Transcript 2-Anti-depressants

What is Depression ?
It is one of the most
common psychiatric
disorder, characterized by
intense feeling of
sadness, hopelessness ,
and despair and inability
to experience ordinary
pressure to cope with
ordinary life events
Complications
When depression is neglected or severe it
can lead to:
-Suicide
-Substance abuse
-Alcoholism
-Heart problems
-Work-related problems -Family conflicts
-Social isolation
Old classification of depression
Unipolar depression
is more common and affects old patients who are
subjected to certain circumstances associated with
Anxiety. Mood remains at one emotional state or pole".[
Patients are usually inert
Bipolar depression
develops early in life and a hereditary factor may
be involved, and patients oscillate between
depression and mania
Types of depression
Major
Depression
(Unipolar)
Dysthymia
low mood almost
daily
Psychotic Depression
Delusions,hallucinations
Manic
Depression
(Bipolar)
Postpartum
depression
Atypical
Depression
(w gain, sleep)
Factors affecting depression
Several risk factors appear to work together
to cause or precipitate depressive disorders,
the most important of these are:
Genetic influences
Environmental
Biological factors
Genetic influences
Some types of depressions like bipolar and
the early onset depression (before the age
of 25) are thought to be genetically
determined disorders. Identical twin
studies revealed that if one of them suffers
from depression or manic-depressive
disorder, the other twin has a 70 % chance
of having the illness
Environmental
1) Early childhood trauma or abuse
2) Loneliness and lack of social support
3) Recent stressful or traumatic life
experiences
4) Alcohol and drugs
5) Finances and employment
6) Health problems or chronic pain
Biological factors
Imbalances of
neurotransmitters ; mainly
serotonin (5-HT) and
norepinephrine (NE) play a
major role in pathogenesis
of depression
5-HT deficiency may cause the sleep problems,
irritability, and anxiety associated with depression
Decreased level of NE, which regulates mood,
alertness, arousal, appetite, reward & drives, may
contribute to the fatigue and depressed
mood of the illness
However, dopamine (D) is important for pleasure,
sex & psychomotor activity
Theories of Depression
The etiology of depression is too complex
to be totally explained by a single theory
1. Neurotrophic hypothesis
2. The monoamine theory
3. The dysregulation hypothesis
4. Neuro-endocrinal hypothesis
Therapies for depression
Pharmacotherapy
Psychotherapy
Electroconvulsive therapy (ECT)
Indications
ECT can be life-saving & produce dramatic
relief for:
-Pregnant patients
-Patients intending suicide
-Intractable mania
-Some cases of psychotic depressions
-People who cannot take antidepressants
due to problems of health or compliance
Monoamine nerves: Neurotransmission
Sites of Action for Antidepressants
1- Monoamine (NE or/ and 5-HT) re-uptake pump inhibitors
2- Blockade of pre-synaptic a2 receptors
3- Inhibition of MAO enzyme
Classification of
Antidepressant Drugs
Tricyclic
Antidepressants
Selective Serotonin
Reuptake Inhibitors
MAO Inhibitors
Mixed - action
Novel Drugs
Tricyclic antidepressants
# TCAs are the oldest class of antidepressant drugs
# They have characteristic three-ring nucleus
# Older agents ‘first generation’ TCAs;
Imipramine – Amitriptyline are the prototypical
drugs of the class as mixed NE & 5-HT reuptake
inhibitors
# They can be used for long duration for Rx of
depression without loss of effectiveness
Mechanism of Action
TCAs inhibit the neuronal reuptake of NE
and 5HT into presynaptic nerve terminals
leading to an increased concentration of
these monoamines in the synaptic cleft in
the brain
N.B. Like phenothiazines, TCAs block
adrenergic (α1), histamine (H1)and
muscarinic (M1)receptors
Classification of TCAs
Tertiary
amines
Secondary amines
- More selective to NE
-Block the reuptake of
5-HT& NE
- more side effects
1- Imipramine
-less side effects
1- Desipramine
2- Nortriptyline
2- Amitriptyline
Tetracyclic antidepressents
Maprotiline: has a strong H1 blocking activity =
sedative effect
TCAs: Secondary vs Tertiary Amines
Tertiary
Secondary
Pharmacological actions
1- Elevate mood
2- Improve mental alertness
3- Increase physical activity
# The antidepressant effect may develop after several
weeks of continued treatment ( 2 - 3 weeks)
4- In non-depressed patients They cause
sedation, confusion & motor incoordination
Clinical indications
1- Treatment of major depression &
panic disorders
2- Depressed phase of bipolar
depression with mood stabilizer
3- Obsessive-compulsive disorders
4- Together with antipsychotics in
Rx of depressed psychotic patients
5-Treatment of resistant depression that
has failed to respond to standard
SSRI therapy
Clinical indications
5- Imipramine used to control
bed-wetting in children
(nocturnal enuresis)
by causing contraction of
’ internal sphincter of ’ bladder
6- Analgesia in neuropathic pain
chronic painful states
(They modulate opioid
systems in the CNS)
Adverse Effects
1- Anticholinergic effects: dry mouth, blurred
vision, constipation & urine retention,
aggravation of glaucoma
2- Antihistaminic effects: Sedation, confusion
Sedation wear off in 1-2 weeks as the antidepressant effect develops
5- Metabolic-endocrine: weight gain, sexual
disturbances
3- CV effects: postural hypotension, due to
blockade of α-adrenoceptors and reflex tachycardia
4- Neurologic: seizures
5- TCAs have narrow therapeutic index.
6- Depressed patients tend to be suicidal
7- may be fatal in overdose (arrhythmia)
Selective Serotonin
Reuptake Inhibitors
Selective Serotonin Reuptake
Inhibitors: SSRI’s
# First highly selective 5HT-reuptake
inhibitors
# Little or no effect on NE reuptake
# First choice for most depression
# Clinical efficacy for major depression
resembles that of the TCAs
Mechanism of Action
.
SSRI’s
* Fluoxetine (Prozac)
prototype of SSRIs
*Sertraline
*Paroxetine
*Fluvoxamine
*Citalopram
* Escitalopram
Advantages of SSRIS
1- SSRIs are much safer in overdose than
other antidepressants
2- They lack many of the adverse effects
of TCAs and MAOIs
No blocking actions at M or α1 receptors,
H1 receptors
*Better side effect profile
Side effects
1- GIT adverse effects are common : GIT upset ,
nervousness, insomnia
2- Diminished sexual functions
3- Headache and sleep disturbances
4- Long-term weight gain
5- CVS side effects are minimal
# Many side effects disappear after the
adaptation phase, when the antidepressant
effects begin ( up to 6 weeks).
# Side effects and their durations are highly
individual and drug-specific.
Therapeutic Uses
1- Major depression,
Generalized anxiety disorder
(GAD) and panic disorders
2- Obsessive-Compulsive Disorder
3- Some eating disorders (bulimia)
4- Premenstrual syndrome
5- Anorexia nervosa
6- Premature ejaculation
Drug Interactions
A dangerous pharmacodynamic interaction may
occur
when fluoxetine is used with
MAOIs leading to the
serotonin syndrome
“Serotonin Syndrome”
Life-threatening condition resulting from
overstimulation of serotonin receptors
This can occur when two antidepressants
are taken together (multiple different
mechanisms of serotonin elevation)
Symptoms: Autonomic instability
( BP , pulse, temperature)
mental confusion, shivering
sweating, rigidity/hypertonia and diarrhea
.
To minimize the risk of
serotonin syndrome
*There must be a 'washout' period of
at least two weeks when switching
from one antidepressant drug to another
(It is necessary to clear the system
completely of one drug before starting
another