Vortioxetine is a serotonin modulator and stimulator approved for major depressive disorder. It is also being studied for generalized anxiety disorder, alcohol use disorder comorbid with depression, and subclinical depression with anhedonia. Common side effects include nausea, diarrhea, headache, and sexual dysfunction. It has drug-drug interactions with CYP2D6 and CYP3A4 inhibitors/inducers. Limited data exists for use in pregnancy and breastfeeding due to risk of adverse effects in newborns. Esketamine is approved for treatment-resistant depression used along with an oral antidepressant under direct medical supervision due to risk of dissociation and need for restricted access program.

2. Serotonin Modulator and Stimulator
(SMS)

3. Indications
• Major depressive disorder (MDD)(approved)
• Generalized anxiety disorder (GAD)
• Alcohol use disorder (AUD) comorbid with
major depressive disorder (MDD) –
preliminary evidence suggests this may be a
rational treatment
• consideration, even in cases of subclinical
depression but clinically significant anhedonia

4. General comments
• Non-US-based trials demonstrated efficacy for MDD at
lower doses (5 mg) compared to US trials
• A network meta-analysis of 24 studies does not indicate
greater benefits or fewer harms of vortioxetine compared
with other second-generation
antidepressants
• Post-hoc analyses of short-term trials to assess safety of
vortioxetine in later life depression (defined as 55 years or
older with a majority having
stable chronic physical diseases for these analyses) suggest no
differences in this population
• Beneficial cognitive effects were initially demonstrated as a
secondary outcome in the late-life depression trial; effects
confirmed in a short-term

5. General comments
• Improvements in functionality, anxiety and qualityof life seem
to be more substantial in GAD subpopulations who are
working or pursuing education
• A Canadian study demonstrated significant economic
savings extending from improved workplace productivity
following treatment with vortioxetine .other studies did not
show the same results.

6. General comments
• Some very limited data derived from post-
hoc analyses demonstrate significant
improvement in depression-related physical
symptoms as well as sleep (quality/continuity)
• As with the other antidepressants,
vortioxetine carries the warning regarding
clinical worsening, suicidality, and unusual
changes in behavior

7. Adverse Effects
CNS Effects
• Fatigue, sedation or somnolence possible but not
common
• During short-term clinical trials in patients with no
history of seizure disorders, seizures were reported in
less than 0.1% of patients receiving vortioxetine
• Headaches common in maintenance trials
• One industry-sponsored RCT suggests vortioxetine (at
10 mg/day over a 15-day period) has no significant
impact on cognitive and psychomotorperformance in
the context of driving

8. Adverse Effects
• Although symptoms of mania/hypomania
were seen in less than 0.1% of patients
treated with vortioxetine in pre-marketing
trials, caution is still
• warranted in using vortioxetine in patients
with a personal or family history of bipolar
disorder, mania or hypomanic symptoms
• Rare reports of restless legs syndrome

9. Adverse Effects
• No significant effects on blood pressure,
heart rate, and ECG parameters were seen in
premarketing trials at doses up to 40
• No significant effect on body weight as
measured by the mean change from baseline
(5.8% of patients in one long-term trial
reported a mean
• weight increase of 1 kg)

10. Adverse Effects
• Rare reports of amenorrhea with or without
hyperprolactinemia
• Nausea was the most common adverse effect (20.9–
30.2%); generally dose related (seems to plateau at 15
mg) and usually transient, with a median duration of
10–16 days. Some suggest splitting daily dose or even
combining low-dose mirtazapine in the short term to
prevent onset of nausea
• Diarrhea common, also dry mouth, constipation,
vomiting, abdominal discomfort, dyspepsia, and
flatulence

11. Adverse Effects
• Liver test abnormalities in a small proportion of patients
(less than 1%) on long-term vorioxetine therapy, but
elevations are usually mild, asymptomatic,
• and transient, reversing even with continuation of
medication. No instances of acute liver injury with jaundice
attributable to vortioxetine
• reported, but the total experience with its use has been
limited
• Impact on sexual function appears to be dose related;
limited comparative evidence suggests rates are likely
lower relative to SSRIs or SNRIs when using 5–10 mg/day

12. Adverse Effects
• When trials used ASEX to evaluate sexual dysfunction
in patients without baseline sexual dysfunction, rates
were higher: Incidence of treatmentrelated sexual
dysfunction (TRSD) across the dosing range was 22–34% for
women and 16–29% for men
• Hypersensitivity Reactions
• Rash and urticaria reported infrequently
• Rare post-marketing reports of angioedema and allergic
dermatitis
• Other Adverse Effects • Generalized pruritis,
hyperhidrosis, nasopharyngitis, and arthralgia relatively
common

13. Discontinuation Syndrome
• In clinical trials, vortioxetine doses of 10mg, 15mg, and 20mg
daily were abruptly discontinued, with non-significant differences
in the Discontinuation–Emergent Signs and Symptoms checklist
total scores vs. placebo (likely explained by long serum half-life)
• However, because of individual variation and sensitivity, some
may still experience withdrawal symptoms. Most likely to occur
within first weeks
• after drug stopped or dose drastically reduced, and typically
disappear within 1 week
• ☞ THEREFORE THIS MEDICATION SHOULD BE WITHDRAWN
GRADUALLY AFTER PROLONGED USE
• Management • Reinstitute the drug at a lower dose and taper
more gradually

14. Precautions
• Strong CYP2D6 inhibitors can result in elevated
plasma levels of vortioxetine. Vortioxetine
should be reduced by 50% in the presence of
stronginhibitors such as bupropion
• Although CYP3A4 is not a primary metabolic
pathway, the product label recommends
increasing the dose of vortioxetine when a strong
CYP3A4 inducer such as carbamazepine,
phenytoin or rifampin is co-administered for
more than 14 days. The maximum recommended
dose should not exceed 3 times the original dose

15. Precautions
• Contraindicated in patients taking MAOIs or
in patients who have taken MAOIs within the
preceding 14 days. Using MAOIs within 21
days of stopping treatment with vortioxetine
is also contraindicated
• As with other serotonergic antidepressants,
serotonin syndrome may occur with
vortioxetine, both when taken alone and
especially when coadministered

16. Precautions
• if concomitant use of vortioxetine with other serotonergic
drugs is clinically warranted (note that linezolid or
intravenous methylene blue use is specifically mentioned as
a contraindication), patients should be made aware of a
potential increased risk for serotonin syndrome,
particularly during treatment initiation and dose increases
• As with other antidepressants, vortioxetine should be
introduced cautiously in patients who have a history of
seizures or in patients with unstable epilepsy
• Treatment with medications that inhibit the serotonin
transporter may be associated with abnormal bleeding,
particularly when combined with NSAIDs, acetylsalicylic
acid, or other medications that affect coagulation

17. Toxicity
• Ingestion of vortioxetine in the dose range of
40–75mg has caused an aggravation of the
following adverse reactions: nausea, postural
dizziness, diarrhea, abdominal discomfort,
generalized pruritus, somnolence, and
flushing. Management of overdose should
consist of treating clinical symptoms and
relevant monitoring

18. Pediatric Considerations
• No approved indications in children and
adolescents
• The safety and efficacy of vortioxetine in
children and adolescents has not been
adequately studied. Limited to a single open-
label exploratory study

19. Geriatric Considerations
• No dosage adjustments recommended on
the basis of age, renal or mild hepatic
impairment
• Elderly patients, especially those taking
diuretics, are at higher risk of developing
hyponatremia

20. Use in Pregnancy
• Very limited human data; in a single case report, a healthy
baby was delivered following 1 month of exposure to
vortioxetine 5mg
• Adverse events such as decreased fetal weight and delayed
ossification observed in animal reproduction studies. Non-
teratogenic effects in the newborn following serotonergic
exposure late in the third trimester include respiratory
distress, cyanosis, apnea, seizures, temperature instability,
feeding difficulty, vomiting, hypoglycemia, hypo- or
hypertonia, hyperreflexia, jitteriness, irritability, constant
crying, and tremor

21. Use in Pregnancy
In the majority of instances, such complications
began immediately or soon (less than 24 h)
after delivery. Symptoms may be due to the
toxicity of serotonergic antidepressants or a
discontinuation syndrome – although no
specific reports of such exist to date related
specifically to vortioxetine exposure, it may be
a possibility

22. Use in Pregnancy
• Epidemiological data suggest that the use of
SSRIs in pregnancy, particularly in late
pregnancy, may increase the risk of persistent
pulmonary hypertension (PPHN) in the
newborn. Although no studies have
investigated the association of PPHN with
vortioxetine treatment, this potential risk
cannot be ruled out, taking into account the
related mechanism of action (increase in
serotonin concentrations)

23. Breast Milk
• No evidence in humans at this time. Available
data in animals have shown excretion of
vortioxetine and metabolites in milk.
• It is expectedthat vortioxetine is excreted into
human milk. A risk to the nursing child cannot be
excluded. A decision must be made whether to
discontinue breastfeeding or
todiscontinue/abstain from vortioxetine, taking
into account the benefit of breastfeeding for the
child and the benefit of therapy for the woman

24. NMDA Receptor Antagonist

25. Indications
• ‡ ( approved) Treatment-resistant depression
(in conjunction with an oral antidepressant)

26. General Comments
• Must be administered under the direct supervision of a
healthcare provider. A treatment session consists of nasal
administration of esketamine and post-administration
observation under supervision for at least 2 h
• Because of the risk of serious adverse outcomes resulting
from sedation and dissociation caused by esketamine
administration, and the potential for abuse and misuse of the
drug, it is only available through a restricted distribution
system, under a Risk Evaluation and Mitigation Strategy
(REMS)
• Monitor all patients for worsening depression and suicidal
thinking

27. General Comments
• A meta-analysis of 5 trials involving 774 patients reported
that intranasal esketamine appears to be an effective
treatment strategy for patients with MDD who are either
treatment resistant or acutely suicidal[22]
• A disproportionality analysis of spontaneous reports was
performed using the FDA Adverse Event Reporting System
(FAERS) database (March 2019 to March 2020) and found
esketamine-related adverse events (962 cases) that
included: dissociation (ROR = 1,612.64), sedation (ROR =
238.46), feeling drunk (ROR = 96.17), suicidal ideation (ROR
= 24.03), and completed suicide (ROR = 5.75). Signals for
suicidal and self-injurious ideation, but not suicide attempt
and completed suicide, remained when comparing
esketamine to venlafaxine

28. Onset & Duration of Action
• In a 4-week study comparing esketamine (plus oral
antidepressant) vs. intranasal placebo (plus oral
antidepressant), a significant improvement in MADRS
score was observed at 4 h with esketamine compared
to placebo with the greatest treatment difference
observed at 24 h
• Patients in stable remission who continued treatment
with esketamine (plus oral antidepressant) experienced
a statistically significantly longer time to relapse of
depressive symptoms than did patients on intranasal
placebo (plus oral antidepressant)

29. Dosing
• Assess blood pressure prior to dosing. If baseline BP is elevated
(e.g., higher than 140 mmHg systolic, higher than 90 mmHg
diastolic), consider the risk of short-term increases in BP and
benefit of esketamine. Do not administer esketamine if an increase
in BP or intracranial pressure poses a serious risk. After dosing,
reassess BP at approximately 40 min (corresponds to Cmax) and
subsequently as clinically warranted
• Dosage adjustments should be made based on efficacy and
tolerability
• Evidence of therapeutic benefit should be evaluated at the end of
the induction phase to determine need for continued treatment
• Induction phase (weeks 1–4, administer twice per week): Day 1
starting dose 56 mg; subsequent doses 56 mg or 84 mg
• Maintenance phase (weeks 5–8, administer once weekly): 56 mg
or 84 mg

30. Dosing
• Maintenance phase (week 9 and after, administer every 2
weeks or once weekly): 56 mg or 84 mg. Dosing frequency
should be individualized to the least frequent dosing to
maintain remission/response
• Esketamine is for nasal use only. The nasal spray device
delivers a total of 28 mg of esketamine. To prevent loss of
medication, do not prime the device before use. Use 2
devices (for a 56 mg dose) or 3 devices (for an 84 mg dose),
with a 5-minute rest between use of each device
• If a patient misses treatment sessions and there is
worsening of depression symptoms, consider returning to
the patient’s previous dosing schedule

31. Adverse Effects
• Dissociation, dizziness, nausea, sedation,
vertigo, hypoesthesia, anxiety, lethargy, blood
pressure increase, vomiting, and feeling drunk
are the most commonly reported side effects
(incidence ≥ 5% and at least twice that of
placebo plus oral antidepressant)
• Approximately 5% of patients will
discontinue treatment due to adverse effects

32. CNS Effects
• Sedation in 49–61% of patients
• Dissociative or perceptual changes (including distortion of
time/space and illusions), derealization, and
depersonalization in 61–75% of patients
• Anxiety 13% in patients treated with esketamine (plus oral
antidepressant) vs. 6% in placebo (plus oral antidepressant)
• Dizziness 29%, lethargy 11%, and feeling drunk 5% in
patients treated with esketamine (plus an oral
antidepressant) vs. 8%, 5%, and 0.5%, respectively, with
placebo (plus oral antidepressant)
• Hypoesthesia 18% in patients treated with esketamine
(plus oral antidepressant) vs. 2% with placebo (plus oral
antidepressant

33. CNS Effects
• Two placebo-controlled studies found
comparable driving performance between
patients treated with esketamine (84 mg) and
placebo at 6 h and 18 h post dose (except two
esketamine-treated patients who discontinued
the driving test at 8 h post dose due to
esketamine-related adverse reactions)
• May impair short-term cognitive performance
(no effect on cognitive performance in a one-year
open-label safety study, but unknown beyond
one year)

34. Adverse effects
• Increase of 40 mmHg in systolic blood pressure (BP) and/or 25
mmHg in diastolic BP in 8–17% of esketamine-treated patients vs.
1–3% of placebotreated patients in the first 1.5 h during the first 4
weeks of treatment
• Increase in BP peaks approximately 40 min after administration End
• Nausea 28% in patients treated with esketamine (plus oral
antidepressant) vs. 9% with placebo (plus oral antidepressant)
• Vomiting 9% in patients treated with esketamine (plus oral
antidepressant) vs. 2% with placebo (plus oral antidepressant)
Other Adverse Effects
• Vertigo 23% in patients treated with esketamine (plus oral
antidepressant) vs. 3% with placebo (plus oral antidepressant)
• Higher rate of lower urinary tract symptoms (pollakiuria, dysuria,
micturition urgency, nocturia, and cystitis) in esketamine-treated
patients than with placebo

35. Discontinuation syndrome
• No discontinuation syndrome noted up to 4 weeks
after esketamine cessation
• Withdrawal symptoms have been reported after
discontinuation of frequently used (more than weekly)
large doses of ketamine for long periods of time.
Such withdrawal symptoms are likely to occur if
esketamine were similarly abused. Symptoms may
include craving, fatigue, poor appetite, and anxiety ☞
THEREFORE THIS MEDICATION SHOULD BE
WITHDRAWN GRADUALLY AFTER PROLONGED USE

36. Contraindications
• Contraindicated in patients with: Aneurysmal
vascular disease or arteriovenous
malformation, history of intracerebral
hemorrhage, or hypersensitivity to
esketamine, ketamine, or any of the excipients
• Esketamine should not be used in patients
with severe hepatic impairment (Child-Pugh
class C) due to lack of studies in this
population

37. Precautions
• Assess blood pressure prior to dosing. If baseline
BP is elevated (e.g., > 140 mmHg systolic, > 90
mmHg diastolic), consider the risks of short-term
increases in BP and benefit of esketamine. Do not
administer esketamine if an increase in BP or
intracranial pressure poses a serious risk. After
dosing, reassess BP at approximately 40 min
(corresponds to Cmax) and subsequently as
clinically warranted
• Monitor for sedation during concomitant
treatment with esketamine and CNS depressants

38. Precautions
• Due to risks of sedation and dissociation, patient must be
monitored for at least 2 h after each treatment session,
followed by an assessment to determine when the patient
is considered clinically stable and ready to leave the
healthcare setting
• Assess each patient’s risk for abuse or misuse prior to
prescribing esketamine and monitor for the development
of these behaviors or conditions, including drug-seeking
behavior, while on therapy
• Monitor all patients for worsening depression and suicidal
thoughts, especially during the initial few months of drug
therapy and at times of dosage changes

39. Pediatric Considerations
• Esketamine is not approved for use in pediatric patients
Geriatric Considerations
• Mean esketamine Cmax and AUC higher in elderly patients
• Efficacy was assessed in a 4-week RCT comparing
esketamine (plus an oral antidepressant) to intranasal
placebo (plus an oral antidepressant) in patients aged 65
years and older. Esketamine was initiated at 28 mg twice
weekly and titrated to 56 mg or 84 mg administered twice-
weekly. At the end of the 4 weeks, there was no statistically
significant difference between the groups on the primary
efficacy endpoint of change from baseline to week 4 using
MADRS

40. Use in Pregnancy
• Not recommended during pregnancy
• Embryo-fetal toxicity; may cause fetal harm
• Insufficient data to draw conclusions about risk of
major birth defects, miscarriage, or adverse maternal
or fetal outcomes
• If a woman becomes pregnant while being treated
with esketamine, treatment should be discontinued
and the patient counseled about the potential risk to
the fetus Breast Milk
• Esketamine is present in human milk
• Potential for neurotoxicity in breastfed infants

41. GABAA Receptor Positive Modulator

42. Indications
• ‡ ( approved) Treatment of postpartum
depression (PPD) in adults

43. Adminstration and dosing
• Administered as a continuous IV infusion over 60 hours (2.5
days) as follows: – 0–4 h: Initiate with a dosage of 30
micrograms/kg/h – 4–24 h: Increase dosage to 60
micrograms/kg/h – 24–52 h: Increase dosage to 90
micrograms/kg/h (alternatively, consider a dosage of 60
micrograms/kg/hr for those who do not tolerate 90
micrograms/kg/h) – 52–56 h: Decrease dosage to 60
micrograms/kg/h – 56–60 h: Decrease dosage to 30
micrograms/kg/h Renal Impairment • No dosage
adjustment recommended in patients with mild (eGFR 60–
89 mL/min/1.73 m2 ), moderate (eGFR 30–59 mL/min/1.73
m2 ), or severe (eGFR 15–29 mL/min/1.73 m2 ) renal
impairment Hepatic Impairment • No dosage adjustment
necessary

44. General Comments
• A healthcare provider must be available on site to
continuously monitor the patient, and intervene as
necessary, for the duration of the infusion
• Initiate brexanolone treatment early enough in the day to
allow for recognition of excessive sedation
• Because of the risk of serious harm resulting from
excessive sedation or sudden loss of consciousness,
brexanolone is available only through a restricted program
under a Risk Evaluation and Mitigation Strategy (REMS)
called the ZULRESSO REM
• A meta-analysis of 3 RCTs reported that a single
brexanolone infusion appears to have ultra-rapid
antidepressant effect for PPD, lasting for up to 1 week

45. Adverse Effects
• Data presented below reflect exposure of brexanolone in
140 patients with PPD; titration to a target dose of 90 or 60
micrograms/kg/h was evaluated in 102 and 38 patients,
respectively (placebo control group: 107 patients). Patients
were followed for 4 weeks CNS Effects
• Headache: 14% (placebo); 18% (60 micrograms/kg/h); 15%
(90 micrograms/kg/h)
• Dizziness, presyncope, vertigo: 7% (placebo); 13% (60
micrograms/kg/h); 12% (90 micrograms/kg/h)
• Loss of consciousness: none with placebo; 5% (60
micrograms/kg/h); 3% (90 micrograms/kg/h)
• Sedation, somnolence: 6% (placebo); 21% (60
micrograms/kg/h); 13% (90 micrograms/kg/h)

46. Adverse Effects
• Dry mouth: 1% (placebo); 11% (60 micrograms/kg/h); 3%
(90 micrograms/kg/h)
• Tachycardia: none with placebo and 60 micrograms/kg/h;
3% (90 micrograms/kg/h)
• Diarrhea: 1% (placebo); 3% (60 micrograms/kg/h); 2% (90
micrograms/kg/h) • Dyspepsia: none with placebo and 60
micrograms/kg/h; 2% (90 micrograms/kg/h)
• Oropharyngeal pain: non with placebo; 3% (60
micrograms/kg/h); 2% (90 micrograms/kg/h)
• Flushing, hot flush: none with placebo; 5% (60
micrograms/kg/h); 2% (90 micrograms/kg/h)
• Rash: 4% (placebo); 3% (60 micrograms/kg/h); 1% (90
micrograms/kg/h)

47. Discontinuation Syndrome
• In the PPD clinical studies conducted, end of
treatment occurred through tapering. Thus, not
possible to assess whether abrupt
discontinuation of brexanolone produced
withdrawal symptoms indicative of physical
dependence
• Recommended that brexanolone be tapered
according to the dosage recommendations,
unless symptoms warrant immediate
discontinuation

48. Contraindications
• Avoid in patients with end stage renal disease
with eGFR of less than 15 mL/min/1.73 m2
because of potential accumulation of the
solubilizing agent, betadex sulfobutyl ether
sodium

49. Precautions
• Suicidal thoughts and behaviors: Consider changing
therapeutic regimen, including discontinuing
brexanolone, in patients whose PPD worsens or who
experience emergent suicidal thoughts and behaviors
• Excessive sedation: In clinical studies, brexanolone
caused sedation and somnolence that required dose
interruption or reduction (5% with brexanolone
compared to none with placebo). Assess for excessive
sedation every 2 h during non-sleep periods. If
excessive sedation occurs at any time during infusion,
immediately stop infusion until symptoms resolve.
Infusion may be resumed at the same or lower dose as
clinically appropriate

50. Precautions
• Sudden loss of consciousness or altered states of
consciousness during infusion reported in some patients
(4% with brexanolone compared to none with placebo).
Time to full recovery, after dose interruption, ranged from
15 to 60 min. All patients recovered with dose interruption
• Hypoxia: Monitor patients for hypoxia using continuous
pulse oximetry equipped with an alarm. Immediately stop
infusion if pulse oximetry reveals hypoxia. Infusion should
not be resumed
• Concomitant use of opioids, antidepressants, or other CNS
depressants such as benzodiazepines or alcohol may
increase likelihood or severity of adverse reactions related
to sedation

51. Pediatric Considerations
• Not approved for use in pediatric patients
• Safety and effectiveness of brexanolone in
pediatric patients have not been established .

52. Use in Pregnancy and breast feeding
• Based on animal studies of other drugs that enhance GABA-
ergic inhibition, brexanolone may cause fetal harm
• No available data on brexanolone use in pregnant women to
determine drug-associated risk of major birth defects,
miscarriage, or adverse maternal or fetal outcomes Breast
Milk
• Brexanolone is present in human milk; however, relative
infant dose is low, 1–2% of maternal weight-adjusted dose.
Also, as brexanolone has low (less than 5%) oral bioavailability
in adults, infant exposure is expected to be low
• The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for
brexanolone

53. Others
• Neursteroids:BrxanoloneZuranolone