Antidepressants: Mechanisms based classification & challenges in therapeutic applications: Dr. Ashok Kumar Batham

Antidepressants : Mechanism Based
Classification & Challenges in Therapeutic
Applications
Dr. Ashok Kumar Batham, Chief Consultant
Dr. Batham Pharma Consultants
phone: +91 9328018777
email: ashokpharmacol@gmail.com

28-06-2020ANTI-DEPRESSANT DRUGS. Dr. Ashok Kumar Batham,M.D.,
2
chanism Based Classification of
tidepressants

Mechanism-based Classification Of Antidepressants
I. Reuptake Inhibitors: Non-selective monoamine (5-HT, NE, DA) reuptake
inhibitors
a. Selective serotonin reuptake inhibitors (SSRIs)
b. Serotonin-Norepinephrine reuptake inhibitors (SNRIs)
c. Norepinephrine-Dopamine reuptake inhibitors (NDRIs)
II. Serotonin receptor antagonists
III. Serotonin receptor modulators and stimulators (SMS)
IV. Mono-amine oxidase inhibitors (MAO-Is)
3

NON-SELECTIVE AMINE REUPTAKE INHIBITORS -
TRICYCLIC ANTIDEPRESSANTS (TCAs)
• Imipramine
• Desipramine
• Clomipramine
• Trimipramine
• Amitriptyline
• Nortriptyline
• Protriptyline
• Amitriptylinoxide
• Doxepin
• Dosulepin
28-06-2020
ANTI-DEPRESSANT DRUGS. Dr. Ashok Kumar Batham,M.D.,
4

TRICYCLIC ANTIDEPRESSANTS (TCAs) - MOA
• Block the neuronal reuptake of NE as well as 5-HT, e.g.
Imipramine, Amitriptyline, Doxepin
• Individual TCAs produce varying effects on NE and 5-HT
reuptake
• Inhibition of NE-reuptake is relatively more than 5-HT
reuptake in case of Desipramine, Nortriptyline, Protriptyline,
Amoxapine
• Clomipramine is more selective in blocking 5-HT reuptake
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TRICYCLIC ANTIDEPRESSANTS (TCAs) - MOA
• All the TCAs produce blockade of alpha1, muscarinic and
histaminergic receptors which is responsible for a number of side
effects
• Some TCAs produce relatively more sedation, e.g. Doxepine,
Trimipramine
• Some TCAs are useful in painful neuropathies and fibromyalgia,
e.g. Amitriptyline
• Doxepine is an effective anti-pruritic when used orally as well
topically
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SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRIs)
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• Fluoxetine
• Sertraline
• Paroxetine
• Citalopram
• Escitalopram
• Fluvoxamine

SSRIs : Mechanisms of action
I. Selective inhibition of serotonin reuptake by blockade of Serotonin Transporter
(SERT) which leads to:
• Increased serotonin levels and dwell-time in the synapse
• Increased serotonin receptor density and sensitivity
• Increased receptor-G protein coupling and cyclic nucleotide signaling (enhanced
GPCR activity)
• Increased expression of downstream gene especially for BDNF (brain derived
neurotrophic factor) responsible for neurotrophic activities
• Increased neurogenesis in hippocampus
• Enhanced serotonergic neurotransmission
8

SSRIs : Mechanisms of action
II Stimulation of presynaptic auto-receptors- 5-HT1A,
5-HT7 and 5-HT1D leading to reduced release of 5-
HT; however, chronic administration of SSRIs leads to
down-regulation and desensitization of auto-
receptors which causes resumption of normal
serotonin release.
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SEROTONIN NOREPINEPHRINE REUPTAKE
INHIBITORS (SNRIs)
• Venlafaxine
• Desvenlafaxine
• Duloxetine
• Milnacipran
• Levomilnacipran
• Nefazodone
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SNRIs : Mechanisms of action
Development of these drugs is inspired by TCAs which inhibit reuptake of
serotonin as well as norepinephrine leading to enhanced neurotransmission as
in case of SSRIs
• These drugs, unlike TCAs, do not block other receptors, like alpha1,
muscarinic and histaminergic, and thus do not produce consequent
undesirable effects
• SNRIs are indicated in Depression, Anxiety, Panic, Neuropathic pain,
Fibromyalgia
• Used off-label in Urinary incontinence, Premenstrual dysphoric disorder,
PTSD, Painful states, Hot flashes, Binge eating disorders, Autism
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NOREPINEPHRINE REUPTAKE INHIBITORS (NRI)
•Reboxetine
•Viloxazine
•Teniloxazine (also inhibits 5-HT2A receptors)
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SEROTONIN RECEPTOR ANTAGONISTS
Agents: Nefazodone, Trazodone, Mirtazapine, Mianserine
MOA:
1. Trazodone and Nefazodone block 5-HT2 and alpha1 receptors
2.Mianserine and Mirtazapine predominantly block (a) H1-receptors and produce
sedation, (b) 5-HT2 family of receptors (5-HT2A, 5-HT2c, 5-HT3) like atypical
antipsychotics.
These drugs are often combined with SSRIs for greater antidepressant effects
Adverse effects: (a) Somnolence, increased appetite and weight gain with
Mirtazapine and Mianserine, (b) Agranulocytosis reported with Mirtazapine,( C)
Nefazodone withdrawn because of hepatotoxicity.
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NOREPINEPHRINE–DOPAMINE REUPTAKE
INHIBITORS (NDRI)
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• Bupropion
• Methylphenidate

NDRI : Bupropion
• Blocks reuptake of NE and Dopamine (DA), enhances neurotransmission
• Possibly also causes pre-synaptic release of NE and DA
• Active metabolite of bupropion, hydroxybupropion, also contributes to the
therapeutic effects
• Used in combination with SSRIs to produced enhanced antidepressant effects
through triple Reuptake Blockade (5-HT,NE and DA)
• Bupropion is used in Depression, Smoking cessation, Seasonal depressive
disorder, PTSD, Neuropathic pain, Fibromyalgia and Weight loss.
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MONO-AMINE OXIDASE INHIBITORS
(MAO-INHIBITORS)
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NON-SELECTIVE MAO-INHIBITORS
• Phenelzine | Isocarboxazid | Tranylcypromine
• All of the above are irreversible non-selective MAO-
Inhibitors (inhibit MAO-A and MAO-B)
• Block metabolic degradation of NE,DA, and 5-HT
• Also produce down regulation of presynaptic alpha2-
receptors
• Use runs the risk of food and drug interactions
17

MAO-B Inhibitor - Selegiline
• Selegiline is a reversible inhibitor of MAO-B which is
located in serotonergic neurons
• Selegiline is used in PD and Depression
18

REVERSIBLE INHIBITORS OF MAO-A (RIMA)
• Moclobemide
• Metralindole
• Pirlindole
• Toloxatone
• Bifemelane – RIMA. and weak NRI
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ANTI-PSYCHOTICS USED AS ADJUNCTS IN DEPRESSION
• Aripiprazole
• Brexpiprazole
• Lurasidone
• Olanzapine
• Quetiapine
• FDC of Olanzapine 6|12 mg and
Fluoxetine 25|50 mg (Symbax)
approved by the US FDA.
• Risperidone – (used off-label)
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OFF-LABEL ADJUNCTS TO ANTIDEPRESSANTS
• Tri-iodothyronine (T3)
• Tetra-iodothyronine (T4)
• Lithium
• Buspirone
• Pindolol
21

ATYPICAL ANTIPSYCHOTICS
• Some of the atypical antipsychotics (Olanzapine, Aripiprazole, Quetiapine,
and Risperidone) are used for augmentation of SSRIs and SNRIs
• FDC of Olanzapine 6|12 mg and Fluoxetine 25|50 mg (Symbax) approved
by the US FDA.
• Quetiapine used for depressive episodes in bipolar disorder, under review
for approval in major depression and GAD.
• Amisulpride is used in dysthymia
• Lurasidone is used for depressive episodes in bipolar disorder
22

OTHERS
• Agomelatine -
5HT2C receptor antagonist and MT1 and MT2 receptor agonist
• 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
23

OTC ANTIDEPRESSANTS
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• 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

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Therapeutic Applications

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
26

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.
27

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.
28

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.
29

30
Augmentation of Antidepressants

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.
31

32
Challenges in the Use of Antidepre

CHALLENGES IN THE USE OF ANTI-DEPRESSANTS
• Therapeutic “lag-period” - need for ECT, Deep Brain Stimulation,
Transmagnetic Brain Stimulation and supportive therapy during
this period
• Side-effects – need for proper counseling and management
• Switch-over phenomenon in case of Bipolar Depressive illness –
TCAs cause switch over to mania. SSRIs and Bupropion are less
likely to cause switch-over.
33

• Suicidality (suicidal ideation, attempts, and successful suicide) -
Antidepressants have been incriminated in increasing suicidality
and a black-box warning to this effect led to an increased
incidence of suicidesstudy of 65,000 patients showed no increase
in suicides.
• It is recommended to weigh the risk of suicidality with treatment Vs
‘no-treatment’
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• Inadequate therapeutic response – 2/3rd patients show 50%
improvement in symptoms of depression over a period of 8-weeks
• Therapeutic strategy, if no response is obtained in 8-weeks with
adequate or maximum recommended dosage:
• Add-on a drug with a different MoA, e.g. SSRI to SNRI
• Add-on Bupropion
• Add-on triiodothyronine
• Add-on an atypical antipsychotics (aripiprazole or olanzapine)
35

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
36

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
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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).
38

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.
39

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.
40

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.
41

ATROPINE-LIKE EFFECTS OF TCA
• Dryness of mouth
• Loss of sweating – interference with heat-regulating mechanisms
• Difficulty in near-vision and photophobia
• Tachycardia, palpitations
• Constipation
• Difficulty in micturition, particularly in presence of obstructive
uropathy, eg BPH
• Mental confusion, delirium
42

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.
43

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.
44

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.
45

THANK YOU
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Antidepressants: Mechanisms based classification & challenges in therapeutic applications: Dr. Ashok Kumar Batham

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