Antidepressant drugs

Major depressive disorders characterized by pervasive mood altering illnesses affecting energy, sleep, appetite, libido and the ability to function.Depression is different from schizophrenia which produces disturbances in thought.

The symptoms of depression are:intense feelings of sadness;hopelessness;despair;the inability to experience pleasure in usual activities.

The amine theory proposes that depression is due to a deficiency of monoamines such as NA and serotonin (5HT) at certain key sites in the brain.All antidepressant drugs (also called thymoleptics) potentiate, either directly or indirectly, the actions of NA, dopamine (DA) and/or serotonin (5HT) in the brain.

Classification of Antidepressants

I) Monoamines re-uptake inhibitors:

Nonselective (Tricyclics (TCAs) and Tetracyclic)

Imipramine Doxepin

Maprotiline Amitriptyline

Selective Serotonin Reuptake Inhibitors (SSRIs)

Fluoxetine Sertraline Paroxetine

Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)

Venlafaxine Duloxetine

Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)*

Bupropion

*Atypical antidepressant

Classification of Antidepressants (Newer)

II) Monoamine Oxidase Inhibitors (MAOIs)

Moclobemide (selective type A)

Nialamide (non-selective – not used now)

III) Atypical antidepressants:

Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)

Nefazodone Trazodone

Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)

Mirtazapine

Noradrenaline Reuptake Inhibitor (NRI)

Reboxetine

Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)*

Bupropion

Contraindications to Use

Use cautiously in schizophrenia, mixed mania and depression

Suicidal tendencies

In severe renal, hepatic or cardiovascular disease

In narrow-angle glaucoma

Seizure disorders

TRICYCLIC ANTIDEPRESSANTS (TCAs)

Imipramine Desipramine

Clomipramine Amitriptyline

Nortriptyline Doxepin

Trimipramine

TETRACYCLIC ANTIDEPRESSANTS

Maprotiline

Amoxapine

MECHANISM OF ACTION of TCAs:

• All tricyclics block reuptake pumps for both 5HT and NE in nerve terminals by competing for binding site of the transport protein

So ↑ concentration of NE and serotonin in the synaptic

cleft & at the receptor site

Facilitation of NE and serotonin transmission ----

improves symptoms of depression.

Other MOA of TCAs

Blocking of receptors

TCAs also block :

Serotonergic receptors

Alpha adrenergic receptors

Histaminic receptors

Muscarinic receptors

Their role in therapeutic benefit is not known

These actions produce the adverse effects

PHARMACOLOGICAL ACTIONS

1- Elevate mood

2- Improve mental alertness

3- Increase physical activity

4- In non-depressed patients They cause sedation,

confusion & motor incoordination

Therapeutic uses of TCAs

Endogenous (Major) Depression -- moderate to severe.

Panic attack /acute episode of anxiety.

Imipramine is used for treatment of nocturnal enuresis in

children and geriatric patients as it constricts internal urethral

sphincter ( anti-muscarinic effect).

Generalized Anxiety Disorder .

Obsessive Compulsive Disorder

Attention Deficit Hyperkinetic Disorder .

Chronic neuropathic pains or Unexplained body pains.

Side Effects of TCAs

TCAs block:

- α1 adrenergic receptors

- H1 histamines receptors

- M1 cholinergic receptors

- 5HT2 receptors

Side Effects of TCAs

Side Effects of TCAs

ANTICHOLINERGIC EFFECTS

Sedation, Delirium, coma

Tachycardia

Mydriasis

Dry mucous membranes and skin

Dry mouth

Decreased or absent bowel sounds

Constipation

Urinary retention

CARDIOVSCULAR EFFECTS

1- Inhibit neuronal catecholeamines reuptake

leading to Cardiac arrhythmias

2- Inhibit alpha-adrenergic receptors induces

vasodilatation and Postural Hypotension

3- Membrane Depressant (quinidine like) effects

cause myocardial depression and cardiac

conduction disturbance due to:

* Sodium channel blockade

* Potassium channel blockade

SEIZURES

* Seizures occur as a result of inhibition of reuptake

of Norepinepherine and serotonin in the brain.

• TCAs lower the seizure threshold.

• The muscular hyperactivity from seizures combined

with decreased sweating can lead to severe

HYPERTHERMIA.

Death

Sudden Death Occurs from:

1- Ventricular fibrillation

2- Status Epilepticus

3- Hyperthermia

Interaction of TCA with other drugs

TCA (inhibitors of monoamine reuptake) should not be given with MAOIs (inhibitors of monoamine degradation) "hypertensive crisis".

Monoamine Oxidase Inhibitors

Monoamine Oxidase Inhibitors (MAOIs)

1- Irreversible and nonselective MAOIs (Classic MAOI)

Nialamide

- Can not distinguish between the two isoenzymes

- MAO-A and B enzyme activity can not be restored

unless new enzyme is synthesized, therefore the

effect of MAOIs persists for a period of 2-3 weeks

after stopping treatment, where a new (fresh)

enzyme has to be synthesized

2-Reversible and selective inhibitors of MAO-A:

- Moclobemide

(antidepressant action, Short acting)

3- Selective inhibitor of MAO-B:

- Deprenyl (neurodegenerative disorder)

- Selegiline (used in the treatment of

Parkinsonism)

MAO Enzyme

MAO-A: Metabolizes norepinephrine, serotonin and tyramine.

Inhibition of MAO-A produces Antidepressant effect .

MAO-B: specific for dopamine.

Inhibition of MAO-B produces Anti-parkinsonian effect.

Therapeutic uses of MAOIs

Considered to be the last –line agents due to

Drug / Food interactions

1. In endogenous depression, specially patients

non responsive / allergic to TCAs

2. Atypical depression

3. Phobic states

Side Effects of MAOIs

1- Hypotension: After MAO inhibition, other amines such as dopamine are able to accumulate in peripheral sympathetic nerve terminals and displace vesicular NA, thus reducing NA release and sympathetic activity (sympathetic block).

2- Antimuscarinic effects (atropine-like side-effects):

Dry mouth

blurred vision

Urinary retention

Side Effects of MAOIs

3- CNS stimulation:

Insomnia

Tremors

Excitement

Convulsions

4- Weight gain: associated with increased appetite

Drug interactions of MAOIs

1- MAOIs and SSRIs - Serotonin syndrome.

2- Levodopa:

precursor of dopamine can interact with

MAOIs leading to hypertensive crisis.

3- Amphetamine and Ephedrine:

Indirectly acting sympathomimetics can interact with MAOIs

causing the liberation of accumulated monoamines in

neuronal terminals leading to hypertensive crisis.

4-TCAs (inhibitors of monoamine reuptake) can interact

with MAOIs (inhibitors of monoamine degradation)

leading to hypertensive crisis.

This occurs when Tyramine rich foods are taken with

MAOIs.

Tyramine rich foods include Old cheese , Concentrated

yeast products, Pickled or smoked fish, Red beans, Red

Wine, Chicken liver, Sausages.

Tyramine in food is normally degraded in the gut by

MAO-A.

Since the enzyme is inhibited by MAOIs, tyramine from

ingested food is absorbed, and then taken up into

adrenergic neurons where it is converted into

octopamine - a false transmitter which causes massive

release of NE and may result in hypertensive crisis ;

severe hypertension, severe headache and fatal

intracranial haemorrhage.

The special advantage claimed for Moclobemide. is

that, No cheese reaction occurs with its use.

Selective 5-HT reuptake inhibitors

(SSRIs)

- Fluoxetine

- Paroxetine

- Sertraline

Selective Serotonin Reuptake Inhibitors

The SSRIs are currently the most widely utilized class of antidepressants in clinical practice.

They act within the brain to increase the amount of the neurotransmitter, serotonin (5-hydroxytryptamine or 5-HT), in the synaptic gap by inhibiting its re-uptake.

Therapeutic Uses of SSRIs

Same as for TCAs, in addition effective in the following conditions

Depression.

Anxiety Disorder.

Eating disorders- bulimia nervosa (fluoxetine).

Post traumatic stress disorder.

Premenstrual dysphoric disorder.

Attention Deficit Hyperkinetic Disorder.

Treatment of premature ejaculation.

Adverse effects of SSRIs:

GIT symptoms: Nausea, vomiting & diarrhea.

Changes in appetite - weight loss/ gain.

Anxiety & Tremors.

Sexual dysfunction: Loss of libido , delayed ejaculation.

Discontinuation syndrome:

Symptoms are headache ,malaise & flu like symptoms, agitation , irritability & nervousness

Drug interactions of SSRIs

SSRIs are potent inhibitors of liver microsomal enzymes.

Therefore they should not be used in combination with TCAs

because they can inhibit their metabolism increasing their

toxicity.

SSRIs should not be used in combination with MAOIs because of

the risk of life-threatening "serotonin syndrome" (tremors,

hyperthermia, cardiovascular collapse and death). Both drugs

require a "washout" period of 6 weeks before the administration

of the other.

Atypical antidepressants: bupropion, mirtazapine, nefazodone, trazodone

BupropionBupropion is a weak dopamine and norepinephrine reuptake inhibitor that is used to alleviate the symptoms of depression. Bupropion is also useful for decreasing cravings and attenuating withdrawal symptoms of nicotine in patients trying to quit smoking.Side effects may include dry mouth, sweating, nervousness, tremor, and a dose dependent increased risk for seizures. It has a very low incidence ofsexual dysfunction.

MirtazapineMirtazapine enhances serotonin and norepinephrine neurotransmission by serving as an antagonist at presynaptic α2 receptors. Additionally, some of the antidepressant activity may be related to antagonism at 5-HT2 receptors. It is sedating because of its potent antihistaminic activity, but it does not cause the antimuscarinic side effects of the TCAs, or interfere with sexual function like the SSRIs. Increased appetite and weight gain frequently occur. Mirtazapine is markedly sedating, which may be an advantage in depressed patients having difficulty sleeping.

Nefazodone and trazodoneThese drugs are weak inhibitors of serotonin reuptake. Their therapeutic benefit appears to be related to their ability to block postsynaptic 5-HT2a receptors. Both agents are sedating, probably because of their potent histamine H1-blocking activity. Trazodone is commonly used off-label for the management of insomnia. Trazodone has been associated with priapism, and nefazodone has been associated with a risk for hepatotoxicity. Both agents also have mild to moderate α1 receptor antagonism, contributing to orthostasis and dizziness.

Mood Stabilizers

In bipolar affective disorder patients suffer episodes

of mania, hypomania and depression, classically

with periods of normal mood in between.

Manic episodes involve greatly elevated mood, often

interspersed with periods of irritability or undue

excitement, accompanied by biological symptoms

(increased energy, restlessness, decreased need for

sleep, increased sex drive), loss of social inhibitions,

irresponsible behaviour and grandiosity. Psychotic

features may be present, particularly disordered

thinking, manifested by grandiose delusions and

“flight of ideas” with rapid speech.

Hypomania is a less dramatic and dangerous

presentation but retains the features of elation or

irritability and the biological symptoms, abnormalities

in speech and in social conduct to overfamiliarity

and mild recklessness.

Depressive episodes include depressive symptoms

described before and may include psychotic features.

Mood stabilizers

Indications: Bipolar, cyclothymia, schizoaffective, impulse control and intermittent explosive disorders.

Classes: Lithium, anticonvulsants, antipsychotics

Which you select depends on what you are treating and again the side effect profile.

Lithium

Only medication to reduce suicide rate.

Effective in long-term prophylaxis of both mania and depressive episodes in 70+% of BAD I pts

Factors predicting positive response to lithium

Prior long-term response or family member with good

response

Classic pure mania

Mania is followed by depression

Lithium

Mechanism of action

Not fully understood

- The main effect of lithium is probably to inhibit hydrolysis of

inositol phosphate, so reducing the recycling of free inositol for

synthesis of phosphatidylinositides.

- Mood-stabilizing effect has been postulated to reduction of

catecholamine neurotransmitter concentration

- Possibly related to Na-K-ATPase to improve membrane transport

of Na ion

- Alternative postulate that Li may decrease cyclic AMP

concentrations, which would decrease sensitivity of hormonal-

sensitive adenylcyclase receptors

Lithium side effects

Most common are GI distress including reduced appetite, nausea/vomiting, diarrhea

Thyroid abnormalities

Nonsignificant leukocytosis

Polyuria/polydypsia secondary to ADH antagonism. In a small number of patients can cause interstitial renal fibrosis.

Hair loss, acne

Lithium side effects

CNS: ataxia, dysarthria, choreoathetoid disturbances,

extrapyrimidal symptoms, confusion, tremor, epileptic

seizures, spasms, stupor, sedation, lethargy.

CVS: arrhythmia, hypertension, circulatory collapse.

Other effects: weight increase, muscular hypotonia,

thirst, rash etc.

Lithium toxicity

Mild- levels 1.5-2.0 see vomiting, diarrhea, ataxia, dizziness, slurred speech, nystagmus.

Moderate-2.0-2.5 nausea, vomiting, anorexia, blurred vision, clonic limb movements, convulsions, delirium, syncope

Severe- >2.5 generalized convulsions, oliguria and renal failure

Thanks!