Antidepressant

ANTIDEPRESSANT DRUGS

Amene T.(B.Pharm, Msc)

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Session objectives Describe MoA and characteristics of TCAs,

including receptor interactions, adverse effects Identify the drugs classified as SSRIs and SNRIs,

and describe their characteristics, including clinical uses, adverse effects and toxicity, and potential drug interactions.

Identify drugs thought to act via block of serotonin receptors, and describe their characteristics including clinical uses, adverse effects and toxicity, and potential drug interactions.

Be aware of the limited role of MAO inhibitors in affective disorders

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Depression

An affective disorder characterized by changes in mood;

Distinct from schizophrenia which produces disturbances of thought

For mood there is a complex interrelationship between noradrenergic, serotonergic (5H-T) and possibly dopaminergic pathways in the CNS.

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Causes of depression

Emotional factors;

Divorce, financial problems, home problems, grief, relationship

ending, death in the family,

Medical conditions;

Chronic diseases, hormonal disturbances, metabolic disorders,

dehydration.

Drugs;

Reserpine, Alpha methyl dopa, Beta blockers, hormonal

contraceptives, corticosteroids.

Postpartum

Alcohol abuse 4

Classification of Major Affective Disorders The most common mood disorders

are

Major/endogenous depression

(unipolar depression)

Bipolar disorder (Mania)

Atypical depression

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Major Endogenous Depression Core Symptoms (nearly daily): five or more Depressed moodLoss of interest in pleasurable activities, WithdrawnSignificant wt. change (loss/gain)Sleep disturbancePsychomotor agitation or retardationFatigue or loss of energy

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Major Endogenous Depression Core Symptoms (nearly daily): five or moreFeeling of worthlessness (Low self esteem, feelings of guilt, inadequacy) Diminished ability to think or concentrate; Indecisiveness, loss of motivation.Recurrent thoughts of death, suicidal ideation (attempt or plan)

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Biological Basis for Depression1. Has a genetic component.2. Depression can be drug-induced.

Reserpine, a drug used in the treatment of HTN and schizophrenia can cause depression because it depletes the vesicular storage of amine NTs (NE, 5-HT, DA).

3. Depression can be treated with Electroconvulsive Therapy (ECT)

ECT causes a massive release of NTs & Is an effective approach

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Neurons are intact but the problem is in neurotransmission

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Biogenic Theory of Depression The precise cause of affective

disorders remains elusive. Evidence implicates alterations in the

firing patterns of a subset of biogenic amines in the CNS, Norepinephrine (NE) and Serotonin (5-HT).

Activity of NE and 5 -HT systems!.

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NE System Almost all NE pathways in the brain originate from

the cell bodies of neuronal cells in the locus coereleus in the midbrain, which send their axons diffusely to the cortex, cerebellum and limbic areas (hippocampus, amygdala, hypothalamus, thalamus).

Mood: -- higher functions performed by the cortex. Cognitive function: -- function of cortex. Drive and motivation: -- function of brainstem Memory & emotion: -- fun. of the hippocampus &

amygdala Endocrine response: -- function of hypothalamus.

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Serotonin System

As with the NE system, serotonin neurons located in the pons and midbrain (in groups known as raphe nuclei) send their projections diffusely to the cortex, hippocampus, amygdala, hypothalamus, thalamus, etc. -- same areas implicated in depression. This system is also involve in:

• Anxiety• Sleep• Sexual behavior• Rhythms (Supra-chiasmatic nucleus).• Temperature regulation• CSF production

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Most antidepressants in clinical use today act by enhancing the neurotransmission of serotonin [5-HT], norepinephrine [NE], or both.

They do so either by blocking the reuptake (transport) of neurotransmitter, blocking the metabolism of neurotransmitter [i.e., monoamine oxidase (MAO) inhibitors], or by direct action on a NT receptor.

Hence, the antidepressants can be classified on the basis of their putative mechanisms of action.

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The monoamine theory doesn't fully address the issue of depression b/c

1. There is a disparity – though antidepressants cause an increase NT synaptic level immediately, their therapeutic onset is very slow usually after 2- 4 weeks. This may explain there may be involvement of

adaptive response to signal transduction components of increased synaptic level of NTs which can be related with therapeutic response.

2. Effective antidepressants are there with a different MOA

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Especially Beta and 5-HT receptors

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Agents that block NT reuptake Can be further divided into

TCAs with mixed action: nonselective Serotonin-selective reuptake inhibitors

(SSRIs), NE-selective reuptake inhibitors (NSRI) Serotonin & norepinephrine selective

reuptake inhibitors (SNRIs)Newer non-selective agents are referred that way to distinguish them from the nonselective TCAs

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A newer category of antidepressants is the "Heterocyclic Antidepressants," to differentiate them from other known antidepressants (most of which also happen to be heterocyclic!).

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Can also be classified as:-

1. Typical antidepressants w/c includes- TCAs & MAOIs.

2. Atypical antidepressants- they belong to the different chemical structure are heterocyclic compounds with again second and third generation antidepressant classification.

E.g. Amoxapine, Bupropion, Duloxetine, Maprotiline, Mirtazapine, Nefazodone, Trazodone, Venlafaxine

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Medication 5-HT NE DA

BA (Oral)

Protein

Binding

t1/2 (in hours)

(Active Metabolite)

Selective Serotonin Reuptake InhibitorsFluoxetine + + +

+0/+ 0 80% 95% 24–72 (146)

Sertraline + + + +

0/+ + >44% 95% 26 (66)

Paroxetine

+ + + +

+ 0 64% 99% 24

Citalopram

+ + + +

0 0 80% <80% 33

Escitalopram

+ + + +

0 0 80% 56% 27–32

Serotonin Norepinephrine Reuptake InhibitorsVenlafaxine

+ + + +

+ + + 0 92% 27% 4 (10)

Duloxetine

+ + ++

++++

0 50% >90% 12 (8–17)

Norepinephrine Reuptake InhibitorsBupropion 0/+ + + >90% 85% 10–21

0, negligible; +, very low; + +, low; + + +, moderate; + + + +, high.

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Antidepressants

1. Tricyclic anti-depressants (TCAs).Imipramine, desipramine, nortriptyline,protryptyline, amytriptiline, doxepin.

2. Monoamine oxidase inhibitors (MAOIs).Isocarboxacid, phenelzine, tranylcypromine.

Both termed as Classical antidepressants3. Selective serotonin reuptake inhibitors (SSRIs)

Fluoxetine, sertraline, paroxetine, trazodone.4. Atypical anti-depressants (Others)

New TCAs, amoxapine, bupropion,alprazolam, maprotiline, nomifensine, mianserin.

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*A - SSRIs and MAOIs desensitize the inhibitory 5-HT1A somato dendritic receptors.

*B SSRIs and MAOIs desensitize the inhibitory 5-HT1B/5-HT1D inhibitory auto receptor on the presynaptic terminal.

After acute administration, the TCAs and the SSRIs inhibit the uptake of 5-HT into the nerve terminal by binding to the imipramine binding site (or its equivalent).

*C TCAs and most non-SSRIs second generation antidepressants sensitize the postsynaptic 5-HT1A receptors thereby increasing serotonergic function

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*D There is experimental evidence that the activity of the 2nd messenger system associated with the 5-HT2A receptor is decreased following chronic antidepressant treatment.

There is also circumstantial evidence that the G protein coupling mechanism between the 5-HT2A receptor and its second messenger is hypo-functional in depressed patients but normalizes following effective treatment.

This suggests that some antidepressants may improve the receptor–2nd messenger G protein coupling mechanism.

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Tricyclic Antidepressants (TCAs) Amitriptyline

Imipramine

Desipramine

Nortriptyline

Protryptyline

Doxepin.27

Tricyclic Antidepressants (TCAs) Between 1960 and 1990 TCAs

represented the major pharmacological treatment for depression.

They have been considered a homogeneous group of drugs differing mostly in their potency to inhibit presynaptic norepinephrine or serotonin uptake and in their propensity for causing variety of unwanted effects.

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Tricyclic Antidepressants (TCAs) The TCAs induce

Anticholinergic, Antihistaminergic, and Cardiotoxic SEs which are related to

their action on muscarinic (mainly M1), Histamine (H1), Adrenergic (α1) receptors and Cardiac Na+ and Ca2+ channels.

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Tricyclic Antidepressants (TCAs) Most are incompletely absorbed, All are metabolized in liver => High first pass

effect

1. Transformation of the tricyclic nucleus => hydroxylation => conjugation => glucoronides.

2. Alteration of aliphatic side chain => demethylation of the nitrogen => active metabolites.

High protein binding, High lipid solubility.

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Medication 5-HT NE DA

BA (Oral)

Protein

Binding

t1/2 (in hours)

(Active Metabolite)

Tricyclic AntidepressantsDesipramine

+ + + + +

0/+ 51% 90% 12–28

Nortriptyline

+ + + + + 0 50% 92% 18–56

Amitriptyline

+ + + +

+ + + +

0 41% 95% 9–46 (18–56)

Imipramine

+ + + + + 0/+ 27% 95% 6–28 (12–28)

Doxepin + + + + 0 27% 70% 11-23

OthersMirtazapin

e

+ + + + + + +

0 50% 85% 20–40

0, negligible; +, very low; + +, low; + + +, moderate; + + + +, high.

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TCAs: MOA Inhibition of NT reuptake. Immediate action = > NE and 5-HT

in synapse. After chronic treatment (2 - 4 weeks)

= > * Adaptive Responses * (dec -AR & 5HT2A R)

Takes up to 4 weeks for all TCA to have an effect.

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TCAs: Side Effects

Atropine-like side effects: dry mouth, constipation, blurred vision, mydriasis, metallic taste, urine retention => muscarinic blockade.

Orthostatic hypotension => 1-AR B Drowsiness, sedation and weight gain

=> Histamine-Receptor blockade.

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TCAs: Side Effects (cont.)

Most serious side effect is cardiac toxicity => Palpitations, tachycardia, dizziness => excessive CNS stimulation => NE in Heart.

Sexual dysfunction, including loss of libido, impaired erection and ejaculation.

COMPLIANCE35

TCAs: Other effects (cont.)

Metabolism is affected by: Smoking, Barbs, estrogens, neuroleptics and anticonvulsants.

Can lower seizure threshold. Vagal block, postural hypotension, arrhythmias,

sinus tachycardia. Potentiate CNS depressants (BZDs, Barbs,

ETOH) => coma and death. Fatal in overdose (a 2 wk. supply can kill

anyone). Lethal dose ≥ 2 gram – restriction on dispensed

dose for reducing fatal acute toxicity

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MAO Inhibitors

MAO-A NE, 5-HT, Tyramine MAO-B DA Selective MAOIs: Inhibitors MAO-A: Moclobemide,

Clorgyline, Paragyline Inhibitors of MAO-B: Selegiline

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MAO Inhibitors

Are readily absorbed from GI tract and widely distributed throughout the body.

May have active metabolites, inactivated by acetylation.

Effects persist even after these drugs are no longer detectable in plasma (1-3 weeks).

Hence they have to be a minimum of 2 weeks gap before the patient receives MAOIs or after cessation of use of MAOIs with OTC drugs - wash out period.

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MAO Inhibitors: MOA

Inhibit MAO enzymes (non-selective):inhibition of MAOA is relevant for antidepressant effect

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, octopamine).

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MAO Inhibitors: MOA

Acute administration causes: NE and 5-HT in synaptic terminals in brain

but NE in PNS. NE synthesis. Acute euphoria Suppressed REM sleep.

Chronic administration causes: NE-stimulated cAMP in brain. Down regulation of receptors. Down regulation of 5-HT2 receptors.

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MAOIs: Wine-&-Cheese Rxn Major limitation, food and drug

interaction. 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.

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MAOIs: Wine-&-Cheese Rxn… DA & tyramine are metabolized by both

MAO isozymes & both types are inhibited by phenelzine, tranylcypromine, and isocarboxazid.

Tyramine is an indirectly acting amines, which must be taken up by sympathetic neurons to release NE

Capable of causing – Hypotension (seems paradoxical), excessive CNS stimulation, wet gain, atropine like effect

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MAOIs: Negative drug intrxns with Any drug metabolized by MAOs* including

SSRIs, TCAs and meperidine, alcohol, CNS depressants, sympathomimetics, phenylephrine (O/C nasal decongestants), amphetamines, and other indirect-acting adrenergic drugs.

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

Other side effects: Hypotension, Hepatotoxicity, Sedation

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SSRIs

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 NT, serotonin (5-hydroxytryptamine or 5-HT), in the synaptic gap by inhibiting its re-uptake.

Instead of being discovered by accident, SSRIs were specifically designed while considering the biological causes of depression.

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SSRIs

Are described as 'selective' because they affect only the reuptake pumps responsible for 5-HT, as opposed to earlier antidepressants, w/c affect other monoamine NTs as well.

B/se of this, SSRIs lack some of the SEs of TCAs & MAOIs. No autonomic side effect No food and drug interaction While Efficacy is equivalent to TCAs But expensive in cost.

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SSRI Drugs

Include many of the popular drugs on market today

• Fluoxetine, Sertraline, Paroxetine, Fluvoxamine

Fluoxetine Sertraline

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Mechanism of action:

Specific serotonin uptake inhibitors increase 5-HT by inhibiting reuptake.

Enhanced stimulation or responsiveness of postsynaptic 5-HT receptors is particularly important in the action of antidepressants.

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Most widely prescribed drugs for depression. They have few side effects and seem to be rather

safe. More rational prescribing & better patient

compliance. Adverse effects include: nausea, decreased libido,

decrease sexual function. Low threat for overdose. Suicide may be considered in severe depression. Cause weight loss, unlike most antidepressant

drugs SSRIs cause weight loss

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Fluoxetine (Prozac)

The first of a new class, SSRIs ~ 70% pts respond to SSRI therapy at the end

of 6 weeks Paroxetine & Sertraline have PK similar to TCAs. It is chemically unrelated to tricyclic,

tetracyclic, or other available antidepressant agents.

Eliminated very slowly. Half-life after a single dose is 2 days 20-60 mg/d standard dose

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Fluoxetine (Prozac)

Common side-effectsAnxiety, restlessness, trembling, weakness, skin rash, Anorgasmia, itching, and a decrease in sexual drive.

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Fluoxetine & paroxetine

Inhibit liver enzymes, CYP- 2D6. Concomitant therapy with drugs also

metabolized by this enzyme system (such as TCA) may lead to drug interactions.

Wide range of D/I, notably with MAOIs

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Drug-Drug interactions:

Dangerous with other antidepressant drugs, MAOIs in particular.

“Serotonin Syndrome” e.g. MAOIs + SSRIs or SNRIs + lithium.

hyperthermia, cognitive reactions, muscle rigidity, myoclonus, rapid changes in mental status and vital signs.

Thus it is important to wait up to 2- 6 weeks after medication is stopped, before starting with another drug.

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Heterocyclics

2nd generation heterocyclics Amoxapine Maprotiline Trazodone Bupropion

Third generation heterocyclics Mirtazapine Venlafaxine Nefazodone

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Heterocyclics

As with the TCA's , they all have variable BA

High protein binding. Some have active metabolites. Trazodone and Venlafaxine have the

shortest plasma half-lives, which mandates divided doses during the day.

Nefazodone and fluvoxamine cause inhibition of CYP3A4.

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5-HT & NE Reuptake Inhibitors (SNRIs) SNRIs were developed more recently than

SSRIs, and there are relatively few of them. Their efficacy as well as their tolerability

appears to be somewhat better than the SSRIs, owing to their compound effect.

These new drugs, because of their specificity for the serotonin and norepinephrine reuptake proteins, lack most of the adverse side effects of TCAs & MAOIs.

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Venlafaxine

The first and most commonly used SNRI. Exhibits dual presynaptic inhibition of serotonin

and noradrenaline reuptake Active metabolite, O-desmethylvenlafaxine

(ODV), It is used primarily for the treatment of

depression, GAD, and social anxiety disorder in adults.

Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α-1 adrenergic receptors

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Venlafaxine Dosage and Side Effects 75mg-225mg per day Because of its relatively short half-life of 4

hours, should be administered in divided dosages throughout the day.

Side effects may include nausea, dizziness, sleepiness, abnormal ejaculation, sweating, dry mouth, stomach pain, abnormal vision, nervousness, insomnia, loss of appetite, constipation, confusion/agitation, tremors, and drowsiness.

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NE & DA Reuptake Inhibitor (NDRI)

The only antidepressant in this group is Bupropion,

Chemically unrelated to tricyclics or SSRIs. It is similar in structure to the stimulant

cathinone, and to phenethylamines in general. Selective catecholamine (NE & DA) reuptake

inhibitor. It has only a small effect on serotonin reuptake. It does not inhibit MAO. Metabolized in the liver; has active metabolites The half-life of 20-33 hrs

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Medication SedationAgitation/Insomnia

Anticholinergic

Effects Orthostasis

GI Effects (Nausea/Di

arrhea)

Sexual Dysfunctio

nWeight Gain

Tricyclic Antidepressants

Desipramine (Norpramin) + + + + + + + + 0/+ + + +

Nortriptyline (Pamelor) + + + + + + + 0/+ + + +

Amitriptyline (Elavil) + + + + 0/+ + + + + + + + + 0/+ + + + + +

Imipramine (Tofranil) + + + 0/+ + + + + + + + 0/+ + + + +

Doxepin (Sinequan) + + + + 0/+ + + + + + + + + 0/+ + + + +

Selective Serotonin Reuptake Inhibitors

Fluoxetine (Prozac) + + + + + 0/+ 0/+ + + + + + + + +

Sertraline (Zoloft) + + + + 0/+ 0 + + + + + +

Paroxetine (Paxil) + + + + + ++ 0 + + + + + + +

Citalopram (Celexa) + + + + 0/+ 0 + + + + ++

Escitalopram (Lexapro) + + + 0/+ 0 + + + + ++

0, negligible; +, very low; + +, low; + + +, moderate; + + + +, high.

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Medication

Sedation

Agitation/

Insomnia

Anticholinergic

Effects

Ortho

stasis

GI Effect

s (N/D)

Sexual

Dysfn

Weight

GainSerotonin Norepinephrine Reuptake Inhibitors

Venlafaxine (Effexor)

+ + + + + 0 + + + + + + +

Duloxetine (Cymbalta)

+ + ++ + 0 + ++ ++ 0/+

Norepinephrine Reuptake InhibitorsBupropion (Wellbutrin)

0 + + + + 0 + 0/+

OthersMirtazapine (Remeron)

+ + + + 0 + + 0/+ + 0/+ + + +

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Other uses of Antidepressants Enuresis – TCA

ADHD – TCA

Neuropathic pain – TCA

OCD – SSRI / Clomipramine

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Mania

Mania alone is rare (10%) and Most frequently cycles with

major/endogenous depression (manic-depressive disease, bipolar disorder).

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Core Symptoms for manic episodes Five or more Inflated self-esteem Decrease need to sleep. More talkative than usual or pressure to keep

talking, go on-and-on about the things they will do. Flighty of ideas Distractibility (attention too easily drawn) Excessive involvement to pleasurable activities Psychomotor agitation Predominant mood is irritability, violence and

impatience

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Anti-Manic Drugs (mood stabilizers) Lithium (Li+) carbonate or Li+-citrate DOC for treatment of acute manic episodes Lithium alone, or in combination with:

Carbamazepine Valproic acid Lamotrigine

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MOA of Li+

Interfere activity of G-proteins (keep in less active state)

A selective action is to inhibit inositol mono-phosphatase and thus interfere with phosphatidylinositol pathway.

This leads to decrease in cerebral inositol concs. interfere neurotransmission mxms by affecting phosphatidylinositol pathway.

Also leads to a decreases in protein kinases fxn in brain tissue, including PK-C; this effect also is shared with valproic acid.

Thus, may alter release of amine NTs.

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Inhibit breakdown of IP2 to IP1 (during PIP hydrolysis) => depletion of DAG and IP3 and [Ca2+] in response to receptor activation (i.e. from 5-HT2R, 1-AR, glutaminergic receptors and others)

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Adverse effects of Lithium

Therapeutic conc. of Li should be 0.5- 1.5 mmol/L If >1.5 mmol/l comma is possible.

Toxicity increases by drugs/situations that increase plasma conc. Diuretics leads to depletion of Na+, particularly

thiazides (Li+ clearance is reduced by 25%) Some NSAIDs (indomethacin) facilitate PT

reabsorption In renal disease (reduced GFR)

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Adverse effects of Lithium

Inhibits ADH => diuresis: polyuria & polydipsia – nephrogenic diabetes insipidus

May decrease thyroid function Tremors, weight gain, acne; seizures

and arrhythmia Teratogenic (tricuspid valve

malformation)

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Anticonvulsants for bipolar disorder Valproic acid, carbamazepine: MOAReduce flux of ions through voltage gated ion channels such as Na+, K+, Ca2+Enhance inhibitory transmission with GABA by increasing its synthesis, release or inhibiting breakdownReducing excitatory neurotransmission with glutamate by reducing its releaseDecreases protein kinases fxn, including PK-C (valproic acid)

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Anti-Manic Drugs: Valproic Acid A known antiepileptic that has anti-

manic effects As effective as lithium during early

weeks of treatment May be used as first line for mania,

although it may not be as effective in maintenance treatment as lithium for some pts.

Nausea being limiting factor in some pts

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THANK YOU

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