drugs used in depression ,types of depression ,mechanism of action of antidepressant drugs

1. Dr.Rahul Bhalsinge
Professor
Department of Pharmacology

2.  Introduction to Depression
 Types of Depression
 Pathophysiology of Depression
 Aim of treatment of depression
 TCAs, MAOIs, SSRI and Atypical antidepressant medications
 Dual actions of antidepressants
 Important feature of Antidepressants
 Summerizing-
- General guidelines – therapy of depression
- Discontinution of Antidepressants

3.  It is a mental illnesses characterized by pathological
changes in mood, loss of interest or pleasure, feelings
of guilt or low self-worth, disturbed sleep or appetite,
low energy and poor concentration.
 It can be severe and some times fatal.

4.  Depresssed mood most of the day….
 Markedly diminished interest or pleasure
 Significant weight loss/gain
 Insomnia or hypersomnia
 Agitation
 Fatigue or loss of energy
 Change in appetite
 Lack of concentration
 Poor self esteem
 Thought of suicide or death

5. Reactive Depression
(The depression state
appears after a
shocking
experience, also appear
following illness(MI),
alcohol abuse, failure
in exam etc.)
Endogenous depression
(Major depression)
Bipolar Depression
(manic depressive
psychoses(MDP))
Unipolar Depression
( It is idiopathic and
has genetic basis) (Cyclic manifestations
of depression followed
by mania)
Antidepressants work very well in major depression as well as in depressive
phase of bipolar depression(MDP). In reactive depression, antidepressants are
often not required.

6. -
- Depression is associated with changes in level of
NTs in brain. e.g. 5HT,NE,DA.
- The levels can be influenced by physical illness,
genetics, substance abuse, diet, hormonal
changes, brain injuries or social circumstances.

7.  The monoamine hypothesis of depression
suggests that depression is related to a
OR
,

9.  Brain is capable of making new neurons- Neurogenesis
 Variety of stimuli can damage neurons and decrease neurogenesis in
particular stress damages hippocampal neurons
 Several factors are known to repair neurons & increase neurogenesis-
among them Antidepressants which act by activate the genes that
control the production of protein called BDNF(Brain Derived
Neurotrophic Factor)
 BDNF - mainly responsible for promoting protective pathways &
inhibiting damaging pathway in neural stem cells(NSCs) & neural
progenitor cells (NPCs)

10.  Alleviate the signs, symptoms and distress
associate with clinical depression
 Improve the lives of persons with debilitating
depression
 Repair the neuronal damage associated with
depression

11. Potentiate directly and indirectly the action of
• Dopamine
• Serotonin
• Norepinephrine
The purpose of antidepressants is to increase the
neurotransmitters in the synapse.

12. They are used for the relief of symptoms of moderate
and severe depression.
Antidepressants are taken for at least 4-6 months.
They can be used alone or in combination with other
medications

13.  Tricyclic anti-depressants (TCAs)
 Monoamine oxidase inhibitors (MAOIs)
,
Moclobemide (RIMA)
 Selective serotonin reuptake inhibitors (SSRIs)
 Serotonin and norepinephrine reuptake inhibitors
 Atypical anti-depressants (Others)

15.  All antidepressant drugs, require a to
produce desirable clinical effects.
- longer t1/2 life & extensive protein
binding
- Neuroadaptive changes at post
receptor (downregulation and desensitisation of
receptors) and 2nd messenger system

16. Tricyclic Antidepressants (TCAs)
 Inhibit the reuptake of norephinephrine & /or
serotonin at the NE & 5HT transporters (NET & SERT)
- Relative proportion of 5HT/NE activity varies for
each drug
 Are also potent antagonists at various receptors
including:
- Cholinergic
- Histaminergic
- α-adrenergic
(Varies by agent)

17.  Muscarinic M1 receptor antagonism - anticholinergic effects
including dry mouth, blurred vision, constipation,
urinary retention and impotence
 Histamine H1 receptor antagonism - sedation & weight gain

18.  Direct membrane effects - reduced seizure threshold,
arrhythmia
 Serotonin 5-HT2 receptor antagonism - weight gain (&
reduced anxiety)
 Adrenergic α receptor antagonism
- postural hypotension

19.  Nonselectivity results in greater side effects
 TCAs can also lead to cardiotoxicity
 Increased LDH leakage
 Slow cardiac conduction
 High potency can lead to mania
 Contraindicated with persons with bipolar disorder or
manic depression

23.  MAO is a mitochondrial enzyme found in nerve & other tissues.
 Monoamine oxidase breaks down NE, 5HT, & DA.
 When monoamine oxidase is inhibited, NE , 5HT, and DA are not broken
down, increasing the concentration of all three NTs in the brain.
 MAOIs may reversibly or irreversibly inactivate the enzymes by making
stable complexes with the enzymes, permitting neurotransmitter
molecules to escape degradation and accumulate within synaptic cleft.
 This may cause activation of NE & 5HTreceptors responsible for anti
depressant action

24.  Dry mouth.
 Nausea, diarrhea or constipation.
 Skin reaction at the patch site.
 Headache.
 Drowsiness.
 Dizziness or lightheadedness.
 Insomnia.

25. 25

26.  Cheese,beer,wine,
yeast product,fish,meat contain
large amount of tyramine &
indirectly acting amine
Due to irreversible block of MAO-A
Tyramine normally degraded in the gut
by MAO-A
Reach to circulation,
displace large amount of norepinephrine
from loaded nerve
Hypertensive crisis
Medical emergency
Rx : IV Phentolamine ,Prazosin

27.  They are the most commonly prescribed group of
antidepressants
 They specifically inhibit serotonin reuptake, having 300- to
3000-fold greater selectivity for the 5HT transporter as
compared to the NE transporter
 Agents: Fluoxetine (Prozac®), paroxetine, sertraline,
fluvoxamine, Citalopram, & Escitalopram (s-citalopram)

29.  Anhedonia
 Apathy
 Nausea/vomiting
 Drowsiness or somnolence
 Headache
 Bruxism (involuntarily
grinding of the teeth)
 Extremely vivid and strange
dreams
 Dizziness
 Fatigue
 Changes in sexual behavior
 Suicidal thoughts

30.  Depression
 Obsessive compulsive disorder (the only indication
for fluvoxamine/citalopram/clomipramine )
 Panic disorder(SSRIs along with Alprazolam)
 Generalized anxiety
 Premenstrual dysphoric disorder
 Bulimia nervosa (only fluoxetine is approved for
this last indication)

31.  Slightly greater efficacy than SSRIs
 Slightly fewer adverse effects than SSRIs
 Current drugs
 Venlafaxine (Effexor)
 Duloxetine (Cymbalta)
 Mechanism of Action
 Very similar to SSRIs
 Works on both neurotransmitters
 Side effects
 Similar to SSRIs
 Suicide
Venlafaxine 1:1
Duloxetine

32. Mitrazapine ( NE/5HT release )
1) Mitrazapine block α2 auto receptor & 5HT1 hetero receptor (NAgic
neuron)
2) 5HT1 autoreceptor and α2 hetero receptor (serotonergic neuron)
Mianserin
Block α2 receptor presynaptically – NE release
Trazodone - Inhibit uptake 5HT& desensitises presynaptic 5HT receptor
5HT release

33. (Bupropion)

34.  Atypical antidepressants are frequently used in
patients with major depression who have inadequate
responses or intolerable side effects during first-line
treatment with selective serotonin reuptake
inhibitors (SSRIs)
 Atypical antidepressants are often first-line
treatment if the drug has a desirable characteristic
(eg, sexual side effects and weight gain occur less
often with bupropion than SSRIs).

35.  Anxiety
 Restlesness
 Blurred vision
 Constipation
 Sedation
 Dry mouth
 Nausea
 Hepatotoxicity
 Weight gain

37.  1st day , use a small dose and divide the daily dose into 2 smaller
doses – watch for any untoward reaction. If no reaction,then
 Increase the dose,rapidly, within a few days- reach the peak
level of dose
 The antidepressant should be continued in the same dose for 9-
12 months after the patient has become totally symptoms free
(Imp =In high risk pts , require 3 year or more continuation of ADDs)
 Then start to withdraw the drug gradually ,(or Cross tapered)
full withdrawal requires about a month, provided symptoms do not
reappear during withdrawal.

38.  Antidepressants should be gradually tapered and
should not be abruptly discontinued.
 Abruptly stopping an antidepressant in some patients
can cause discontinuation syndrome.