Definition

Depression is one of the most common

psychiatric disorders.
Depression is a heterogeneous disorder that
has been characterized and classified in a
variety of ways.
It is a common condition with both
psychologic and physical
manifestations.
Etiology
Depression is due to the deficiency of
monoamine such as nor adrenaline,
serotonin, and dopamine at certain key
sites in the brain.
Mania is caused by overproduction of these
neurotransmitters.
Mania (mental illness) characterized by
opposite behavior that is enthusiasm, rapid
thought, speech patterns, extreme self
confidence, and impaired judgment.
Symptoms
Persistent sadness
Hopelessness ,Tearfulness
Loss of energy (fatigue)
Self criticism (feeling of guilt)
A sense of worthlessness, Irritability
Inability to concentrate
Decrease interest in daily life
Changes in appetite ,Insomnia or excessive
sleep
Recurrent thoughts of death or suicide
Treatment
Psychotherapies, behavioral therapies,
electroconvulsive therapies and
psychoactive drugs are effective in the
treatment of depressive disorders.
All antidepressant drugs potentiate either
directly or indirectly, the action of Nor-
adrenaline, dopamine, serotonin in the
brain.
Types of depression
(1) Reactive or Secondary depression
(most common):
Occurring in response to real stimuli, such as grief,
illness, etc;
It affects 60% of the patients that are diagnosed in
response to a known event.
(2)Major depression or endogenous depression:
A genetically determined biochemical disorder (family
history).
It affects 25% of the patients.
Usually responds to antidepressants or
electroconvulsive therapy.
Types of depression
(3) Bipolar disorder (Manic-depressive):

Depression associated with bipolar affective

(manic-depressive) disorder.
It affects 10-15% of the patients.
Lithium carbonate stabilizes mood. Mania may
require antipsychotic drugs as well; depression
managed with antidepressants.
Classification of antidepressant
drugs
Classification of antidepressant drugs
1)Tri cyclic antidepressants (TCAs) or
First generation antidepressant drugs:
Protryptilline 20-40mg
Nortryptilline 75-150mg
Imipramine (Tofranil) 75-200mg
Amitryptilline 75-200mg
Desipramine 75-200mg
Trimipramine 75-200mg
Clomipramine (Anafranil) 75-300mg
Doxepine 75-300mg
Classification of antidepressant drugs
2)Second generation antidepressants (Heterocyclic
antidepressants):

Amoxapine 150-300mg

Maprotiline 75-300mg

Trazadone 50-600mg

Bupropion 200-400mg
Classification of antidepressant drugs
3)Third generation antidepressants:
(Heterocyclic antidepressants):
Nefazodone 200-600mg

Venlafaxine 75-225mg

Mirtazapine 15-60mg
Classification of antidepressant drugs
4) Selective serotonin reuptake inhibitors
(SSRIs):
Escitalopram 10-30mg
Fluoxetine (Prozac) 10-60mg
Paroxetine (Paxil) 20-50mg
Citalopram (Celexa) 20-60mg
Sertraline (Zoloft) 50-200mg
Fluvoxamine 100-300mg
Classification of antidepressant
drugs
5) Monoamine oxidase inhibitors:
Irreversible inhibitors (non selective)
Isocarboxazide
Tranylcypramine
Phenelzine
Reversible inhibitors:
Moclobemide
Brofaromine
Tricyclic antidepressants
Mechanism of action:
Blocking the reuptake of serotonin and
noradrenaline into presynaptic nerve
terminal and increase in the levels of
monoamines in synaptic cleft resulting
antidepressant effect.
In addition TCAs bind to alpha, histamine
and cholinergic receptors which accounts
for many of the side effects seen with these
agents.
Actions
TCAs elevate mood, improve mental
alertness, increase physical activity.

All TCAs have similar therapeutic efficacy

and the choice of drug depends on
tolerance of side effects and duration of
action. Patients who do not respond to one
TCA may benefit from different drug in this
group.
Side effects
Anticholinergic effects: Dry mouth,
constipation, blurred vision, urinary retention
Cardiac effects: Orthostatic hypotension, reflex
tachycardia, arrhythmias
Endocrine effects: Weight gain, sexual
disturbances
Sedation (during first several weeks of
treatment).
Convulsions, confusion, hallucinations
Allergic reactions
Headache, drowsiness, tremor
Drug Interactions
Administered concurrently with MAOI produce
severe reactions like convulsions, hyperpyrexia,
and coma, hypertension
TCAs with ethanol produce toxic sedation.
TCAs inhibit the activity of guanethidine and
methyldopa this leads to increase blood pressure.
Caution is required with administering these
agents to patients with cardiovascular disease,
glaucoma, BPH, seizures, urinary retention.
Uses
Major depressive disorder
Panic disorder
Obsessive compulsive disorders
Imipramine has been used to control bed-wetting
in children (older than 6yrs) by contraction of the
internal sphincter of the bladder.
Attention deficit hyperactivity disorder
Contraindication
Liver impaired functions and cardiac problems.
Second generation drugs
Amoxapine
Is a metabolite of the antipsychotic drug
loxapine, and retains some of its antipsychotic
action and dopamine receptor antagonism.

A combination of antidepressant and

antipsychotic actions might make it a suitable
drug for depression in psychotic patients.
Side effects
Dopamine antagonism may cause:
akathisia
parkinsonism
amenorrhea-galactorrhea syndrome.
Maprotilline (Heterocyclic drug)
Is most like desipramine interms of its
potent norepinephrine uptake
inhibition.

It has fewer sedative and antimuscarnic

actions than older tricyclics.
Third generation agents
Nefazodone:
Is closely related to trazodone but is less
sedating.
It produces fewer adverse sexual effects than
the SSRIs but is a potent inhibitor of
CYP344.
Third generation agents
Venlafaxine:
Is a potent inhibitor of serotonin reuptake
and a weaker inhibitor of norepinephrine.
Low doses it behaves like an SSRIs. at high
doses (more than 225mg/d) it produces mild
to moderate increases heart rate and BP by
Nor adrenaline reuptake inhibition.
Third generation agents
Mirtazapine:
Is a potent antihistaminic with greater sedating
effects than the other second and
third generation drugs.
Inhibits pre synaptic alpha-2 receptors which
leads to increases central concentration of Nor
adrenaline.
Unlike the SSRIs, mirtazapine has strong affinity
for
5-HT receptors.
Side effects
Somnolence
Dry mouth
Weight gain
Constipation
Sedation
The difference between Tricyclics and the
second and third generation agents
The difference between Tricyclics and the
second and third generation agents is the
Degree of sedation they produce (greatest with
amitryptiline, doxepine, trazadone, mirtazapine)

Antimuscarinic effects (greatest with

amitryptiline and doxepine)

SSRIs are free of sedative effects safe in

overdose.
SSRIs
Mechanism of action
Inhibit the reuptake of serotonins into the
presynaptic nerve terminal and increases
the concentration of serotonin in synaptic
cleft.

Lack many of the toxicities of the

tricyclic and heterocyclic
antidepressants.
Possible site of action of SSRI
Side effects
Loss of libido,
delayed ejaculation
Seizures(overdose)
Anxiety,
insomnia,
headache,
anorexia,
weight loss
SSRIs Drug Interactions
If SSRIs is given with MAOI----- increase 5HT
concentration(serotonin syndrome)
Fluoxetine inhibit P450 drug metabolism of
haloperidol, TCAS, some beta antagonists,
some anti arrhythmic drugs.
Uses:
Obsessive-Compulsive disorders, eating
disorders (fluoxetine).
MAO Inhibitors
Mechanism of action
Mechanism of action
MAO inhibitors prevent inactivation of
monoamines with in neuron causing excess
neurotransmitter to diffuse into synaptic
space.
MAO-A is primarily responsible for
Norepinephrine, serotonin, tyramine
metabolism
MAO-B is more selective for dopamine.
Mechanism of action
The irreversible inhibitors are
nonselective and block both enzymes.
Irreversible block of MAO, allows significant
accumulation of tyramine, as a result there
are very high risks of hypertensive reactions
to tyramine ingested in food.

The reversible MAO-I (Moclobemide)

appears to be relatively free of this reaction
(hypertension)
Side effects
Headache,
drymouth,
blurred vision,
constipation,
weight gain,
sexual dysfunction,
postural hypotension
Drug Interactions
Food rich in tyramine particularly cheese, meat,
beer, chocolate, should be avoided.
MAO inhibitors potentiate the action of drugs
like alcohol, barbiturates, morphine,
amphetamine, antihistamines,
anticholinergics, TCAs.
Contraindication
Hepatic or renal impairment and cardiovascular
diseases.
Antimanic drugs
Eg: Lithium

Mechanism of action:
Not clear. The major possibilities being investigated
include:
Effects on electrolytes and ion transport:
It blocks sodium channels
Mechanism of action
Effects on neurotransmitters:
Blocks dopamine receptors, may
decrease NA also.
Effects on second messangers:
Depletion of IP3 and DAG
Side effects
Edema
Weight gain
Bradycardia-tachycardia (sick sinus syndrome)
Decrease thyroid function
Tremor
Polydipsia and polyurea
Leukocytosis
Drug Interactions
ACE inhibitors, NSAIDs , Thiazides, Fluoxetine
increase lithium concentrations.
Lithium+antipsychotics or Benzodiazepines may
increase risk for neurotoxicity particularly with
long term combination therapy.
Acetazolamide, osmotic diuretics, theophylline
increase lithium excretion.
Contraindication
Acute renal failure
Pregnancy
Thyroid disease
Cardio vascular disease.
Pharmacokinetics

Peak plasma levels in 30 min-2 hrs

No protein binding
Excreted through urine, plasma half
life about 20 hrs
Dosage: 0.5 mg/kg/day in divided
doses