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 When depression is neglected or severe it can lead to:can lead to:

-Suicide -Substance abuse -Alcoholism -Heart problems-Work-related problems -Family conflicts-Social isolation

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

Old classification of depression

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 influencesGenetic influences

Some types of depressions like bipolar and Some types of depressions like bipolar and the early onset depression the early onset depression (before the age (before the age

of 25) of 25) are thought to be genetically are thought to be genetically determined disorders. determined disorders. Identical twin Identical twin

studies revealed that if one of them suffers studies revealed that if one of them suffers from depression or manic-depressive from depression or manic-depressive

disorder, the other twin has a disorder, the other twin has a 70 %70 % chance chance of having the illnessof having the illness

EnvironmentalEnvironmental

11 ) )Early childhood trauma or abuseEarly childhood trauma or abuse

22 ) )Loneliness and lack of social supportLoneliness and lack of social support

33 ) )Recent stressful or traumatic lifeRecent stressful or traumatic life

experiencesexperiences

44 ) )Alcohol and drugsAlcohol and drugs

55 ) )Finances and employmentFinances and employment

66 ) )Health problems or chronic painHealth 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 depressedmood of the illness

However, dopamine )D) is important for pleasure,sex & psychomotor activity

Theories of DepressionTheories 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

Pharmacotherapy

Electroconvulsive therapy )ECT)

Psychotherapy

Therapies for depression

IndicationsIndicationsECT can be life-saving & produce dramatic ECT can be life-saving & produce dramatic relief forrelief for::

--Pregnant patientsPregnant patients

--Patients intending suicidePatients intending suicide

--Intractable maniaIntractable mania

--Some cases of psychotic depressionsSome cases of psychotic depressions

--People who cannot take antidepressants People who cannot take antidepressants due to problems of health or compliancedue 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 2 receptors

3 -Inhibition of MAO enzyme

Classification of Classification of Antidepressant DrugsAntidepressant Drugs

Tricyclic antidepressantsTricyclic antidepressants

# #TCAs are the oldest class of antidepressant drugsTCAs are the oldest class of antidepressant drugs

# #They have characteristic three-ring nucleusThey have characteristic three-ring nucleus

# #Older agents ‘first generation’ TCAs;Older agents ‘first generation’ TCAs; Imipramine – Amitriptyline Imipramine – Amitriptyline are the prototypical are the prototypical

drugs of the class as mixed NE & 5-HT reuptakedrugs of the class as mixed NE & 5-HT reuptake

inhibitorsinhibitors

# #They can be used for long duration for Rx of They can be used for long duration for Rx of depression without loss of effectivenessdepression without loss of effectiveness

  Mechanism of ActionMechanism of Action

TCAs inhibit the neuronal reuptake of TCAs inhibit the neuronal reuptake of NE NE

and 5HTand 5HT into presynaptic nerve terminals into presynaptic nerve terminals

leading to an increased concentration of leading to an increased concentration of

these monoamines in the synaptic cleft in these monoamines in the synaptic cleft in

the brainthe brain

N.B. Like phenothiazines, TCAs block N.B. Like phenothiazines, TCAs block

adrenergic (adrenergic (αα11), histamine (H), histamine (H11)and )and

muscarinic (Mmuscarinic (M11)receptors)receptors

Classification of TCAsClassification of TCAs

Tertiary aminesTertiary amines --Block the reuptake ofBlock the reuptake of

55--HT& NEHT& NE

- -more side effectsmore side effects

11 - -ImipramineImipramine

22 - -AmitriptylineAmitriptyline

Secondary aminesSecondary amines - -More selective to More selective to NENE

--less side effectsless side effects

11 - -DesipramineDesipramine

22 - -NortriptylineNortriptyline

Tetracyclic antidepressentsTetracyclic antidepressentsMaprotiline: has a strong H1 blocking activity = Maprotiline: has a strong H1 blocking activity =

sedative effectsedative effect

TCAs: Secondary vs Tertiary AminesTCAs: Secondary vs Tertiary Amines

Tertiary

Secondary

Pharmacological actionsPharmacological actions

11 - -Elevate moodElevate mood

22 - -Improve mental alertnessImprove mental alertness

33 - -Increase physical activityIncrease physical activity

# #The antidepressant effect may develop after several The antidepressant effect may develop after several

weeks of continued treatment ( 2 - 3 weeks)weeks of continued treatment ( 2 - 3 weeks)

44 - -In non-depressed patients In non-depressed patients They cause They cause

sedation, confusion & motor incoordinationsedation, confusion & motor incoordination

1 -Treatment of major depression& panic disorders

2 -Depressed phase of bipolar depression with mood stabilizer

3 -Obsessive-compulsive disorders4 -Together with antipsychotics in

Rx of depressed psychotic patients5-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)

Clinical indications

Adverse Effects

1 -Anticholinergic effects: dry mouth, blurred vision, constipation & urine retention,

aggravation of glaucoma2 -Antihistaminic effects: Sedation, confusion

Sedation wear off in 1-2 weeks as the anti- depressant 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

SSelective elective SSerotonin erotonin RReuptake euptake IInhibitors: SSRI’snhibitors: SSRI’s

# #First highly selective 5HT-reuptake First highly selective 5HT-reuptake inhibitorsinhibitors

# #Little or no effect on NE reuptakeLittle or no effect on NE reuptake

# #First choice for most depressionFirst choice for most depression

# #Clinical efficacy for major depression Clinical efficacy for major depression resembles that of the TCAsresembles that of the TCAs

.

Mechanism of Action

SSRI’sSSRI’s** FluoxetineFluoxetine )Prozac) )Prozac)

prototype of SSRIsprototype of SSRIs **SertralineSertraline

**ParoxetineParoxetine **FluvoxamineFluvoxamine

**CitalopramCitalopram ** EscitalopramEscitalopram

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

Advantages of SSRIS

1 -GIT adverse effects are common : GIT upset , nervousness, insomnia

2 -Diminished sexual functions3 -Headache and sleep disturbances

4 -Long-term weight gain5 -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 .

Side effects

1 -Major depression, Generalized anxiety disorder

) GAD (and panic disorders2 -Obsessive-Compulsive Disorder3 -Some eating disorders (bulimia)

4 -Premenstrual syndrome5 -Anorexia nervosa

6 -Premature ejaculation

Therapeutic Uses

DrugDrug InteractionsInteractions

A dangerous pharmacoA dangerous pharmaco--

dynamic interaction maydynamic interaction may

occuroccur

when when fluoxetinefluoxetine is used with is used with

MAOIsMAOIs leading to theleading to the

serotonin syndromeserotonin syndrome

““Serotonin SyndromeSerotonin Syndrome””

Life-threatening condition resulting fromoverstimulation 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

.

*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

To minimize the risk of serotonin syndrome