Anti-Depressants

Dr Nauman

 Increased

morbidity and mortality. Disrupts marital, familial, social life. Affects work, leads to job related problems. Increased incidence of medical illnesses,accidents. Risk of suicide.

Monoamine hypothesis of depression

Depression

is caused by a functional insufficiency of monoamine neurotransmitters (norepinephrine, serotonin or both)

In any case, Reversal of Depression Should be possible by Increasing

CNS Neuronal Transmission

5HT

NA

Classification
AMINE

UPTAKE INHIBITORS INHIBITORS

MAO

Amine Uptake Inhibitors

TRICYCLIC ANTIDEPRESSANTS HETROCYCLIC

ANTIDEPRESSANTS (ATYPICAL ANTI-DEPRESSANTS)

SSRIs

Tricyclic Antidepressants
Dibenzazepines

Clomipramine Imipramine Desipramine Trimiparine

TCAs
Dibenzocycloheptadienes

Amitriptyline Protriptyline Nortriptyline

Hetrocyclic or Atypical Antidepressants

Second

Generation Amoxapine Maprotiline Trazodone Bupropion

Hetrocyclic or Atypical Antidepressants

Third

Generation Antidepressants Mirtazepine Nefazodone Venlaxafine

Selective Serotonin Reuptake Inhibitors (SSRIs)

Fluoxetine Paroxetine Citalopram Sertarline

Monoamine Oxidase Inhibitors

Hydrazine

Derivatives Phenelzine Isocarboxazid Iproniazid Non-Hydrazine Deratives Tranylcypromine Meclobemide

Tricyclic Antidepressants
Characteristic

three ring nucleus. Most are incompletely absorbed, all are metabolized in liver => High first pass effect: Some have active metabolites High protein binding, high lipid solubility.

Mechanism of Action: Immediate

-Inhibition of NT reuptake Immediate action = > NE and 5HT in synapse - But depression is not relieved immediately - WHY?
-

After 2-4 Weeks

After chronic treatment (2 - 4 weeks) NE-R and 5-HT2R. NE release and turnover. NE-stimulated cAMP in brain. Sensitization of 5-HT receptors. * Adaptive Responses * - Takes up to 4 weeks for all TCA antidepressants to have an effect.

 Some

have more Effect on NE Uptake than Serotonin and Vice Versa

More

Effect on NE Reuptake Desipramine More effect on Serotonin Reuptake Amitriptyline

Block of Other Receptors

Muscarinic

Receptors Alpha1 Receptors Histamine H1 Receptors

Produce Adverse effects of TCAs

Actions of TCAs
CNS

In normal people

Clumsiness, sleepiness, difficulty in concentrating, unsteady gait Unpleasant feeling and anxiety

In depressed People Little effects at start except sedation Elevation of mood after 2-3 weeks, then other symptoms improve

Decrease

Seizure Threshold AND Produce convulsions in overdose

ANS, CVS
All

typical features of antimuscarinic drugs and alpha blockers

Tachycardia,

other arrythmias ECG: T wave suppression

Tolerance and DEPENDENCE

Tolerance to Anticholinergic, hypotensive and sedative effects will develop gradually Physical dependence occurs Malaise, chills, muscle pains

Know this too ! Electro-convulsive therapy ( Shock treatment) for severely depressed and suicidal patient

Uses of TCAs
Major

Depression Bipolar Depression Obsessive Compulsive Disorder (OCD) Anxiety Disorders

Phobias Panic

Disorders Attention Deficit Hyperactivity Disorder (ADHD)

Eating

Disorders (Anorexia Nervosa and Bulimia Nervosa)

Stress Syndrome

(PTSD) Schizo-affective Disorders Schizophrenia along with anti-psychotics

Non-Psychiatric Uses
Chronic

pain syndromes Migraine Pruritis

Adverse Effects of TCAs

Extension ANS

of The actions

Anticholinergic Effects CVS Postural Hypotension Cardiac Arrhythmias ECG Abnormalities- T Wave inversion AV Conduction abnormalities

CNS

Mania or hypomania Sedation Increased appetite and weight gain Lowered seizure threshold Miscellaneous Sexual Dysfunction Rashes, jaundice rare

Toxicity-Overdose of TCAs
Life threatening- very serious Overdose common in already depressed

patients All above adverse effects are pronounced Cardiotoxicity, Anticholinergic effects, Respiratory depression, Convulsions Coma and death may occur

Treatment of Toxicity
1. Symptomatic Gastric Lavage Activated Charcoal Respiratory Support IV Fluids Maintain BP 2. Drugs Diazepam- Convulsions Propranolol, Lignocaine Na Bicarbonate- Acidosis

Drug Interactions Pharmacokinetic Interactions

Phenytoin, phenylbutazone and Aspirin displace TCAs from Plasma Proteins Phenobarbitone induces metabolism of TCAs while Carbamazepine inhibits metabolism of TCAs SSRIs inhibit the metabolism of TCAs leading to toxicity By their anti-cholinergic properties, the absorption of drugs may be increased or decreased

Pharmacodynamic Interactions
Potentiate actions of directly acting sympathomimetics Inhibit actions of indirect acting sympathomimetics Block actions of Guanethedine and Clonidine by preventing their transport into adrenergic neurons Potentiate CNS depressants including alcohol

With MAOIs may cause hypertensive crisis With other Anti-cholinergics, added Anticholinergic effects Increases alpha blocking effect with other alpha blockers Increased sedation with antihistamines

Selective Serotonin Reuptake Inhibitors (SSRIs)

Fluoxetine Sertraline Paroxetine Citalopram

Mechanism of Action
Specific serotonin uptake inhibitors increase 5-HT by inhibiting reuptake. Delayed mechanisms Desensitization of 5-HT1A,D,7 Autoreceptors Decrease in 5-HT2A receptors

Uses Of SSRIs
Similar

to TCAs They are preferred over TCAS because of lesser adverse effects Do not cause toxicity in overdose They both have same efficacy

Adverse Effects of SSRIs

Nausea,

vomiting, headache Sexual Dysfunction Interferes with orgasm or ejaculation Mild anxiety, restlessness and insomnia Mania or hypomania

Differences Between SSRIs and TCAs

SSRIs-Advantages: Less or no effect on H1 receptors Less or no effect on Muscarinic Receptors Less effect on Alpha-1 Receptors No seizure precipitating property No cardiotoxicity Less weight gain SSRIs: Disadvantage: are enzyme inhibitors

Similarities Between TCAs and SSRIs

Both have similar uses Both have similar efficacy Both cause sexual dysfunction Both may cause mania or

hypomania

Drug Interactions of SSRIs

Inhibit

drug metabolizing enzymes, thus cause increased levels of Warfarin Beta Blockers Carbamazepine

TCAs Haloperidol Clozapine Benzodiazepines

Monoamine Oxidase Inhibitors (MAOIS)

Hydrazine Derivatives

Phenelzine Isocarboxazid Iproniazid Non-Hydrazine Derivatives Tranylcypromine Meclobemide

X. MAO INHIBITORS
Developed

for the treatment of tuberculosis (iproniazid derivatives) - 1951. These drugs are not widely used today, although a small number of patients appear to do better with MAOIs than TCAs or the newer drugs. Effects persist even after these drugs are no longer detectable in plasma (1-3 weeks).

Mechanism of Action
MAO enzyme metabolizes catecholamines Two types: MAO-A: Metabolizes norepinephrine, serotonin and tyramine MAO-B: Metabolizes Dopamine Important way of terminating action of catecholamines

MAOIs Inhibit MAO enzymes (nonselective): 1) Irreversible MAO inhibitors Phenelzine and isocarboxazid => hydrazides. 2) Reversible MAO Inhibitors. Tranylcypromine => non-hydrazide Prolonged blockade, but reversible within 4hr. Decrease metabolism of most biogenic amines (NE, 5HT, DA, tyramine)

Selective MAOIs:
Inhibitors

of MAO-A Meclobemide, Clorgyline Inhibitors of MAO-B. Deprenyl, Selegiline (Used in Parkinsonism, not depression)

Mechanism
Acute

administration causes: NE and 5-HT in synaptic terminals in brain but NE in PNS. NE synthesis and turnover administration causes: NE-stimulated cAMP in brain. Down regulation of receptors. Down regulation of 5-HT2 receptors.

Chronic

Figure 31-3: Monoamine Oxidase Inhibitors: Mechanism of Action

Menu

Uses of MAOIs
LESS

USED Depression especially not responding to SSRIs or TCAs Atypical Depression Bulimia OCD

Adverse Effects
Sexual

Dysfunction Sedation Weight gain Urinary hesitancy Hepatotoxicity

Drug InteractionsWine-and-Cheese Reaction

Fatal interaction with tyramine-containing foods (fermented foods in particular, such as wine and cheese). MAO-A => Tyramine in the body => NE in circulation => induces hypertensive crisis => can lead to intracranial bleeding and other organ damage.

Foods that Contain Tyramine

cheese, chicken

liver, Tomatoes, ketchup beer, red wine

Smoked/pickled

or aged meats, Many types of fish Poultry (herring, sausage, corned beef, salami, pepperoni) Yeast extracts Italian broad beans (fava beans)

Thus

MAOIs are less used because of the dietary inhibitions

Drug InteractionsSerotonin Syndrome

Occurs

when combined with SSRIs Hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status and vital signs. Treat with BZD or dantrolene

Drug InteractionsHyperexcitation Syndrome

Interaction with drugs metabolized by MAOs (e.g. Meperidine (opioid analgesics) => hyperpyrexia or hyperexcitation syndrome involving high fever, delirium and hypertension).

OTHER DRUG INTERACTIONS

Hypertensive

crisis when combined with sympathomimetics (e.g., decongestants found in OTC cold remedies) Inhibition of Metabolism of many drugs
Thus

it is important to wait up to 6 weeks after medication is stopped, before starting with another drug.

Hetrocyclic Anti-depressants
They

all have different mechanisms of action and different adverse effects

Buproprion Nefazodone Venlafaxine

Mechanisms
1) NE reuptake inhibitors Maprotiline, Amoxapine 2) 5-HT receptor antagonism (5HT2A or 2C receptors) Nefazodone, Mirtazepine, 3) Dopamine reuptake Inhibitor Bupropion

Overview
3

Major classes of Antidepressants

TCAs SSRIs MAOIs