seminar on antidepressants

ANTIDEPRESSANTS

Martha I. Dávila-García, Ph.D.

Howard University College of Medicine

Spring 2002

Classification of Major Affective Disorders

E pisoda lD epress ion

S easona lA ffec tiveD isorder

A typica lD epress ion

M a jor/E ndogenousD epress ion

M ania Bipola rdepress ion

M a jor A ffec tive D isorders

Episodal (reactive) Depression

Adverse life events.Physical illness.Hormonal steroids.Drugs.Other psychiatric disorders.

Reactive (episodal) Depression

More than 60% of all depressions.Core depressive syndrome: feelings

of misery, apathy, inadequacy, pessimism, anxiety, tension, guilt.

Bodily complaintsMay respond spontaneously or to a

variety of administrations.

Major Endogenous Depression

• Recurrent, Cyclic, Seasonal.

• Degree of depression is not adequate for precipitating event.

• Automaton (unresponsive).


Core Symptoms: • Feeling of misery, apathy and pessimism.• Withdrawn.• Low self –esteem, feelings of guilt, inadequacy and

ugliness.• Loss of interest in pleasurable activities.• Indecisiveness, loss of motivation.• Retardation of thought and action. Sleep

disturbance and significant weight change (without dieting or changes in appetite).

• Psychomotor agitation or retardation.


Core Symptoms (con’t): • In severe cases, it is accompanied by

hallucinations and delusions. • Recurrent suicidal ideation, a suicide attempt or a

specific suicide plan.

Mania

• Mania alone is rare (10%) and most frequently cycles with Major/endogenous depression (Manic-Depressive Disease, Bipolar Disorder).

Mania

Core Symptoms:• It is characterized by an elevated “high” mood.• Talkative, go on-and-on about the things they will

do. • Increased self-esteem.• Auditory hallucinations.• Decrease need to sleep.• Lack judgement, indiscrete.• SuperME

III. Biological Correlates of Depression

1. Hypersecretion of cortisol.

2. Escape from dexamethasone suppression.

3. Blunted TSH response to TRH.

4. Blunted GH response to hypoglycemia.

5. Altered 24hr rhythm of prolactin secretion.

6. Decreased 5-HT metabolites in plasma.

7. Decreased REM latency.

IV. Biological Basis for Depression

1. Has a genetic component.

2. Depression can be drug-induced.

3. Depression can be drug-repressed.

4. Depression can be treated with drugs.

5. Depression can be treated with

Electroconvulsive Therapy (ECT).

• 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?.

V. Biogenic Theory of Depression

VI. 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 and emotion: -- function of the

hippocampus and amygdala.• Endocrine response: -- function of hypothalamus.

and receptors.

VII. 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 (Suprachiasmatic nucleus).• Temperature regulation.• CSF production.

Antidepressants

• TCAs

MAOIs

SS

RIs

TCAs

TCAs

TCAs

TC

As

SSRIs

SSRIs

SS

RIs

SSRIs

MAOIs

MAOIsMAOIs

MAOIs

MAOIs

MAOIs

Venflaxine

Ven

flaxine

Ven

flaxine

MAOIs

MAOIs

maprotiline

Amoxepine

doxepin

isocarboxazide

Nortriptyline

Antidepressants

1. Tricyclic anti-depressants (TCAs).

Imipramine, desipramine, nortriptyline,

protryptyline, amytriptiline, doxepin.

2. Monoamine oxidase inhibitors (MAOIs).

Isocarboxacid, phenelzine, tranylcypromine.

3. Selective serotonin reuptake inhibitors (SSRIs)

Fluoxetine, sertraline, paroxetine, trazodone.

4. Atypical anti-depressants (Others)

New TCAs, amoxapine, bupropion,

alprazolam, maprotiline, nomifensine, mianserin.

Mechanism of Action

1. Inhibition of NE and 5-HT reuptake. (TCAs, SSRIs, Newer TCAs).

2. Inhibition of MAO enzymes.(MAOIs).

3. 5-HT2A and 5-HT2C antagonists.(Nefazodone, trazodone, mirtazapine)

4. Alteration of NE output . (Bupropion)

5. Stimulation of 5-HT1A receptors.(

6. 2–AR antagonists.(mirtazapine)

Tricyclic Antidepressants (TCAs)

•amytriptiline

• imipramine

•desipramine

•nortriptyline

•protryptyline

•doxepin.


• Characteristic three ring nucleus.• 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.


/ CH3 / H

N N

\ CH3 \ CH3

tertiary amine secondary amine

3o => 2o


3°Amines: Imipramine, Amitriptyline

2°Amines: Desipramine, Nortriptyline

Selectivity 2o Amines -- NE > 5-HT

3o Amines -- 5-HT > NE

Tricyclic Antidepressants (TCAs)Mechanism of Action:

- Inhibition of NT reuptake.

- Immediate action = > NE and 5-HT in synapse.

- 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.

Tricyclic Antidepressants (TCAs)Side Effects:

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

• Orthostatic hypotension => 1-AR and possibly 2-AR blockade.

• Drowsiness, sedation and weight gain => Histamine-Receptor blockade.

Tricyclic Antidepressants (TCAs)Side Effects (con’t):

• 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 and anorgasmia

. COMPLIANCE

Tricyclic Antidepressants (TCAs)Other effects (con’t):• Metabolism is affected by: Smoking, Barbs,

estrogens, neuroleptics and anticonvulsants.• Can lower seizure threshold.• All TCAs can cause: vagal block, postural

hypotension, arrythmias, sinus tachycardia.• All potentiate CNS depressants (BZDs, Barbs,

ETOH) => coma and death.• TCA administration in bipolar disorder may

precipitate acute mania or rapid cycling.• Fatal in overdose (a 2 wk supply can kill anyone).

X. MAO INHIBITORS

•Isocarboxacid

•Phenelzine

•Tranylcypromine.

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 in MAOIs than TCAs or the newer drugs.

• 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).

X. MAO INHIBITORS

Mechanism of action:Inhibit MAO enzymes (non-selective):

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).

X. MAO INHIBITORS

Mechanism of action (con’t):

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.

X. MAO INHIBITORS

MAO-A NE, 5-HT, Tyramine

MAO-B DA

Selective MAOIs:Inhibitors MAO-A

Moclobemide, Clorgyline Inhibitors of MAO-B.

Deprenyl, Selegiline

X. MAO INHIBITORS

Wine-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.

X. MAO INHIBITORS

Negative drug interactions with:

Any drug metabolized by MAOs* including SSRIs, TCAs and meperidine, alcohol, CNS depressants, sympathomimetics, phenylephrine (O/C nasal decongestants), ampetamines, and other indirect-acting adrenergic drugs.

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

X. MAO INHIBITORS

Other side effects:

• Hypotension

• Hepatotoxicity.

• Sedation.

XI. SSRIs

•Fluoxetine

•Sertraline

•Paroxetine

•Fluvoxamine(Labeled for obsessive-compulsive disorder)

XI. SSRIs

• Most widely prescribed drugs for depression.

• They have few side effects and seem to be rather safe. More rational prescribing and better patient compliance.

• Adverse effects include: nausea, decreased libido, decrease sexual function.

• Low threat for overdose. Suicide may be considered in severe depression.

XI. SSRIs

Mechanism of action:• Specific serotonin uptake inhibitors increase

5-HT by inhibiting reuptake.

Current theory holds that:• Enhanced stimulation or responsiveness of

postsynaptic 5-HT1A receptors is particularly important in the action of antidepressants.

XI. SSRIs

Fluoxetine is the prototype.• Approximately 70% of depressed patients will

respond to an SSRI therapy at the end of 6 weeks (4 to 6 weeks before effects are evident to patient).

• T1/2 of 16 – 24 hrs. except for fluoxetine’s metabolite norfluoxetine (T1/2 = 8 days).

• Fluoxetine and paroxetine inhibit liver enzymes, particularly P450-2D6.

• Paroxetine and Sertraline have PK parameters similar to TCAs.

XI. SSRIs

Drug-drug interactions:

dangerous with other antidepressant drugs, MAOIs in particular.

”Serotonin Syndrome”:– hyperthermia, muscle rigidity, myoclonus, rapid

changes in mental status and vital signs.

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

XII. Heterocyclics2nd Generation heterocyclics

• amoxapine• maprotiline• trazodone• bupropion

Third Generation heterocyclics• mirtazapine• venlafaxine• nefazodone

XII. Heterocyclics• The second and third generation antidepressants

are by no means a homogeneous group.• As with the TCA's , they all have variable

bioavailability.• 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.

XII. Heterocyclics

Mechanism of Action:1) NT reuptake inhibition.

maprotiline.2) 5-HT receptor antagonism (for 5-HT2A

or 2C receptors).nefazodone, mirtazapine, and trazodone

3) Alteration of NE Output.bupropion, amoxapine, and

trazodone.

XII. Heterocyclics

Amoxapine. Metabolite of Loxapine (an anti-psychotic) -- retains some antipsychotic activity and DA receptor antagonism => parkinson's-like symptoms. May be useful if psychosis is present. NE output.

Maprotiline. A tetracyclic drug, resembles desipramine with less sedative and antimuscarinic side effects. Evokes seizures at high doses. Blocks NT reuptake.

XII. Heterocyclics

Trazodone. Antagonist of 5-HT2A or 2C receptors. Unpredictable efficacy. Highly sedative (hypnotic), but minimal antimuscarinic action.

Bupropion. Resembles amphetamine. Blocks DA reuptake (not important in depression). Causes CNS stimulation. Inhibits appetite. Aggravates psychosis. NE output.

XII. Heterocyclics Third Generation

Mirtazapine. A derivative of mianserin. Antagonist of 5-HT2A or 5-HT2C receptors. Also antagonizes 2-adrenergic receptors, thus increasing NE and 5-HT release. Very sedating.

Venlafaxine. Short plasma half-live, thus needs to be given in divided doses. Potent inhibitor of 5-HT uptake and weaker at NE reuptake (at low concentrations it acts like an SSRI).

Nefazodone. Antagonist of 5-HT2A or 5-HT2C receptors. Moderately sedating. Potent inhibitor of CYP3A4, so cannot be given with cisapride

XII. Atypical/Heterocyclic 2nd Generation heterocyclics

• Amoxapine• Maprotiline• Trazodone• Bupropion

Third Generation heterocyclics• Mirtazapine• Venlafaxine• Nefazodone

Similar to TCAs

5-HT antagonists

2-AR antagonist

SSRI-like

NE output

Noradrenergic Control of Serotonergic Release

NE5-HT

NE

2-AR

1-AR

1 2 3

Mianserin

5-HT1

5-HT2

5-HT3

Receptors

XIV. Alternative Therapies

No way of a priori knowing which therapy will be best for a patient.

• Light Therapy

• Psychological Treatment

• ECT

• St. John’s Wort

XVI. Anti-Manic DrugsLithium (Li+) remains the drug of choice for the

treatment and prophylaxis of mania.• Acute manic episodes are managed with lithium

salts (carbonate or citrate) alone, or in combination with:

1) Antipsychotics (carbamazepine, similar in structure to TCAs but not effective in depression).

2) Valproic acid

3) Calcium-channel blockers (nifendipine, diltiazem, verapamil).

XVI. Anti-Manic Drugs

Li+

• Small monovalent cation (between H+ and Na+).

• Distributed in total body water, similar to sodium.

• May partially inhibit Na+-K+ ATPase.• Inhibits ADH => diuresis.• May decrease thyroid function.• Teratogenic (tricuspid valve malformation).• Excreted by kidney.


Li+

• Not to be taken with thiazide diuretics (e.g. chlorthiazide).

• Lithium clearance is reduced by 25%.

• All neuroleptics (with the exception of clozapine), produce more severe extrapyramidal syndromes when combined with lithium.


Li+

• Helps alleviate the depressive phase of bipolar illness.

• Useful in refractory depression when added to SSRIs or TCAs, but not a good antidepressant alone.


Li+

Mechanism of action:• Does not alter receptor numbers but alters the

coupling of the receptors with their second messengers by reducing coupling of G-proteins.

• Regulation of -AR and DAR.• Can reduce release of NTs (5-HT) and affinity of

binding to receptor.


Li+

Mechanism of action (Con’t):Inhibits 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, muscarinic receptors and others).

• Alterations in adenylate cyclase and phospholipase C.


PIP

PIP2

G IP3

IP2

IP1

InositolPI

X Li+

PLC

DAG

Ca 2+


Valproic AcidA well known antiepileptic has been found to

have antimanic effects. Shows efficacy equivalent as that of lithium during the early weeks of treatment and is being evaluated for maintenance treatment. Titrated well, the sedation can be controlled. Nausea being the only limiting factor in some patients.

May be used as first line treatment for mania, although it may not be as effective in maintenance treatment as lithium for some patients.

Mechanism of action: ???


CarbamazepineEffective as an antimania medication

Mechanism of action (Con’t):

May be due to decrease overexcitability of neurons (anticonvulsive effect).


Ca2+ Channel blockersNifedeipine

Verapamil

Mechanism of action (Con’t):

NT Release?

seminar on antidepressants

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