Anti-depressant drugs. Dr. Ashok Kumar Batham,M.D.,

ANTI-DEPRESSANT DRUGS
Dr Ashok Kumar Batham, Chief Consultant
Dr Batham Pharma Consultants

EVOLUTION OF TREATMENT OF DEPRESSION
•Psychoanalysis (Sigmund Freud) -1800s.
•ECT -1930s
•MAO-Is – 1950s (From an anti-TB drug Iproniazid)
•TCAs -1950 1960s
•SSRIs -1970 1980s
13-10-2019ANTI-DEPRESSANT DRUGS. Dr. Ashok Kumar Batham,M.D.,
3

MONOAMINERGIC THEORY OF DEPRESSION
& ITS TREATMENT
• Endogenous depression is caused by synaptic deficiency of
neurotransmitters – NE, 5HT and DA in brain associated with up-
regulation of post-synaptic receptors
• Depletion of monoamines by reserpine leads to Depression
• TCAs and SSRIs block neuronal reuptake mechanisms, thereby
building up monoamine levels and allaying depression
• MAO-Is lead to build-up of monoamines and alleviate
depression
• Lithium controls manic episodes by reducing brain NE levels
4

FUNCTIONS OF NEUROTRANSMITTER -
SEROTONIN
• “Feel good hormone”
• Contributes to feeling of well-being and good mood
• Appetite control
• Social behavior
• Obsessions
• Compulsions and
• Regulation of sleep-wake cycle and internal clock.
• Abnormality in Serotonin neurotransmission leads to obsession and
compulsion
5

FUNCTIONS OF NEUROTRANSMITTER –
NOREPINEPHRINE
• Regulation of emotions
• Increases alertness and focus
• Helps retrieval of memory
• Prepares the brain for action
• Abnormality in NE neurotransmission leads to lethargy and
apathy
6

FUNCTIONS OF NEUROTRANSMITTER -
DOPAMINE
• Reward-motivated behaviour - creates feelings of pleasure and reward,
which motivates to repeat a specific behaviour,
• Attention,
• Enthusiasm,
• Memory,
• Imagery,
• Control of muscle tone and motor movement, and
• Nausea.
• Abnormality in Dopamine neurotransmission leads to reduced ability to
feel pleasure, decreased attention, cognitive slowing, apathy, reduced
imagery
7

HISTORY OF DEVELOPMENT OF ANTI-DEPRESSANTS -1
• In 1951, Irving Selikoff and Edward H. Robitzek (de), working out of Sea
View Hospital on Staten Island, NY, began clinical trials on two new anti-
tuberculosis agents developed by Hoffman-LaRoche, isoniazid and
iproniazid.
• 1952-53 - A Cincinnati psychiatrist Max Lurie and Harry Salzer reported
that isoniazid improved depression in two thirds of their patients and
coined the term antidepressant. MoA was understood to be weak MAO-
Inhibition.
• 1953 - Selikoff and Robitzek also experimented with another anti-
tuberculosis drug, iproniazid; it showed a greater psychostimulant effect,
due to MAO-Inhibition. Turned out to have more pronounced toxicity
(withdrawn in 1961 due to lethal hepatotoxicity)
8

• Roland Kuhn in conjunction with Geigy Pharmaceutical
Company discovered the tricyclic compound "G 22355", later
named imipramine.
• Imipramine had a beneficial effect in patients with depression
who showed mental and motor retardation.
• Kuhn described his new compound as a "thymoleptic" "taking
hold of the emotions," in contrast with neuroleptics, "taking hold
of the nerves" in 1955–56.
HISTORY OF DEVELOPMENT OF ANTI-DEPRESSANTS - 2
9

• Rational drug design led to identification of antihistamine-
derived compounds to selectively target Serotonin reuptake.
The first such compound to be patented was zimelidine in 1971,
while the first to be released for clinical was indalpine.
• Fluoxetine was developed at Eli Lilly and Company in the early
1970s by Bryan Molloy, Klaus Schmiegel, David T. Wong and
others.
• Fluoxetine approved for commercial use by the US FDA in 1988,
and became the first blockbuster SSRI.
• Novel antidepressants, such as SNRIs and NRIs with various
selective effects developed.
HISTORY OF DEVELOPMENT OF ANTI-DEPRESSANTS -3
10

11

NON-SELECTIVE AMINE REUPTAKE INHIBITORS -
TRICYCLIC ANTIDEPRESSANTS (TCAs)
•Imipramine (hydrochloride and pamoate)
•Desipramine
•Clomipramine
•Trimipramine
12

•Amitriptyline
•Nortriptyline
•Protriptyline
•Amitriptylinoxide
•Doxepin
•Dosulepin
13

•Lofepramin
•Melitracen
•Noxiptiline
•Opipramol
•Pipofezine
•Dibenzepin
•Dimetacrine
•Nitroxazepine
14

SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRIs)
• Fluoxetine
• Citalopram
• Escitalopram
• Paroxetine
• Fluvoxamine
• Sertraline
15

SEROTONIN NOREPINEPHRINE
REUPTAKE INHIBITORS (SNRIs)
• Venlafaxine
• Desvenlafaxine
• Duloxetine
• Milnacipran
• Levomilnacipran
• Nefazodone
16

TETRACYCLIC ANTIDEPRESSANTS
• Amoxapin
• Maprotiline
• Mianserin
• Mirtazapin
• Septipiline
17

SEROTONIN MODULATORS AND
STIMULATORS (SMS)
• Vilazodone
• Vortioxetine
18

SEROTONIN ANTAGONISTS
•Trazodone (5-HT1A)
•Nefazodone (5-HT1A)
•Mirtazapine (5-HT2 and 5-HT3)
19

BLOCKADE OF PRE-SYNAPTIC ALPHA2
RECEPTORS
•Mirtazapine
20

DOWN-REGULATION OF PRE-SYNAPTIC
ALPHA2 RECEPTORS
•Tricyclic antidepressants (TCAs)
•MAO-Inhibitors
21

NOREPINEPHRINE REUPTAKE
INHIBITORS (NRI)
•Reboxetine
•Viloxazine
•Teniloxazine - also inhibits 5-HT2A receptors
22

NOREPINEPHRINE–DOPAMINE REUPTAKE
INHIBITORS (NDRI)
• Bupropion
• Methylphenidate
23

MONO-AMINE OXIDASE INHIBITORS
(MAO-INHIBITORS)
24

NON-SELECTIVE MAO-INHIBITORS
• Phenelzine
• Isocarboxazid
• Tranylcypromine
25

REVERSIBLE INHIBITORS OF MAO-A
(RIMA)
• Moclobemide
• Metralindole
• Pirlindole
• Toloxatone
• Bifemelane – RIMA. and weak NRI
26

ATYPICAL ANTIPSYCHOTICS
• Quetiapine – for depressive episodes in bipolar
disorder
• Amisulpride – for dysthymia
• Lurasidone – for depressive episodes in bipolar
disorder
27

OTHERS
• Agomelatine -
5HT2C receptor antagonist and MT1 and MT2 receptor agoni
st
• Ketamine – non-competitive NMDA receptor antagonist,
used in depression off-label
• Tandospirone – 5-HT1A receptor partial agonist
• Tianeptine – weak and atypical μ-opioid receptor agonist
• Minocycline – Microglia inhibitor
28

OTC ANTIDEPRESSANTS
• Hypericum perforatum [St. John's Wort (SJW)]
• Tryptophan – precursor in serotonin biosynthesis
• 5-Hydroxytryptophan (5-HTP) – precursor in serotonin biosynthesis
• Ademetionine [S-Adenosyl-L-methionine (SAMe)] – cofactor in monoamine
neurotransmitter biosynthesis
• Rubidium chloride [RbCl] (Rubinorm) – unknown/unclear mechanism of action
29

APPROVED ADJUNCTS TO ANTIDEPRESSANTS-
ANTI-PSYCHOTICS
• Aripiprazole
• Brexpiprazole
• Lurasidone
• Olanzapine
• Quetiapine
• Risperidone – (used off-label)
30

OFF-LABEL ADJUNCTS TO
ANTIDEPRESSANTS
• Tri-iodothyronine (T3)
• Tetra-iodothyronine (T4)
• Lithium
• Buspirone
• Pindolol
31

APPROVED COMBINATIONS
OF ANTIDEPRESSANTS
• Amitriptyline-Perphenazine
• Flupentixol-Melitracen
• Olanzapine-Fluoxetine
• Tranylcypromine-Trifluoperazine
32

USES OF ANTIDEPRESSANTS
• Major depressive disorder
• Dysthymia
• Bipolar disorder
• Generalized anxiety disorder
• Social anxiety disorder
• Obsessive–compulsive disorder
(OCD)
• Fibromyalgia
• Neuropathic pain
• Migraine
• Eating disorders - Bulimia
nervosa, Binge eating
• Agitation
• Childhood enuresis
(bedwetting)
• Sleep disorders
33

EFFICACY OF ANTIDEPRESSANTS
• Strong evidence supports use of antidepressants in
chronic and severe depression.
• Conflicting results studies analysing the efficacy of
Antidepressants Vs Placebo in acute mild to moderate
depression.
• A metaanalysis of 21 clinical trials, published in Lancet,
found antidepressants to be more effective than placebo
in major depressive disorder in adults.
34

LIMITATIONS OF ANTIDEPRESSANTS
•In clinical studies, approximately 1/3rd of patients
achieved full remission, 1/3rd experienced partial
response and 1/3rd turned out as non-responders.
•30% - 50% of individuals treated with a given
antidepressant do not show a response.
35

AUGMENTATION & COMBINATION OF
ANTIDEPRESSANTS
American Psychiatric Association guidelines suggest
 Adding a drug from another class with a different MoA,
and
 Augmentation therapy with drugs like, Lithium, thyroxine,
dopamine agonists, sex steroids, NRIs, glucocorticoid-
specific agents, or the newer anticonvulsants and
psychostimulants.
36

LONG TERM USE
• High relapse rate after conclusion of treatment.
• A meta-analysis of 31 placebo-controlled antidepressant trials of
1-year treatment, in 2003, found that 18% of responders
relapsed during therapy and 41% patients switched-over to
Placebo relapsed.
• Therefore, pharmacotherapy for acute episode followed by
psychotherapy.
37

GENERAL ADVERSE EFFECTS OF
ANTI-DEPRESSANTS
38

SEROTONIN SYNDROME
• Serious ADR reported with high doses, and in
combination with other drugs
• Rarely fatal
• Characterized by mania, restlessness, agitation,
emotional lability, insomnia and confusion
39

HYPERTENSIVE CRISIS-CHEESE REACTION WITH MAO-
INHIBITORS
• MAOIs. Can cause a serious, pronounced, and sometimes fatal
interactions with:
 Certain drugs (sympathomimetics),
 OTC medications for common cold containing nasal decongestants,
 Foods containing very high levels of tyramine (mature cheese, cured
meats, or yeast extracts).
• Characterized by a potentially lethal hypertensive crisis.
• At lower doses an increased BP causing headache, giddiness, confusion,
agitation
40

RISK OF SUICIDE
• Use of antidepressants is correlated with an increased risk of suicidal
behaviour and thinking (suicidality) in those aged under 25.
• US FDA - the heightened risk of suicidality is within the first one to
two months of treatment.
• NICE places the excess risk in the "early stages of treatment".
• No effect or possibly a mild protective effect in patients aged 25 to
64 years (OR=0.79).
• Protective effect against suicidality among those aged 65 and over
(OR=0.37).
41

ANTI-DEPRESSANT-INDUCED MANIA
• Patients with bipolar disorder run the risk of getting
antidepressant-induced mania.
• Can occur in 20–40% of patients of bipolar disorder.
• Most often SSRIs can exacerbate or trigger symptoms of
hypomania and mania.
• Since many cases of bipolar depression are very similar to
unipolar depression, therefore, bipolar patient can be
misdiagnosed and exposed to the risk of precipitation of mania.
42

EMOTIONAL BLUNTING
•Emotional blunting - both positive and negative
can occur.
•This may necessitate a dose reduction or change
of medication.
•The mechanism of this effect is unknown.
43

EFFECTS ON BODY WEIGHT
• Body weight changes depend on the predominant effect
of antidepressant on neurotransmitters.
• Mirtazapine and paroxetine produce weight gain
and/or increased appetite.
• Fluoxetine, Bupropion and Venlafaxine cause weight loss
due to decreased appetite.
44

ATROPINE-LIKE EFFECTS OF TCA
• Dryness of mouth
• Loss of sweating – interference with heat-regulating mechanisms
• Difficulty in near-vision due to interference with accommodation of
lense
• Tachycardia, palpitations
• Constipation
• Difficulty in micturition, particularly in presence of obstructive uropathy,
eg BPH
• Mental confusion, delirium
45

SEXUAL SIDE EFFECTS
• Common with SSRIs, and include loss of sexual drive, failure to reach orgasm, and erectile
dysfunction.
• In a study of 1022 outpatients, overall sexual dysfunction with all antidepressants averaged
59.1%.
• MoA relating to effects of serotonin on 5-HT2 and 5-HT3 receptors; decreased
dopamine; decreased norepinephrine; blockade of cholinergic and α1-adrenergic
receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels.
• Moclobemide, a RIMA does not cause sexual dysfunction, and can actually lead to an
improvement in all aspects of sexual function.
• Mirtazapine is reported to have fewer sexual side-effects, most likely because it
antagonizes 5-HT2 and 5-HT3 receptors and may, in some cases, reverse sexual
dysfunction induced by SSRIs by the same mechanism.
• Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido
as a result of SSRI treatment.
46

SAFETY IN PREGNANCY
• Increased risk of spontaneous abortion of about 1.7-fold, preterm birth and
low birth weight with SSRIs.
• A study found a 27% increased risk of major malformations in SSRI
exposed pregnancies.
• Fluoxetine-exposure during pregnancies caused a 12% increase in the risk
of major malformations in a study.
• A systematic review and meta-analysis in 2013 could not show statistically
significant increased risk of major birth defects in antidepressant-exposed
pregnancies compared to non-exposed pregnancies.
• The FDA advises for the risk of birth defects with the use of paroxetine
• MAO-Is should be avoided.
47

DISCONTINUATION SYNDROME
• Antidepressant discontinuation symptoms were first reported
with imipramine in the late 1950s, and similar reports appeared
for monoamine oxidase inhibitors (MAOIs), SSRIs, and SNRIs.
• By the year 2001, at least 21 different antidepressants,
representing all the major classes, were reported to cause
discontinuation syndromes mostly in case reports.
• Incidence is difficult to determine and controversial.
48

THANK YOU
49

Anti-depressant drugs. Dr. Ashok Kumar Batham,M.D.,

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