Pharmacological management of depression

1. Pharmacological
Management of Depression
By : Dr. Priyash Jain
JR-2

2. Content
• General Considerations
• An overview of Antidepressants
• Drug Treatment of Depression
• Refractory Depression
• Antidepressants in special population
• Symptom based approach to depression
• Antidepressant combinations
• Newer antidepressants

3. General Considerations

4. General Considerations
• Antidepressants are not recommended as a first‐line treatment in
recent‐onset, mild depression – active monitoring, individual
guided self‐help, cognitive behavioural therapy (CBT) or exercise
are preferred.
• Antidepressants are recommended for the treatment of moderate
to severe depression and for dysthymia.

5. General Considerations
• Discuss with the patient choice of drug and utility/availability of other,
non‐pharmacological treatments.
• Discuss with the patient likely outcomes, such as gradual relief from
depressive symptoms over several weeks.
• Prescribe a dose of antidepressant (after titration, if necessary) that is
likely to be effective.
• For a single episode, continue treatment for at least 6–9 months after
resolution of symptoms (multiple episodes may require longer).
• Withdraw antidepressants gradually; always inform patients of the risk
and nature of discontinuation symptoms.

6. General Considerations
• It is widely held that antidepressants do not exert their effects for
2–4 weeks. This is a myth. All antidepressants show a pattern of
response in which the rate of improvement is highest during weeks
1–2.
• Selective serotonin reuptake inhibitors (SSRIs) are well tolerated
compared with the older tricyclic antidepressants (TCAs) and
monoamine oxidase inhibitors (MAOIs), and are generally
recommended as first‐line pharmacological treatment for
depression.

7. An overview of Antidepressants

8. An overview of Antidepressants
• SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
• Citalopram, Escitalopram
• Fluoxetine, Fluvoxamine
• Paroxetine, Sertraline
• SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)
• Desvenlafaxine, Venlafaxine
• Duloxetine, *Levomilnacipran
• *ansofaxine, *nefopam
* - Newer drugs

9. An overview of Antidepressants
• TRICYCLIC ANTIDEPRESSANTS (TCAs)
• Amitriptyline, Nortriptyline, Protriptyline
• Amoxapine, Doxepin
• Clomipramine, Desipramine, Imipramine, Trimipramine
• MONOAMINE OXIDASE INHIBITORS (MAOIs)
• Isocarboxazid, Phenelzine, Selegiline, Tranylcypromine

10. An overview of Antidepressants
• Norepinephrine-dopamine reuptake inhibitor (NDRI) such as bupropion.
• Serotonin receptors antagonist with serotonin reuptake inhibition (SARI) such as
trazodone, nefazodone, and *vortioxetine.
• Serotonin 5-HT1A autoreceptor partial agonist with serotonin reuptake
inhibition (SPARI) such as *vilazodone
• Noradrenergic α2 -receptor antagonist with specific serotonergic receptors-2
and -3 antagonism (NASSA) such as mirtazapine and *mianserin.
• Norepinephrine reuptake inhibitor with serotonin receptors antagonism (NRISA)
such as *maprotiline.
• Melatonergic MT1 and MT2 receptors agonist and selective serotonergic 5-HT2B
and 5-HT2C receptors antagonism (MASSA)– Agomelatine, Ramelteon,
Tasimalteon
* - Newer drugs

11. Minimum Effective Doses

12. Drug Treatment of Depression

13. Drug Treatment of Depression

14. Drug Treatment of Depression
• Switching between drug classes in cases of poor tolerability is not
clearly supported by published studies but has a strong theoretical
basis.
• Having said that, in practice, many patients who cannot tolerate
one SSRI will readily tolerate another.
• Switch treatments early (e.g. after a week or two) if adverse
effects are intolerable or if no improvement at all is seen by 3–4
weeks. Opinions on when to switch vary somewhat but it is clear
that antidepressants have a fairly prompt onset of action and that
non‐response at 2–6 weeks is a good predictor of overall
non‐response.

15. Refractory Depression

16. Refractory Depression

17. First choice
Agent Disadvantages
Lithium • Sometimes poorly tolerated at higher
plasma levels
• Potentially toxic
• Usually needs specialist referral
• Plasma level monitoring is essential (and
TFTs, e‐GFR)
• May not be effective in patients
refractory to multiple treatments
Combine olanzapine and fluoxetine • Risk of weight gain
• Most data relate to bipolar depression
Add quetiapine • Dry mouth, sedation, constipation can be
problematic
• Weight gain risk in the longer Term

18. First choice
Agent Disadvantages
Add aripiprazole • Akathisia and restlessness common at
standard doses (≥10 mg/day)
• Insomnia may be problematic
SSRI + bupropion • Not licensed
SSRI or venlafaxine + mianserin (30 mg/day)
or
mirtazapine
• Theoretical risk of serotonin syndrome
(inform patient)
• Risk of blood dyscrasia with Mianserin

19. Second Choice
Agent Disadvantages
Add ketamine (0.5 mg/ kg IV over 40
minutes)
• IV needs to be administered in hospital
• Cognitive effects (confusion, dissociation,
etc.) do occasionally occur
• Associated with transient increase in BP,
tachycardia and arrhythmias. Pre‐
treatment ECG required with IV form
• Adverse effects may have been
underestimated
• Repeated treatment necessary to
maintain effect
• Not widely available

20. Second Choice
Agent Disadvantages
Add lamotrigine • Slow titration
• Risk of rash
• Appropriate dosing unclear
• Two failed RCTs
SSRI + buspirone Up to 60 mg/day • Higher doses required
• Poorly tolerated (dizziness common)
• Not widely used
Add risperidone • Hypotension
• Hyperprolactinaemia
• Generally less robust RCT support than for
other SGAs

21. Second Choice
Agent Disadvantages
Add tri‐iodothyronine (20–50 μg/day)
Higher doses have been
safely used
• Clinical and biochemical TFT monitoring
required
• Usually needs specialist referral
• Some negative studies
• No advantage over antidepressant alone
in non‐refractory illness
High‐dose venlafaxine (>200 mg/day) • Limited support in literature
• Nausea and vomiting more common
• Discontinuation reactions common
• Can increase BP. Blood pressure
monitoring essential

22. Other reported treatments
• Amantadine
• Buprenorphine
• Cabergoline
• D‐cycloserine
• Stimulants: amfetamine; methylphenidate
• Oestrogens
• Pindolol
• Tryptophan
• Zinc

23. Psychotic Depression
• TCAs are probably drugs of first choice in psychotic depression.
• SSRIs/SNRIs are a second‐line alternative when TCAs are poorly
tolerated.
• Augmentation of an antidepressant with olanzapine or
quetiapine is recommended.
• ECT should always be considered where a rapid response is
required or where other treatments have failed.

24. Role of Folic Acid
• Folate deficiency can contribute to depressed mood and folate
supplementation is beneficial in patients, and a plausible mechanism
implicates serotonin.
• In many studies, folate deficiency was associated with low levels of the
serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the
cerebrospinal fluid (CSF).
• In one study, supplementation with folate restored CSF 5-HIAA levels to
normal.
• There is also a decrease in serotonin synthesis in patients with 5,10-
methylenetetrahydrofolate reductase (MTHFR) deficiency, a disorder
of folate metabolism.

25. Role of Folic Acid
• While the mechanism relating folate deficiency to low serotonin is not
known, it may involve S-adenosylmethionine (SAMe).
• SAMe is a major methyl donor formed from methionine.
• Folate is involved in a cycle that regenerates methionine from
homocysteine after SAMe is demethylated to S-adenosylhomocysteine,
with subsequent conversion to homocysteine.
• Thus, there is some consistency in what is known about the
interrelations of folate, SAMe and depression.
• Ability of folate to potentiate the action of standard antidepressant
therapies.

26. Role of Folic Acid

27. Antidepressants in special population

28. Childhood and Adolescent depression
• Psychological intervention be considered as first‐line treatment
for depression in children and adolescents and specifically so in
cases of mild to moderate depression.
• SSRI + CBT (But controversial evidence available)
• Fluoxetine is the recommended first‐line pharmacological
treatment and is superior to placebo in children and adolescents
• Fluoxetine and escitalopram are the only antidepressants
approved by the US Food and Drug Administration (FDA) for
adolescents and fluoxetine is the only FDA‐approved medication
for pre‐pubertal children (from age 8 years).

29. Childhood and Adolescent depression
• If there is no response to fluoxetine and pharmacotherapy is still
considered to be the most favourable option, an alternative SSRI
such as sertraline or escitalopram should be considered.

30. Childhood and Adolescent depression
• Sertraline, citalopram and escitalopram are quickly metabolised
by children and twice daily dosing should be considered.
• When prescribing SSRIs it is important that the dose is increased
slowly to minimise the risk of treatment‐emergent agitation and
that patients are monitored closely for the development of
treatment‐emergent suicidal thoughts and acts.
• antidepressants increase the risk of suicidal behavior and
aggression.
• The TADS study: the combined treatment of fluoxetine and CBT
reduced the risk of suicidal events to the greatest extent

31. Depression during pregnancy and post partum
• Patients who are already receiving antidepressants and are at high
risk of relapse are best maintained on the same antidepressant
during and after pregnancy.
• Those who develop a moderate‐severe or severe depressive illness
during pregnancy should be treated with antidepressant drugs.
• If initiating an antidepressant during pregnancy or for a woman
considering pregnancy, previous response to treatment must be
taken into account. The antidepressant that has previously proved
to be effective should be considered.
• For previously untreated patients, sertraline may be considered.

32. Depression during pregnancy and post partum
• When taken in late pregnancy, SSRIs may increase the risk of
persistent pulmonary hypertension of the newborn. The absolute
risk is very low.
• The neonate may experience discontinuation symptoms, which are
usually mild, such as agitation and irritability, or rarely respiratory
distress and convulsions (with SSRIs).
• The risk is assumed to be particularly high with short half‐life
drugs such as paroxetine and venlafaxine. Continuing to
breastfeed and then ‘weaning’ by switching to mixed
(breast/bottle) feeding may help reduce the severity of reactions.

33. Depression during pregnancy and post partum
• Paroxetine has been specifically associated with cardiac
malformations, particularly after high dose (>25 mg/day)
first‐trimester
• A higher risk of some cardiac birth defects has been reported to
be associated with paroxetine and fluoxetine compared with other
SSRI (controversial evidence)

34. Antidepressants in Hepatic failure and Renal
failure
• SSRIs - All are hepatically metabolised and accumulate on chronic
dosing. Dosage reduction (including reduction of maximum dose by
50% and/or reduced dosing frequency) may be required.
• Citalopram, escitalopram and paroxetine have minimal effects on
hepatic enzymes and may be the SSRIs of choice although
occasional hepatotoxicity has been reported.
• All are hepatically metabolised, highly protein bound and will
accumulate. They vary in their propensity to cause sedation and
constipation. All are associated with raised LFTs and rare cases of
hepatitis. Sedative TCAs such as trimipramine, imipramine,
dosulepin (dothiepin) and amitriptyline are best avoided.

35. Antidepressants in Hepatic failure and Renal
failure
• No agent clearly preferred to another,
• however: citalopram (care: QTc‐prolonging effects) and sertraline
are suggested as reasonable choices

36. Symptom- Based approach to treating
depression

37. Symptom-based antidepressant selections
• First, symptoms are constructed into a diagnosis and then
deconstructed into a list of specific symptoms that the individual
patient is experiencing
• Next, these symptoms are matched with the brain circuits that
hypothetically mediate them
• Finally, available treatment options that target these
neuropharmacological mechanisms are chosen to eliminate
symptoms one by one

38. Symptom-based antidepressant selections
• Example 1
• in a patient with the symptoms of “problems concentrating” and
“decreased interest” as well as “fatigue,”
• this approach suggests targeting both NE and DA with first-line
antidepressants plus augmenting agents that act on these
neurotransmitters
• Example 2
• on the other hand, for “insomnia,” this symptom is hypothetically
associated with an entirely different malfunctioning circuit
regulated by different neurotransmitters

39. Symptom-based antidepressant selections
• therefore, the treatment for this symptom calls for a different
approach, namely the use of hypnotics that act on the GABA
system or sedating antidepressants that work to block rather than
boost the serotonin or histamine system
• possibly faster way of reducing specific symptoms with more
tolerable treatment selections for that patient than a purely
random approach

42. Antidepressant Combinations

43. Antidepressant Combinations
• Given the disappointing number of patients who attain remission
from a major depressive episode even after four consecutive
treatments and who can maintain that remission over the long run
• the paradigm of prescribing a sequence of monotherapies each
with a single mechanism of therapeutic action for major
depression is rapidly changing to one of administering multiple
simultaneous pharmacologic mechanisms, often with two or more
therapeutic agents.

44. Antidepressant Combinations
Triple-action combo: SSRI/SNRI ± NDRI

45. Antidepressant Combinations
• California rocket fuel: SNRI plus mirtazapine
• This potentially powerful combination utilizes the pharmacologic
synergy obtained by adding the enhanced serotonin and
norepinephrine release from inhibition of both dual serotonin and
norepinephrine reuptake by an SNRI to the disinhibition of both
serotonin and norepinephrine release by the α2 antagonist actions
of mirtazapine
• This combination can provide very powerful antidepressant action
for some patients with unipolar major depressive episodes.

46. Antidepressant Combinations
• California rocket fuel: SNRI plus mirtazapine

47. Antidepressant Combinations
• Arousal combos
• The frequent complaints of residual fatigue, loss of energy, motivation,
sex drive, and problems concentrating/problems with alertness may be
approached by combining either a stimulant or modafinil with an SNRI to
recruit triple monoamine action and especially enhancement of
dopamine.
• lisdexamfetamine, which links the amino acid lysine to the stimulant d-
amphetamine, and which slows the delivery and potentially reduces the
abuse liability of d-amphetamine after oral administration, is in late-
stage clinical testing as an augmenting agent to SSRIs/SNRIs in
treatment-resistant depression.

48. Newer antidepressants

49. Newer Antidepressants
• Triple reuptake inhibitors (TRIs) or serotonin–norepinephrine–
dopamine reuptake inhibitors (SNDRIs) are in clinical testing
• to confirm that if one mechanism is good (i.e., SSRI) and two
mechanisms are better (i.e., SNRI), then maybe targeting all three
mechanisms of the trimonoamine neurotransmitter system would
be the best in terms of efficacy.
• amitifidine, GSK-372475, BMS-820836, tasofensine, PRC200-SS,
SEP-225289

50. Newer Antidepressants
• Multimodal agents - it appears that combining multiple modes of
monoaminergic action may enhance efficacy for some patients with
depression
• reuptake blockade (at SERT, DAT, NET) with actions at G-protein
receptors (e.g., 5HT1A,5HT2C,5HT7, α2 receptors) with actions at ion-
channel receptors (5HT3 receptors and possibly NMDA receptors).
• vilazodone (combination of SERT plus 5HT1A partial agonist actions)
• Vilazodone has been speculated to have three potential benefits
including faster onset of action, greater efficacy, and better tolerability
owing to its SPARI properties

51. Newer Antidepressants
• Vortioxetine acts via all three modes with a combination of five
pharmacologic actions: reuptake blocking mode (SERT), Gprotein
receptor mode (5HT1A and 5HT1B/D partial agonist, 5HT7
antagonist), and ion-channel mode (5HT3 antagonist).
• The clinical properties of vortioxetine suggest antidepressant
efficacy without sexual dysfunction, and the pharmacologic
properties suggest the potential for either pro-cognitive effects,
or enhanced antidepressant efficacy compared to agents with
fewer modes of action and effects on fewer neurotransmitters.

52. Newer Antidepressants
• NMDA Blockade
• One of the most interesting developments in recent years has
been the observation that infusions of subanesthetic doses of
ketamine can exert an immediate antidepressant effect in
patients with treatment resistant unipolar or bipolar depression,
and can immediately reduce suicidal thoughts.
• Unfortunately, the effects are not sustained for more than a few
days, but this has led investigators to search for an oral ketamine-
like agent that could have rapid onset and sustained efficacy in
treatment-resistant patients.

53. Newer Antidepressants
• Ketamine acts as an open channel inhibitor at NMDA glutamate
receptors and causes downstream release of glutamate
• One candidate for an “oral ketamine” that acts on NMDA receptors
is the cough medicine dextromethorphan.
• Both ketamine and dextromethorphan share actions not only at
NMDA receptors, but also at σ receptors, µ-opioid receptors, SERT,
and NET, but with different affinities
• Esketamine, the S-enantiomer of racemic ketamine, which has a
higher affinity for the NMDA receptor than the R-enantiomer, has
recently been approved

54. Newer Antidepressants
• Glutamate activity heavily modulates synaptic potentiation;
• this is specifically modulated through NMDA (N-methyl-D-
aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-
propionic acid) receptors.
• Ketamine is an NMDA receptor antagonist; however, its rapid
antidepressant effects may also be related to indirect effects on
AMPA receptor signaling and the mammalian target of rapamycin
(mTOR) pathway.
• it may be that blockade of the NMDA receptor leads to rapid activation of
AMPA and mTOR signaling pathways.
• this in turn would lead to rapid AMPA-mediated synaptic potentiation.

55. Newer Antidepressants

56. Newer Antidepressants

57. Newer Antidepressants
• Rapastinel (former developmental code names GLYX-13, BV-102) is
a novel antidepressant.
• acts as a selective, weak partial agonist (mixed
antagonist/agonist) of an allosteric site of the glycine site of the
NMDA receptor complex.
• In addition to rapastinel, another novel congener compound NRX-
1074 (Apimostinel) has been developed.
• Apimostinel is an orally bioavailable compound and is more potent
than rapastinel.

58. Newer Antidepressants
• Agomelatine
• belongs to the melatonergic MT1 and MT2 receptors agonist and
selective serotonergic 5-HT2B and 5-HT2C receptors antagonism
(MASSA) class.
• Resynchronization of biological rhythms may be a therapeutically
relevant property for an antidepressant agent as depression
involves a disruption of normal circadian rhythm.

59. Newer Antidepressants
• Estrogen based treatment options for perimenopausal women
• many different kinases that are controlled by estrogens regulate
neurotransmitter transporters.
• E2 can rapidly alter several signaling pathways to cause efflux of
dopamine via the DAT;
• PKC and MEK (the enzyme upstream of the MAPK-ERKs) are
activated by E2.
• Multiple estrogens induce activation of MAPKs which in turn affect
DAT.

60. Newer Antidepressants
• Estradiol replacement therapy (ERT) has demonstrated efficacy in
treating perimenopause-related depression.
• Unfortunately, there are long-term risks associated with ERT.
• Selective estrogen receptor modulators (SERMS), such as
raloxifene, and phytoestrogens, such as rimostil, have estrogen-
like properties and may offer a safer alternative to ERT.

61. Newer Antidepressants
• Brexanolone
• Brexanolone (BRX) is a solution of allopregnanolone that modulates the
GABA-A receptor
• BRX might be an ideal treatment in women with access to hospitals and
who have a history of severe PPD with a prolonged recovery time or
limited response to psychotherapy or serotonin reuptake inhibitors.
• The findings of efficacy studies are limited because they did not report
outcomes for study subjects beyond 30 days; therefore, further trials are
needed to assess BRX’s long-term efficacy and safety and its place in
treatment algorithms.

62. Newer Antidepressants
• Drugs acting on HPA axis
• pexacerfont, a CRF1 antagonist
• Antalarmin, a novel CRH receptor type 1 antagonist
• Glucocorticoid receptor antagonists like metyrapone,
ketoconazole, and aminoglutethimide.
• Vasopressin 1B receptor antagonists - TS-121, ABT‐436.

63. References
• TAYLOR D. MAUDSLEY PRESCRIBING GUIDELINES IN PSYCHIATRY. [S.l.]:
WILEY-BLACKWELL.
• Stahl S. Stahl's Essential Psychopharmacology. Cambridge:
Cambridge University Press; 2014.
• Sadock B, Sadock V, Ruiz P. Kaplan & Saddocks comprehensive textbook
of psychiatry, volume 1 and 2. 10th ed. Philadelphia: Lippincott Williams
and Wilkins; 2009.
• Fasipe O. J. (2019). The emergence of new antidepressants for clinical
use: Agomelatine paradox versus other novel agents. IBRO reports, 6, 95–
110. https://doi.org/10.1016/j.ibror.2019.01.001
• Scarff J. R. (2019). Use of Brexanolone for Postpartum Depression.
Innovations in clinical neuroscience, 16(11-12), 32–35.

64. References
• Raloxifene and Rimostil for Perimenopause-Related Depression -
Full Text View - ClinicalTrials.gov. Clinicaltrials.gov.
https://clinicaltrials.gov/ct2/show/NCT00030147. Published 2021.
Accessed March 23, 2021.
• Walf, A. A., & Frye, C. A. (2010). Raloxifene and/or estradiol
decrease anxiety-like and depressive-like behavior, whereas only
estradiol increases carcinogen-induced tumorigenesis and uterine
proliferation among ovariectomized rats. Behavioural
pharmacology, 21(3), 231–240.
https://doi.org/10.1097/fbp.0b013e32833a5cb0

65. References
• Barden N. (2004). Implication of the hypothalamic-pituitary-
adrenal axis in the physiopathology of depression. Journal of
psychiatry & neuroscience : JPN, 29(3), 185–193.
• Faquih, A. E., Memon, R. I., Hafeez, H., Zeshan, M., & Naveed, S.
(2019). A Review of Novel Antidepressants: A Guide for Clinicians.
Cureus, 11(3), e4185. https://doi.org/10.7759/cureus.4185
• Guardiola-Lemaitre B, De Bodinat C, Delagrange P, Millan M,
Munoz C, Mocaër E. Agomelatine: mechanism of action and
pharmacological profile in relation to antidepressant properties.
Br J Pharmacol. 2014;171(15):3604-3619. doi:10.1111/bph.12720

66. Thank You