“A paradigm Shift from Monoamine to Glutamate/GABA Theory” 13th Class of Antidepressants “Glutaminergic/ GABAergic drugs” Esketamine Brexanolone

1. Novel Fast-Onset Antidepressants:
“A paradigm Shift from Monoamine to
Glutamate/GABA Theory”
Prof. Sawsan Aboul-Fotouh
Department of pharmacology, faculty of Medicine, Ain shams University

2. Major depressive disorder
(MDD)
•Globally, >264 million suffer from MDD.
•MDD is a leading cause of disability
•Contributor to global burden of disease .
•Mortality 1.7 times > G population
(WHO, 2020)

3. What is the problem?
• Delayed Onset: 2-4 Weeks need to ↑Mood
• Remission only in 60-70%.
• Treatment-resistant depression ≈ 30% (JAMA, 2019)
• Side effects as sexual dysfunction & Weight gain
• Bipolar Depression respond poorly to traditional antidepressants
With Current Antidepressants
60-70%
≈ 30%
Depression
Normal Mood

4. Why the Problem Standing along
Several Decades?
• Nearly, All approaches that have been developed target the
Monoamines (5HT, NE, DA) by developing triple
monoamine reuptake inhibitors or by adding selective receptor
subtype action in a trial to ↑efficacy and/or ↓side effects,
Monoamines

5. 12 Classes of Antidepressants
“Monoaminergic drugs”
1. TCAs as amitriptyline, imipramine, desipramine, nortriptyline, clomipramine
2. MAOIs as phenelzine, tranylcypromine, moclobemide, selegiline
3. SSRIs as fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine
4. SNRIs as venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran.
5. NDRI as bupropion
6. Selective NRIs as reboxetine and atomoxetine.
7. SARI as trazodone, nefazodone, and vortioxetine
8. SPARI as vilazodone
9. NASSA as mirtazapine and mianserin
10. NRISA as maprotiline
11. SNRISA as amoxapine
12. Atypical antipsychotics weak D2 Blockade +strong 5-HT2A/2C blockade olanzapine,
quetiapine, risperidone, lurasidone, aripiprazole, and brexpiprazole
(1959 → 2013)

6. 1959
Imipramine
(TCA)
1961
Amitriptyline (TCA)
Phenelzine,
tranylcypromine
(MAOI)
1981
Trazodone
(SARI)
Bupropion
(NDRI)
1985
1987
Fluoxetine
(SSRI)
1988 Maprotiline (NRISA)
1991
1993
2009
1992
Sertraline (SSRI)
Amoxapine (SNRISA)
Venlafaxine (SNRI)
1995
1997
1998
2002
2006
2008
Mirtazapine
(NASSA)
Reboxetine
(Selective NRIs)
Citalopram
(SSRI)
Escitalopram
(SSRI)
Selegiline TP
(MAOI)
Desvenlafaxine
(SNRI)
Quetiapine
(Atypical)
2013
2011
Vilazodone
(SPARI)
Vortioxetine
(SARI)
2004
Duloxetine
(SNRI)
By Dr. Esraa M Elnahas

7. Theories of Depression

8. A. Monoamine theory: “The Oldest 1960s & All 12 Groups of Antidepressants”
Deficit in function or amount of monoamines (5-HT, NE, DA) is central to the biology of depression.
B. Neurotrophic theory: Depression → ↓neurotrophic support (↓BDNF)
and effective antidepressant→ ↑neurogenesis & synaptic connectivity (cortical & hippocampus)
C. Neuroendocrine theory: Dysregulation of HPA axis
D. Neuro-inflammatory theory: Gut theory & ↑ inflammatory cytokines (IL-1β, IL6, TNFα).
E. Glutamate Theory: (→Esketamine)
↑ glutamate in CSF of depressed patients and ↓ glutamine/glutamate ratios in their plasma.
E. GABAergic Theory: (→Brexanolone)
Functional ↓ cortical GABAergic inhibition in MDD (↓GABA levels, ↓ expression GAD & GABAA receptors).
Theories of Depression

9. A paradigm Shift from Monoamine
to Glutamate/GABA Theory”
• Blocking NMDA receptor and activating AMPA receptor →
↑expression of BDNF gene and promote neuroplasticity
synergistically. Glutamate is a 1ry regulator of neuroplasticity.
• Since 1990s, studies focused on the postsynaptic response to
antidepressants, involving signaling mechanisms downstream
of monoamine receptors.
Monoamines
Neuroplasticity

10. ↓5-HT & NE signaling → depression, So, Drugs
Target to → ↑5-HT and NE .
5-HT and NE neurons are based in the
midbrain and pons, respectively, and
modulate the activity of higher brain centers
Shift to cortical and limbic mechanisms.
Depression as a disorder of cortico-limbic function, The
neurons in the higher brain centers release glutamate
and GABA . then glutamatergic and GABAergic signaling
would be implicated.

11. 13th Class of Antidepressants
“Glutaminergic/ GABAergic drugs”
Esketamine
Brexanolone
Both Approved in Mar 2019

12. What is Ketamine?
It is a phencyclidine (PCP or Angel Dust) derivative
of , with anesthetic, analgesic, & amnestic Action

13. Ketamine and Depression
“From Off-label use to FDA approval”
Esketamine

14. Berman et al., 2000
Ketamine and Depression
“From Off-label use to FDA approval”

15. What is the Mechanism of Action of
Ketamine in Depression ??
Presynaptic & Postsynaptic
NMDA-Receptor Blocker
→ Glutamate Surge

16. 1. It blocks presynaptic NMDA-R on GABAergic neurons →↓ disinhibition of glutamatergic n → a surge of
glutamate release → ++postsynaptic AMPA-R, ↑Na+ & Ca2+ influx → release BDNF → ++(TrkB) receptors, →
++mTOR →+++ synaptic plasticity & ↑dendritic spines → Antidepressant Effect.
Ketamine
Glutamate
Surge
+ synaptic plasticity
↑dendritic spines
2. It blocks postsynaptic NMDA-R → --eEF2→↑ BDNF & shuttles AMPA-R to synapse→ Their Action…………

17. Ketamine strengthens connections between brain cells.
Compared with a control (top), a rat neuron (red) treated with
ketamine (bottom) has grown more dendritic spines (yellow arrows)
Rong-Jian Liu, George Aghajanian & Ronald S. Duman
Control
Ketamine
Plastic synaptic remodeler

18. More mechanisms of action than just NMDA blockade
https://doi.org/10.1016/j.tacc.2014.03.002

19. Recently, Some clinical and experimental studies found
that the antidepressant and antisuicidal effects of
ketamine were blocked by opioid antagonist Naltrexone.
PNAS | February 4, 2020
ketamine does not act as a μ-opioid agonist, but functional μ-receptors are
permissive for the antidepressant effects of ketamine. ??!!
Interaction??
NMDA-R
www.pnas.org/cgi/doi/10.1073/pnas.1916570117
Mu=-opioid R

20. Pharmacokinetics of Ketamine
➢ Rapid Onset (0.5 min), Short half-life of 1 - 3 hours
➢ Peak conc. = 1 min. after IVI & 10-15 min. after IMI
➢ Highly Lipid Soluble→ Rapid cross BBB & redistribution
➢ Metabolized in Liver
➢ Ketamine & its metabolites are renally excreted (detected in urine)
➢ Routes: IV or IM; epidurally, intrathecally, and intranasally, may be
used orally in pain TTT (??!!), Oral bioavailability (17% - 20%)

21. Ketamine, a racemic mixture of R-(−) enantiomer of ketamine (arketamine)
and the S-(+) enantiomer (esketamine).
NMDA receptor affinity of esketamine is 3-4 times> arketamine
Ketamine’s antidepressant effects are due to action on NMDA-glutamate
neurotransmission, → esketamine might yield the best Antidepressant effect.

22. Dose (subanesthetic): 0.5-1.0 mg mg/kg over 40-60 minutes.
Onset of antidepressant effect: few hours ≈ 4-6 hrs
Duration: 1-2 weeks, may extend to 4 weeks with 1mg/kg dose
IV infusion of ketamine
Initial Therapy:
6-9 treatments
(3 TTT /week for 2 -3 weeks).
Maintenance therapy:
every 2-3 weeks for 1-9 years
(Royal College of Psychiatrists, 2017)
NO clarity on optimal mode of drug administration

23. 1. During treatment, OBSERVE vital signs (BP, HR, and behavior) /15 minutes. Infusion
rate ↓ up to 50% of initial rate if dissociation or anxiety results.
2. If anxiety occur → Oral or IM lorazepam or midazolam
3. if hypertension occur → Oral prazosin (1-2 mg ).
4. If anxiety history→ give 20 mg oral propranolol before the infusion.
5. if nausea history → give Ondansetron (oral or IM 4-8 mg, 30 min prior infusion).
6. 50-ml saline flush following a ketamine infusion.
7. Observe 30 - 90 minutes post-treatment for vital signs and behavior (delirium).
8. Investigations: CBC, urine drug screen, urinalysis, hepatic profile, and hCG for women of
childbearing age are obtained prior treatment and every 90 days thereafter. ECG is
patients with CVS disease.
Precautions with IV infusion of ketamine

24. - Intranasal esketamine "Spravato”: FDA approved (Mar 2019) in
conjunction with oral antidepressant (AD), for treatment-resistant depression
- It improves symptoms within 24 hours.
Each device delivers: 2 sprays, 1 spray into each nostril. • Total volume to be
delivered (per device): 0.2 mL, equivalent to 28 mg of esketamine

25. Intranasal esketamine Dosing Regimen

26. Indications of Ketamine/Esketamine in depression
1. Treatment-resistant depression (TRD)
as Adjunctive therapy.
Esketamine, FDA Approved, 2019 BUT IV
infusion, off-label.
2. Effective Anti-suicidal drug.
(Wait FDA Approval??)
Improve suicidal ideation at 4 hours, ASPIRE trials 1&2
Is ketamine an appropriate alternative to ECT for patients with treatment resistant
depression? A systematic review Journal of Affective Disorders 281 (2021) 82–89

27. 1. Common CNS: Dizziness, blurred vision,
headache, poor coordination& concentration
restlessness, Anxiety → resolving within 60 min.
prolonged sedation, patients must be monitored for at
least 2 hours at each IV treatment session.
2. Common GIT:
nausea or vomiting, dry mouth
Ketamine Adverse Effects

28. 3. ↑ blood pressure and heart rate (Central sympathetic stimulation, inhibition of NE
transporter or reuptake) during infusion and lasted up till 80 min. after dosing.
- Contraindicated for aneurysms, AV malformation, history of intracerebral hemorrhage.
- Midazolam Premedication reduces risk of rise in blood pressure and postoperative
psychomimetic effects.
Ketamine Adverse Effects

29. 4. Psychotomimetic effects, as hallucination, suspiciousness/paranoia, disorganized
thought, blunted affect and emotional withdrawal. (may also, delirium, Agitation,
unpleasant dreams especially after infusion) monitored for at least 2 hrs after session
5. Working memory deficits.
6. Hepatotoxicity has been reported after repeated use of ketamine.
7. Urinary tract (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis).
8. Drug abuse and dependence: Ketamine& esketamine are a Schedule III ??!!
Ketamine Adverse Effects

30. 1. CNS depressants (e.g., benzodiazepines,
opioids, alcohol): →↑ sedation.
2. Psychostimulants ( amphetamines,
methylphenidate, modafinil, armodafinil): →↑BP
3. MAOIs →↑BP . So, Close monitor BP
Ketamine Drug interactions

31. 1. Psychosis.
“Ketamine or esketamine should be initiated only if the benefit outweighs the risk”
2. Substance abuse (within past 6 months).
3. Severe personality disorders or Axis II disorder as primary diagnosis.
4. CVS: Aneurysm, or AV malformation, History of intracerebral hemorrhage
5. Pregnancy or Lactation (potential harm to baby) and in Children <18 years age.
7. Hypersensitivity to esketamine, ketamine, or any of the excipients.
Contraindications

32. Finally, open questions remain regarding the possible impact of ketamine/
esketamine-related addictive behaviors and the safety of long-term
exposure on cognitive function.

33. Brexanolone IV (Zulresso), The first-ever drug take FDA-approval for
postpartum depression in Mar 2019. continues IV infusion over 60 hrs (2.5 days).
Brexanolone
Brexanolone
Allopregnanolone (ALLO)
(Antidepressant effect within hours (6-7hrs) and No relapse through 30 days)

34. What is Brexanolone ?
Synthetic Allopregnanolone, Neuroactive steroid NS. (GABA A ++)
produced in Suprarenal glands, Feto-placental unit, Gonads & Brain. (80 ys,
1938).
↓ NS synthesis is found in premenstrual dysphoric disorder, depression
, panic disorder , schizophrenia and bipolar disorder
(ALLO)

35. - GABA-A receptor (δ) Alterations occur 2ry
to progesterone (&ALLO) fluctuations in
menstrual cycle, pregnancy & postpartum
-ALLO affect HP axis and neurogenesis.
- ALLO ↓ in serum & CSF in depression.
- SSRI →↑ ALLO synthesis
- ALLO ↑ during Preg. (Peak in 3rd trimester)
then sudden ↓ after Labor.
(ALLO)
ALLO, is GABA A +ve
Allosteric Modulator
Depression
Brexanolone synthetic ALLO experimental
& clinical studies for Postpartum Depression
& ALLO

36. Brexanolone
Mar 2019

37. What is the Mechanism of Action of
Brexanolone in Depression ??
GABA A Positive
Allosteric Modulator ??!!
Brexanolon
e

38. Mechanism of action of Brexanolone:
↑ synaptogenesis
Brexanolone, a +ve allosteric modulator restores GABAergic inhibition→Rapid recovery of glutamate receptors (AMPA &NMDA) surface
expression→ Normalize Neuronal Balance (GABA/Glutamate)→ ↑BDNF & Neuroplasticity & synaptogenesis
GABAergic hypothesis of resilience

39. The most common adverse reactions (≥5%)
1. Sedation/somnolence,
2. Loss of consciousness (Monitor)
3. dry mouth, flushing/hot flush.
Pharmacokinetics
- Brexanolone half-life is ̴ 9 hours.
- It is metabolized by non-cytochrome P450
- No significant differences in the pharmacokinetics of renal or hepatic impairment.

40. 1959
Imipramine
(TCA)
1961
Amitriptyline (TCA)
Phenelzine,
tranylcypromine
(MAOI)
1981
Trazodone
(SARI)
Bupropion
(NDRI)
1985
1987
Fluoxetine
(SSRI)
1988 Maprotiline (NRISA)
1991
1993
2009
1992
Sertraline (SSRI)
Amoxapine (SNRISA)
Venlafaxine (SNRI)
1995
1997
1998
2002
2006
2008
Mirtazapine
(NASSA)
Reboxetine
(Selective NRIs)
Citalopram
(SSRI)
Escitalopram
(SSRI)
Selegiline TP
(MAOI)
Desvenlafaxine
(SNRI)
Quetiapine
(Atypical)
2013
2011
Vilazodone
(SPARI)
Vortioxetine
(SARI)
2004
Duloxetine
(SNRI)
Esketamine
Brexanolone
Glutamate/
& GABAAction
2019
?
By Dr. Esraa M Elnahas

41. Psilocybin has serotonergic +
glutamatergic action
(Hallucinogen or Psychedelic as DMT & LSD)
Magic Mushroom
Psilocybin has lower addiction liability and toxic effects compared with ketamine &and is not associated
with long-term perceptual, cognitive, or neurological dysfunction
Nov. 2020