Professor of Pharmacology Antidepressant Drugs By Dr. Yieldez Bassiouni Professor of Pharmacology

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

When depression is neglected or severe it can lead to: 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

Postpartum depression Types of depression Major Depression (Unipolar) Dysthymia low mood almost daily Delusions,hallucinations Psychotic Depression Manic Depression (Bipolar) Atypical Depression (w gain, sleep) Postpartum 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 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 اليقظة والإثارة، وشهية 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

Electroconvulsive therapy (ECT) Therapies for depression Pharmacotherapy Psychotherapy Electroconvulsive therapy (ECT)

Electroconvulsive therapy

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

combination of pharmacotherapy & psychotherapy may improve the treatment response, enhance the quality of life Psychotherapy

Pharmacotherapy

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 Mixed - action Novel Drugs Selective Serotonin Reuptake Inhibitors MAO Inhibitors

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 -Block the reuptake of 5-HT& NE - more side effects 1- Imipramine 2- Amitriptyline Secondary amines - More selective to NE -less side effects 1- Desipramine 2- Nortriptyline Tetracyclic antidepressents Maprotiline: has a strong H1 blocking activity = sedative effect

TCAs: Secondary vs Tertiary Amines

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 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

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 النموذج

Advantages of SSRIS No blocking actions at M or α1 receptors, 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 2- Fluoxetine is approved for use in children & adolescence and is relatively safe in pregnancy

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.  A number of drugs are not associated with sexual side effects (such as bupropion, mirtazapine and maprotiline, As a result, sexual dysfunction caused by SSRIs can sometimes be treated by several different medications. These include: bupropion (norepinephrine and dopamine reuptake inhibitor) buspirone (serotonin 5-HT1A receptor partial agonist) Mirtazapine

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 6- Premenstrual syndrome. 7- Alcohol abuse. 8- Anorexia nervosa. 9- Generalized anxiety disorder (GAD).

Drug Interactions A dangerous pharmaco- dynamic 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

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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