant medications or have
untoward side effects to medications
may be good candidates for TMS. However,
given the lower effect size
of TMS, for urgent or severely refractory
cases, ECT would remain the
ultimate gold standard treatment.

43. Transcranial Direct Current
Stimulation
• It is a noninvasive form of treatment that
uses very weak (1 to 3 mA) direct
electrical current applied to the scalp. The
small device is very portable and
usually operated by readily available DC
batteries.

44. • A. Side effects. There are no known
serious adverse effects of tDCS. It is
well tolerated, with reported common side
effects in the literature listing
mostly minimal tingling at the site of
stimulation, with a few reported
cases of skin irritation.

45. • B. Mechanism of action. Direct current
polarizes current, and tDCS is
believed to act via the alteration of
neuronal membrane polarization, but
little is known about the actual mechanism
of action of tDCS.

46. • C. Clinical studies. Preliminary research
suggests that tDCS may enhance
certain brain functions independent of
mood; however, tDCS technology
and its use in psychiatry are in the early
stages of exploration.

47. Cranial Electrical Stimulation
A. Definition. CES, like tDCS, uses a weak
(1 to 4 mA) current. It is
traditionally applied via saline-soaked, felt-
covered electrodes clipped
onto the earlobes.
B. Mechanism of action. The exact
mechanism of action has not been
elicited, and there is no agreement among
researchers on the
predominant mode of action.

48. Cranial Electrical Stimulation
C. Side effects. It is believed that the CES
stimulation is not harmful,
primarily due to its low voltage power supply
(9-V battery) and lack of
any reported adverse event by the FDA.
Local skin effects, as well as a
general feeling of dizziness, have been
reported.

49. D. Clinical studies. In a meta-analysis by the
Harvard School of Public
Health the overall pooled result showed
CES to be better than sham
treatment for anxiety at a statistically
significant level.

50. Magnetic Seizure Therapy
• A. Definition. MST is a novel form of a
convulsive treatment, given using
a modified TMS device that is under
development in several research
institutions. The aim is to produce a seizure
whose focus and patterns of
spread may be controlled. MST is a convulsive
treatment, in many ways
similar to ECT and requires approximately the
same preparation and
infrastructure as ECT. It is not FDA approved.

51. Magnetic Seizure Therapy
• B. Mechanism of action. Induction of a
seizure is hypothesized to be the
underlying event responsible for the likely
multiple specific mechanisms
of action of MST treatment.

52. • C. Side effects. Adverse effects are like
those of ECT, are largely
connected to the risks associated with
anesthesia and generalized
seizure. Studies show MST results in less
retrograde and anterograde
amnesia than ECT.
D. Current status in treatment algorithms.
It is still an investigational
protocol and treatments outside of
research are not FDA approved.

53. Vagus Nerve Stimulation
• A. Definition. VNS is the direct, intermittent
electrical stimulation of the
left cervical vagus nerve via an implanted
pulse generator, usually in the
left chest wall. The electrode is wrapped
around the left vagus nerve in
the neck and is connected to the generator
subcutaneously.

56. Vagus Nerve Stimulation
• B. Side effects and contraindications. VNS
is generally well tolerated.
The most common side effects are voice
alteration, dyspnea, and neck
pain.

57. Current status in treatment
algorithms
• C.. The FDA indicated VNS for
the adjunctive long-term treatment of
chronic or recurrent depression in
patients 18 years or older experiencing a
major depressive episode in the
setting of unipolar or bipolar disease who
have not had an adequate
response to four or more adequate
antidepressant treatments.

58. Current status in treatment
algorithms
• D. Patient selection. VNS is approved as
an adjunctive long-term
treatment for chronic or recurrent
depressive episodes in adults with a
major depressive episode who have not
had a satisfactory response to
four or more adequate antidepressant
trials. The efficacy of VNS in other
disorders is unknown.
.

59. Current status in treatment
algorithms
• E. Dosing. The optimal dosing for
psychiatric applications of VNS is still
largely an area of investigation. The
published studies do not identify
optimal dosing parameters like time on,
time off, frequency, current, or
pulse width.

60. Deep Brain Stimulation
• The procedure involves placement of
small-diameter brain “leads” (e.g.,
approximately 1.3 mm) with multiple
electrode contacts into subcortical
nuclei or specific white matter tracts. The
surgeon drills burr holes in skull
bone under local anesthesia and then
places the leads, guided by
multimodal imaging and precise
stereotactic landmarking.

61. Deep Brain Stimulation
• Later, the
“pacemaker” (also known as an
implantable neurostimulator or pulse
generator) is implanted subdermally (e.g.,
in the upper chest wall) and
connects it, via extension wires tunneled
under the skin, to the brain leads.

62. • A. Indications. It is used to treat people
with advanced Parkinson’s disease,
dystonia, and essential tremor whose
symptoms are no longer controlled
by medication.

63. • B. Outcome with deep brain stimulation
1. Obsessive-compulsive disorder. DBS
has been shown to have
clinically significant symptoms reduction in
patients with intractable
OCD. DBS is placed at the ventral anterior
limb of the internal
capsule and adjacent ventral striatum
(VC/VS).

64. • 2. Major depression. Functional
neuroimaging research implicates the
subgenual cingulate cortex as a node in
circuits involved in the
normal experience of sadness, symptoms
of depressive illness, and
responses to depression treatments.

65. • The treatment is in early stages
and being studied but chronic DBS for up
to 6 months showed
sustained remission of depression in a
small number of patients. The
advent of DBS in psychiatry has created
tremendous interest and
considerable research activity..

66. • DBS may therefore be accepted by
patients who would not choose to undergo
lesion procedures
(although the reverse is also true). With all
of its advantages, DBS
requires that patients be treated by highly
specialized teams willing
and able to provide long-term care.

67. Future therapeutic
Approaches
Approach Example Mechanism
1. CRF ? Antagonize effects of CRF in amygdala
2. Sub. P antagonist ? Antagonize effects of sub. P on raphe
nucli
3. Neuro active peptide
antagonists
?? CCK and NK antagonism
4. 5HT1A agonist Flesinoxon
Eptapirone
 5HT1A activity
5. 5HT2a/c Deramciclane  5HT 2a/c
6. GABA receptors
modulators
Suriclone Act near GABA and have properties
similar to BZ
7. Glutaminergic agents ? Act via glutamate in dorsal raphe nuclei
(for treatment resistant cases)