Anti-depressants

• Depression is considered to be due to functional deficit of neurotransmitters like norepinephrine and / or serotonin.

• Antidepressants act by increasing the concentration of neurotransmitters norepinephrine and / or serotonin in the brain.

Anti-depressants

Drugs used in depression are :• Tricyclic Antidepressants (TCA).• Selective Serotonin Reuptake

Inhibitors (SSRI).• Atypical Antidepressants.• MAO-A inhibitors.

Anti-depressants

TCA : NE / 5-HT reuptake inhibitors : • Tertiary amines : Block reuptake of 5-HT

(serotonin) to a greater extent than NE.

Amitriptyline, Imipramine, Clomipramine• Secondary amines : Block the reuptake of

NE more than serotonin.

Desipramine, Nortriptyline, Amoxapine

Anti-depressants TCA

Anti-depressants

Adverse effects of TCA : • Antimuscarinic effects – dry mouth, blurred

vision and urinary retention.• Alpha-1 blocker – Hypotension. • Histamine -1 blocker – Weight gain. • Arrhythmia.• Seizures.• Induction of mania.

Anti-depressants TCATCA block α-1, muscarinic and histamine -1 receptors.

Anti-depressantsTCA Sedation Antimuscarinic

Hypotension

Imipramine(Tofranil)

++ +++ +++

Clomipramine(Anafranil)

+++ +++ +++

Amitriptyline(Elavil)

+++ +++ +++

Desipramine(Norpramin)

+ + +

Nortriptyline(Pamelor)

+ + +

Amoxapine* (Ascendin)

+ + +

Anti-depressants

Drug interactions of TCA : • Hypertensive crises when given with MAO

Inhibitors.• Serotonin syndrome with SSRI and MAO

Inhibitors.

Anti-depressants

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI):

• Fluoxetine (Prozac)

• Fluvoxamine (Luvox)

• Sertraline (Zoloft)

• Paroxetine (Paxil)

• Citalopram (Celexa)

• Escitalopram (Lexapro)

SSRI GI effects Sexual effects Agitation

Fluoxetine (Prozac)

++ +++ +++

Sertraline (Zoloft)

+++ +++ +

Paroxetine (Paxil)

++ +++ +/-

Fluvoxamine (Luvox)

++ +++ +/-

Citalopram (Celexa)

++ +++ +/-

Escitalopram (Lexapro)

++ +++ +/-

Anti-depressants

Adverse effects of SSRI: • Nausea.• Insomnia.• Sexual dysfunction.• Suicidal ideation• Weight loss initially but regained after 12

months.• Induction of mania/hypomania.

Anti-depressants

Drug Interactions of SSRI:• Most SSRI are inhibitors of cytochrome

P 450 and can ↑ levels of TCA.• One major contraindication of SSRI is the

concomitant use of MAOI. This is likely to cause severe serotonin syndrome.

• Serotonin syndrome characterized by restlessness, tremor, myoclonus, ↑↑ temperature and death.

Anti-depressants

SEROTONIN / NOR EPINEPHRINE REUPTAKE INHIBITORS : (SNRI):

Venlafaxine (Effexor):• It is a serotonin and NE reuptake inhibitor in

a dose dependent manner.• It does not block muscarinic, adrenergic, or

histaminic receptors.• It is used for the treatment of depression and

anxiety disorders.• Adverse effects includes nausea, sexual

dysfunction, hypertension, suicidal thoughts.

Anti-depressants

SEROTONIN / NOR EPINEPHRINE REUPTAKE INHIBITORS : ( SNRI ) :

Duloxetine (Cymbalta):• Used in major depression, anxiety and also

diabetic neuropathic pain.• It causes nausea and ↑ risk of suicide.

Anti-depressants

ATYPICAL ANTIDEPRESSANTS:Bupropion (Wellbutrin):• It is an inhibitor of reuptake of NE and

dopamine.• Used in ADHD and adjunct therapy for

cessation of smoking.• No weight gain and sexual dysfunction• Very less risk for “switching” to

mania/hypomania.• It causes seizures at high dose.

Anti-depressants

ATYPICAL ANTIDEPRESSANTS:

Mirtazapine (Remeron) :• It enhances the noradrenergic

transmission by blocking presynaptic α - 2 receptors

• It is a potent anti-histaminic with greater sedating effects and weight gain.

Anti-depressants

ATYPICAL ANTIDEPRESSANTS:

Trazodone (Desyrel), Nefazodone (Serzone)• These act mainly by blocking 5-HT-2A

receptors.• Trazodone causes sedation and priapism.• Nefazodone can cause serious hepatic

injury.

Anti-depressants

MAO INHIBITORS :

Phenelzine (Nardil), Tranylcypromine (Parnate), Moclobemide.

• MAO inhibitors are useful in atypical depression.

• MAO-A inhibitors are used when all other antidepressants are not useful and ECT refused.

MAO-Inhibitors

Anti-depressants

MAO INHIBITORS : Adverse effects :

Phenelzine, Tranylcypromine• The most common adverse effects of MAO

inhibitors is postural hypotension.• Anti-cholinergic side effects like dry mouth

are less common compared with TCA.• Impotence and anorgasmia are noted with

MAO inhibitors.

Anti-depressants

MAO INHIBITORS:Interactions:• MAO Inhibitors interact with tyramine –

dangerously leading to hypertensive crisis – cheese reaction.

• Avoid Cheese, Wine, Beer, Pickled fish, Brewer’s yeast, Fava beans, Beef, Chicken liver.

• Avoid sympathomimmetic drugs like phenylephrine.

Anti-depressantsSelegiline (Emsam):• It is the first MAO inhibitor in transdermal patch

form used for major depression.• It can be used without the dangers of dietary

interactions associated with oral MAOI.

St. John’s Wort : • This herbal medication is effective and safe for

mild or moderate depression.• The active ingredient is hypercium.• It inhibits MAO and also appears to block the

reuptake of serotonin.

Anti-depressants

Anti-depressant effect seen after 2-4 weeks

Anti-depressants

Uses of Antidepressants:• Enuresis – TCA • ADHD – TCA • Anxiety disorders like panic / phobia and

bulimia nervosa – SSRI • OCD – SSRI / Clomipramine• Neuropathic pain – TCA

SeizuresHypotension

Anticholinergic

SedationCardiac effects

Sexual effects

TCA +++ +++ +++ +++ +++ +++

SSRI + - - Insomnia - +++

Bupropion ++ - - Psychosis - -

MAOI + ++ +++ Insomnia - +++

Anti-depressants

Conclusions:

• SSRIs are safe and effective for the treatment of major depression.

• SSRIs are first line for chronic treatment of anxiety disorders including OCD.

• MAO inhibitors are effective for the treatment of atypical depression.

• Psychotic depressed patients usually requires ECT.

Bipolar disorder

Mood stabilizers

• LITHIUM is a monovalent cation• Lithium has a narrow therapeutic index• Lithium is used for prevention and the

treatment of bipolar disorder. • Valproate and carbamazepine are the

alternatives for the BPD.• Lamotrigine also acts as a mood stabilizer.

Mood stabilizers

MECHANISM OF ACTION: LITHIUM• Inhibits inositol monophosphatase and thus

interfere with phosphatidyl inositol pathways

• Decrease the recycling of inositol in the neuronal cell membrane.

• Decrease the cAMP.

Mood stabilizers

PHARMACOKINETICS OF LITHIUM:• Orally absorbed. • Slow onset. • Plasma levels ~ 1 meq / liter.• Thiazides, NSAIDS enhances lithium

toxicity.

Mood stabilizers

Adverse effects of Lithium :• Tremors, weight gain, acne.• Polyuria and polydipsia – nephrogenic

diabetes insipidus – Amiloride.• Hypothyroidism.• Seizures and arrhythmia.• Teratogenicity - Ebstein’s malformation.

Mood stabilizers

• Symbyax is a combination of olanzapine and fluoxetine for the treatment of bipolar depression.

• Aripiprazole (Abilify) is approved for the treatment of acute manic and mixed episodes associated with bipolar disorder.