Introduction________________________________________

Zuranolone is a medication being investigated for its potential use in

treating mood disorders, particularly major depression (MDD) and
postpartum depression(PPD).
Zuranolone belongs to a class of drugs called neuroactive steroids, which
are substances that affect the central nervous system. Among the several
neurotransmitters in the brain, gamma-aminobutyric acid (GABA) receptors
are most responsive to the allosteric modulation of Zuranolone.
Zuranolone was developed as part of the ongoing effort to find new and
more effective treatments for depression and related diseases. It has been
studied in clinical studies, and early research suggests it may have a rapid
effect that may be beneficial for people with major depression.

Symptoms_____________________________________
Some women have a special kind of sadness after giving birth, called
postpartum depression (PPD). The degree of postpartum depression
symptoms varies from woman to woman, and some women may not
experience any of the symptoms at all. Among the signs of postpartum
depression are:

Impact on patients________________________________
Postpartum depression (PPD) has many effects on affected individuals,
affecting their overall health, family dynamics, and daily functioning.
Parents with postpartum depression often experience persistent
depression, low self-esteem, and problems bonding with their newborn; this
can affect parent-child relationships and good care of the baby. As partners
struggle to understand these changes, family dynamics can become
stressful, leading to stress and conflict. Isolation is common as people
withdraw from activities and support systems weaken. PPD can affect
thinking and decision-making, interfering with professional and personal
responsibilities. Additionally, untreated postpartum depression increases
the risk of relapse and negative physical consequences. Recognizing
postpartum depression and addressing it through professional interventions
such as counseling and medication when appropriate is critical to reducing
these effects and establishing health and support for individuals and their
families.

Epidemiology_________________________________________
Within the first six weeks after giving birth, postpartum depression is
common. Approximately 6.5% to 20% of women develop PPD. Premature
moms, young women, and women who live in urban areas are at a higher
risk. Symptoms were first seen by African American and Hispanic moms
within two weeks after giving birth, but white mothers noticed them later.
Region Prevalence of Mean Age
PPD in (%)

Asia 10-20 43.3

North America/ 12-25 37.9

Europe/Australia/New Zealand

Middle East/Africa 5-13 35.4

Table 1 gives rough estimates of PPD over the globe.

Classification___________________________________________________________________

Baby blues

About 2-3 days after birth, some women begin to feel anxious, depressed,
and irritable. They may be angry at their newborn, their partner, or their
child and they also:

May cry for no reason

May have difficulty sleeping, eating, and making choices.

May question their ability to take care of the baby.

Hyperthyroidism

Mood problems are a possible outcome of these illnesses. The TSH as well
as free T4 levels may be evaluated to do this.

Postpartum Psychosis

Suicide and infanticide have been linked to postpartum psychosis, making

it a mental health emergency. Hallucinations, insomnia, anger, strange
conduct, and unpleasant emotions are all possible for women. In the first
few weeks of life, it might indicate the presence of manic or depressive
psychosis.

What Causes Postpartum depression_________________________________________

Postpartum depression (PPD) can be caused by a combination of many

factors, These factors include:

Hormonal Imbalances, Estrogen, and progesterone levels drop in the hours

after birth. These changes can be stressful, just as small changes in
hormones can cause mood swings and tension.
Fatigue, it can take many weeks for women to regain their normal strength
and energy

History of depression, A history of depression can be a major cause of

postpartum depression in women.

Targets for drug discovery____________________________________________

Zuranolone is a good allosteric modulator of gamma–aminobutyric acid

(GABA) receptors, a neurotransmitter associated with central nervous
system sedation. The focus of drug discovery is often on specific
biomolecules or pathways that interact with drugs to produce therapeutic
effects. In the case of Zuranolone, the main target is the GABA-A receptor.
These are ionotropic receptors that respond to the neurotransmitter GABA
and inhibit neuronal activity in the brain. “By acting as good allosteric
modulator, Zuranolone enhances the effects of GABA on GABA-A
receptors, thereby increasing inhibitory activity and theoretically having
sedative effects.
Summary of current treatments and advantages of Zuranolone

Feature Brexanolone Zuranolone

1. Chemical Brexanolone, also Zuranolone, also known as

structure known as SAGE-547 SAGE-217, is an oral
is an intravenous neuroactive steroid that is
formulation of chemically different from
allopregnalone, a
brexanolone
neuroactive steroid
2. Administration Administered Administered orally
intravenously
3. Cost $8k/20ml $15,900 for a 14-day
treatment cycle
4. Developmental Brexanolone was Zuranolone was approved by
Stage approved by the the FDA in 2023 to treat
FDA in 2019 to treat postpartum depression under
 postpartum the brand name Zurzuvae.
depression under
the brand name
Zulresso.
5. Treatment Administered as a Typically administered orally
Duration continuous infusion providing a different
over about 60 hours approach.
6. Commercial Commercially Commercially available as
Availability available as Zurzuvae for treatment of
Zulresso for the postpartum depression.
treatment of
postpartum
depression.
7. Side effects Dry mouth Sleep disturbances
Sedation Gastrointestinal
Flushing disturbances

Table 2 summarizes the differences between the drugs for PPD and gives the cost-effectiveness of Zuranolone.

Drug Design and Discovery___________________________________

To put it simply, Zuranolone is an effective positive allosteric modulator
(PAM) of GABAA receptors at both the presynaptic and postsynaptic levels.
Phasic gamma aminobutyric acid activity is associated with synaptic
receptors, whereas tonic activity is associated with extra synaptic
receptors. Unlike Zuranolone (which increases GABA receptor expression),
benzodiazepines bind synaptic GABA receptors. The use of
benzodiazepines has been linked to a reduction in the activity of these
receptors.
Figure 3 – Chemical structure of Zuranolone (Sage-217)

Figure 4- 3d model of Zuranolone (Sage- 217) chemical structure

Zuranolone’s positive allosteric modulation of GABBAA receptors is

speculated to be involved in its anti-PPD effects, however this is just a
hypothesis.

Zuranolone is a positive modulator of GABAA receptors, however it works

differently than benzodiazepines, which bind to the α/β subunit interface
rather than the / subunit interface shared by all GABAA receptors. Thus,
both the 2α2βγ subunits of synaptic GABAA receptors and the
2α2βδ subunits of extra synaptic GABAA receptors are bound by
Zuranolone.
Efficiency and Safety of Zuranolone in the treatment of PPD_________

By stimulating many subtypes of the GABAA receptor, synthetic NAS

enhances GABAergic transmission in the central nervous system. Synthetic
NAS-positive allosteric receptor modulator of the GABAA receptor
Zuranolone has the potential to cure depression by improving synapse
potency and neuronal transmission; it is also orally bioavailable. Due to the
favorable results reported with injectable allopregnanolone formulations like
Brexanolone (used to treat parental depression), it is vital to investigate the
security and effectiveness of Zuranolone.
To evaluate the effectiveness, safety, and tolerability of Zuranolone, a
double-blind, placebo-controlled study was conducted using 108 healthy
volunteers, and both multiple ascending dose (MAD) and single ascending
dose (SAD) trials were conducted. Dosages ranging from 0.3 to 0.7 mg
were tested in 9 groups including 36 people in the MAD trial, and 72
persons in the SAD investigation. In the MAD study, 13 participants were
randomly assigned to receive either the active treatment (15mg, 30mg, or
35mg) or a placebo for 7 days. Twelve studies had a 6:2 ratio of
participants getting a placebo or active therapy. Studies have shown that
Zuranolone has a t-max of around 1 hour and a half-life of about 15-22
hours. In the MAD trial, the most effective dose was 30 mg, whereas in the
SAD study, the highest effective dose was 55 mg. This study found that the
drug was well tolerated.
Pathophysiology of major depressive disorder with peripartum onset_

Perinatal depression has been related to hypothalamic-pituitary axis

dysfunction. Increases in cortisol, estrogen, and progesterone result from
increased activity of the hypothalamic-pituitary-adrenal (HPA) axis, which
occurs during the third trimester of pregnancy. A newborn's HPA axis
normally weakens, and hormone levels drop after birth. High levels of
cortisol and other stress hormones are common in patients suffering from
severe depression.

The HPA axis was inadequately responsive in only patients between 6 and
12 weeks of age.” Treatments that aim to boost the HPA axis via positive
feedback seem to have the opposite effect on depressive symptoms. Since
these are characteristics that almost all pregnant and postpartum women
have, they play an important role in the pathophysiology of the disorder as
well.
As an excellent allosteric modulator of gamma-aminobutyric acid (GABA)
receptors, neuroactive steroids (NAS) like allopregnanolone are crucial in
reducing HPA axis activity during pregnancy. NAS levels fluctuate as the
pregnancy progresses. Allopregnanolone levels have been proved to
increase during pregnancy and decline again after the baby is delivered.

Figure 5 GABAA receptor composition structure and binding sites for GABA and benzodiazepines.
Zuranolone
50 mg PO qPM x 14 days
Recommended dose Use beyond 2 weeks in a single course has not been
established

Formulations available Capsule-PO route

Contra – indications None

Interactions No known interactions

Usage and Administration____________________________________________

Table 3 summarizes the monograph on Zuranolone.

Pharmacodynamics_____________________________________________________________

Zuranolone did not cause a clinically significant prolongation of the QTc

interval to twice the maximum recommended range. Repeated
administration of Zuranolone with alcohol or alprazolam at a daily dose of
50mg may cause impairment of mental performance.

Zuranolone can increase phasic and tonic postsynaptic currents associated

with the modulation of synaptic and extra-synaptic GABBA receptors,
respectively. Because tonic current can be more reactive than phasic
current, Zuranolone ability to alter tonic current provides a better
opportunity to increase GABA conductance.
Pharmacokinetics
Blood samples were collected at scheduled times to measure plasma
Zuranolone levels and analyzed at a central laboratory. For single
measurements in parts A, B (cycles 1, 2, and 3), before a dose (0 hours)
and at 0.5, 1, 2, 3, 4, 5, dose 6, 8 after, 10, 12, 24, 36, 48 and 72 hours.

The following parameters were evaluated: maximum plasma concentration-

time curve (AUC). additive AUC from zero to infinity (AUCO-inf). Time from
time to infinity (AUCO). Time from zero initial AUC to final measurable
concentration after administration and volume of distribution as a function
of terminal clearance time.

This study of Zuranolone in Tokyo showed that all doses tested below
30mg were effective and the Pharmacokinetics profile was not significantly
affected by race or age. Plasma exposure to Zuranolone is more frequent
during fasting. Zuranolone 30mg enhanced low beta potency.
Figure 6: Pharmacokinetics of Zuranolone.
Side Effects

Likelihood Side effect

 Dry mouth
 Very common  Abdominal pain
 Flatulence

 Weakness
 Lack of energy
 Common  Nasal congestion
 Runny nose
 Dehydration

 Dehydration
 Hypokalemia
 Decreased appetite
 Orthostatic hypotension
 Uncommon
 Vomiting
 Nausea
 Defecation urgency
 Tooth Ache

 Diarrhea
 Rare  Diarrhea

 Angina
 Unknown  Heart Burn

Table 4 Shows the side effects of Zuranolone.

Electroencephalography____________________________________
There was no significant difference in changes in low beta power between
the Zuranolone 10mg and placebo groups (Figure 7 mentioned below). Low
beta power recorded at 5,6 and 8 hours after dosage showed an increase
in the Zuranolone 30mg group compared to the placebo group.

Figure 7 Electroencephalography of Zuranolone

Low beta band power as a function of time with Zuranolone 10mg and 30mg
Placebo
Do the benefits outsource the side effects?
_______________________
Zurzuvae, a GABA-A type receptor subunit provides a novel mechanism of
action for the treatment of depression it works quickly, with reductions in
depression symptoms seen within 3 days of starting the medication,
compared to three to six off-label treatments for PPD, such as selective
serotonin-norepinephrine. Reuptake inhibitors. Additionally, Zurzuvae,
which is an intensive treatment that lasts only two weeks, is particularly
suitable for patients who do not need long-term treatment, especially for
mothers who are concerned about chemicals mixing with their breast milk.
FDA has not approved Zurzuvae to treat major depressive disorder even
though PPD is approved.
Zurzuvae, despite having some side effects is less costly than
Brexanolone. It is also easier to administer. The benefit of treating PPD is
far greater than leaving it unattended or giving the patient intravenous
infusions for a great period, giving the patient undesirable discomfort and
agony. Considering my arguments, it is fair to say that Zurzuvae is more
beneficial than its harm.

Conclusion______________________________________________________________________________
Postpartum depression is common among women who have just given
birth, and the drug Zuranolone (marketed under the trade name Zurzuvae)
is used to treat this condition. Healthcare providers should make every
effort to identify and treat postpartum depression as soon as possible
because of the devastating repercussions it may have for women and their
families if left untreated. Since mental problems are so common, it's
important to check depressed women for conditions like OCD and panic
disorder as well. Allopregnanolone's potential as an antidepressant stem
from its role as a novel agonist at GABAA receptors. Allopregnanolone has
a more faster antidepressant impact than standard therapy.
They may also be used to help smooth the transition from induction
treatment to SSRI medication. Since endogenous allopregnanolone plays a
role in PPD, using this medication may result in high expenses and the
danger of untreated PPD. Zuranolone was produced as a development of
the nerve neurosteroid Brexanolone and has oral absorption and partial
bioavailability- a lifestyle ideal for once-daily usage. It has a longer half-life
than Brexanolone, at about 16-23 hours against around 9 hours.
The most prevalent adverse effects are Weakness, Lack of energy, Runny
nose, and Dehydration.
The public and pharmacists may both benefit from this information. Due to
the drug's recent introduction, very little data is currently available.
However, the results of this study demonstrate that Zuranolone is superior
to other therapies for PPD symptoms and should be widely used. This
study also demonstrates that compared to other options, Zuranolone is
safer.
Zuranolone is a relatively new drug and the research material on it is
limited it has recently been approved by the FDA in August 2023. It is being
commercially sold under the name of Zurzuvae.
It is orally administered over the course of two weeks and its major side
effects are yet to be established. According to my research, Zuranolone is
more advantageous than Brexanolone being less costly and easier to
consume compared to Brexanolone’s intravenous infusion and high cost.

References______________________________________________________
Freeman MP, Davis M, Sinha P, Wisner KL, Hibbeln JR, Gelenberg AJ. Omega-3
fatty acids and supportive psychotherapy for perinatal depression: a randomized
placebo-controlled study. J Affect Disord 2008:142–8.
Gunduz-Bruce H, Takahashi K, Huang MY. Development of neuroactive steroids
for the treatment of postpartum depression. J Neuroendocrinol. 2021; e1 3019.
Brunton PJ. Neuroactive steroids and stress axis regulation: Pregnancy and
beyond. J Steroid Biochem Mol Biol.2016;160:160-8.
Maguire, J., and I. Mody. 2008. GABA(A)R plasticity during pregnancy:
Relevance to post-partum depression. Neuron 59(2):207–213
Pavlov, I., L. P. Savtchenko, I. Song, J. Koo, A. Pimashkin, D. A. Rusakov, A.
Semyanov. 2014. Tonic GABAA conductance bidirectionally controls interneuron
firing pattern and synchronization in the CA3 hippocampal network. Proceedings
of the National Academy of Sciences 111(1):504–509.
Nishi D, Ishikawa H, Kawakami N. Prevalence of mental disorders and mental
health service use in Japan. Psychiatry Clin Neurosci. 2019; 73: 458–65.
Watanabe K, Fujimoto S, Marumoto T, Kitagawa T, Ishida K, Nakajima T, et al.
Therapeutic potential of vortioxetine for anhedonia-like symptoms in depression: a
post hoc analysis of data from a clinical trial conducted in Japan. Neuropsychiatr
Dis Treat. 2022; 18: 363–73.
Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, et al. (2022). "GABAkines -
Advances in the discovery, development, and commercialization of positive
allosteric modulators of GABAA receptors". Pharmacology & Therapeutics. 234:
108035.
"FDA Approves Zurzuvae (Zuranolone), the First and Only Oral Treatment
Approved for Women with Postpartum Depression and Issues a Complete
Response Letter for Major Depressive Disorder" (Press release). Biogen Inc. 4
August 2023.”

Griffin, C. E., Kaye, A. M., & Bueno, F. R. (2020). The role of allopregnanolone
in depression and anxiety. Neurobiology of Stress, 12, 100215.

Kanes, S., Colquhoun, H., Doherty, J., Raines, S., Hoffmann, E., Rubinow, D., &
Jonas, J. (2017). Open-Label, Proof-of-Concept Study of SAGE-547 Injection in
Patients with Severe Postpartum Depression. Neuropsychopharmacology, 42(14),
2422–2428.

Gunduz-Bruce, H., Silber, C., Kaul, I., Rothschild, A. J., Riesenberg, R., Sankoh,
A. J., & Li, H. (2019). Trial of SAGE-217 in Patients with Major Depressive
Disorder. New England Journal of Medicine, 381(10), 903–911.

Meltzer-Brody, S., Colquhoun, H., Riesenberg, R., Epperson, C. N., Deligiannidis,

K. M., Rubinow, D. R., ... & Jonas, J. (2018). Brexanolone injection in post-
partum depression: two multicenter, double-blind, randomized, placebo-controlled,
phase 3 trials. The Lancet, 392(10152), 1058-1070.

Jonas, J., Epperson, N., Kanes, S., Colquhoun, H., Stern, T., Rothschild, A., ... &
Meltzer-Brody, S. (2019). Brexanolone (SAGE-547 injection) in post-partum
depression: a randomized controlled trial. The Lancet Psychiatry, 6(6), 477-487.
Marx W. Penninx B. Solmi M. et al. Major depressive disorder. Nat Rev Dis
Primers. 2023; 9: 44

Rush A.J. Trivedi M.H. Wisniewski S.R. et al. Acute and longer-term outcomes in
depressed outpatients requiring one or several treatment steps: a STAR∗D report.
Am J Psychiatry. 2006; 163: 1905-1917

Kverno K.S. Mangano E. Treatment-resistant depression: approaches to treatment.

J Psychosoc Nurs Ment Health Serv. 2021; 59: 7-11

Ashton A.K. Jamerson B.D. Weinstein L.W. Wagoner C. Antidepressant-related

adverse effects impacting treatment compliance: results of a patient survey. Curr
Ther Res Clin Exp. 2005; 66: 96-106

Martinez Botella G. Salituro F.G. Harrison B.L. et al. Neuroactive steroids. 2. 3α-
Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one
(SAGE-217): a clinical next-generation neuroactive steroid positive allosteric
modulator of the (γ-aminobutyric acid)(A) receptor. J Med Chem. 2017; 60: 7810-
7819

Yan C.G. Chen X. Li L. et al. Reduced default mode network functional

connectivity in patients with recurrent major depressive disorder. Proc Natl Acad
Sci U S A. 2019; 116: 9078-9083

Rajkowska G. O'Dwyer G. Teleki Z. Stockmeier C.A. Miguel-Hidalgo J.J.

GABAergic neurons immunoreactive for calcium-binding proteins are reduced in
the prefrontal cortex in major depression. Neuropsychopharmacology. 2007; 32:
471-482

Bixo M. Johansson M. Timby E. Michalski L. Bäckström T. Effects of GABA

active steroids in the female brain with a focus on the premenstrual dysphoric
disorder. J Neuroendocrinol. 2018; 30

Uzunova V. Sheline Y. Davis J.M. et al. Increase in the cerebrospinal fluid content
of neurosteroids in patients with unipolar major depression who are receiving
fluoxetine or fluvoxamine. Proc Natl Acad Sci U S A. 1998; 95: 3239-3244

Meltzer-Brody S. Colquhoun H. Riesenberg R. et al. Brexanolone injection in post-

partum depression: two multicenter, double-blind, randomized, placebo-controlled,
phase 3 trials. Lancet. 2018; 392: 1058-1070
 Deligiannidis K.M. Meltzer-Brody S. Gunduz-Bruce H. et al. Effect of Zuranolone
vs placebo in postpartum depression a randomized clinical trial. JAMA Psychiatry.
2021; 78: 951-959

Kato M. Nakagome K. Baba T. et al. Efficacy and safety of Zuranolone in

Japanese adults with major depressive disorder: a double-blind, randomized,
placebo-controlled, phase 2 clinical trial. Psychiatry Clin Neurosci. 2023; 77: 497-
509

Clayton A.H. Lasser R. Parikh S.V. et al. Zuranolone for the treatment of adults
with major depressive disorder: a randomized, placebo-controlled phase 3 trial. Am
J Psychiatry. 2023; 180: 676-684

Gunduz-Bruce H. Silber C. Kaul I. et al. of SAGE-217 in patients with major

depressive disorder. N Engl J Med. 2019; 381: 903-911

Clayton A.H. Lasser R. Nandy I. Sankoh A.J. Jonas J. Kanes S.J. Zuranolone in
major depressive disorder: results from MOUNTAIN-A phase 3, multicenter,
double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2023;
8422m14445

Stahl S.M. Hammond R. Garcia M. et al. Zuranolone, a positive allosteric

modulator of the GABAA receptor: hypothesized mechanism of action in major
depressive disorder. CNS Spectr. 2023; 28: 260-261

Self-
Assessment_______________________________________
Assessment Area Weight Mark Criteria Brief Evidence justifying the
/100 Awarded mark awarded
The document 10 XX Template Followed, Information I believe I got 10 in this section
in correct sections. Good clear because my structure followed the
 tables, figures, and schemes. proforma as I didn’t miss any
Correctly Referenced Accurate headings or subheadings. My tables
spelling and grammar and figures are clearly referenced
and are all in the same color and
design scheme, making it easier to
understand. Spelling and grammar
seem excellent throughout. Finally,
I believe I referenced. Correctly
using Harvard-style referencing
Factual content 50 XX Appropriate breadth, depth, All my sections are roughly the
same length, and the same amount
quality and quantity of of time and effort was spent on
each section. There are no gaps in
content in each section. the report as I have covered all
bases as specified in the proforma.
Appropriate sources used. All content was derived from
official articles that had been peer
reviewed and these have been
referenced appropriately. In some
sections of the report, little
information was available. I made
this clear in my report after
discussing it with my advisor who
also couldn’t find any information
in those sections. All figures and
tables have captions that explain
their meaning and relevance.
Explanation, 40 XX Explaining what information I have explained the significance of
Critical appraisal and means. The significance, value, all the factual content in this report.
interpretation, and impact of the information I displayed this skill by talking
originality gathered, or task performed. about how Zuranolone is more
advantageous over current
treatments. In addition, I also
mentioned the drawbacks
associated with Zuranolone to give
a balanced insight into the drug.
My conclusion perfectly
summarizes the key content of the
report.
Self-Assessment Pass/Fail Pass