Depression&Antidepressant Drugs
Depressionfeelings of hopelessness, worthlessness, sadness, guilt, and desperation.
Loss of appetite, insomnia, crying, diminished sexual desire, loss of ambition, fatigue and agitation.
Pain, sever digestive disturbances, and difficulty breathing.
Suicide rates (7-15% in depressed individuals) 1-1.5% in total population
untreated episodes usually last 7-14 months
recur and often increase in frequency with age
Affective Disorders: Depression
characterized by extreme and inappropriate exaggeration of mood
most individuals are "normal" in between episodes.
Depressive and anxiety disorders are the leading causes of disability, 25% of all visits to health care centers worldwide.
10-20% lifetime prevalence in U.S.
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.Steroidal hormonesDrugs.Other psychiatric disorders.
More than 60% of all depressions.
ocurring in response to real stimuli:
Major Endogenous Depression
A genetically determined biochemical disorder
manifested by inability to experience ordinary pleasure or to cope with ordinary life events
About 25% of all depressions.Recurrent, Cyclic
The monoamine hypothesis
The Neuroendocrine hypothesis
The genetics hypothesis
The Biologic hypothesis
………
The pathogenesis of major depression:
Depression due to deficit of monoamines and mania due to excess
effect of antidepressants– SSRIs– TCAs– MAOIs
Reserpine induced depression (prevents vesicular storage of monoamines
Attenuation of serotonin in depressed patients
Monoamine Hypothesis
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,protriptyline, amitriptyline, 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,
maprotiline, nomifensine, mianserin.
Mechanism of Action
• Combined NE and SE uptake inhibition– Tricyclic antidepressants (TCAs)– Venlafaxine
• Serotonin uptake inhibition– Serotonin selective reuptake inhibitors (SSRIs)
• 5-HT2 receptor blockers and serotonin uptake – Nefazodone – DA and NE uptake inhibition– Bupropion
• Monoamine oxidase inhibitors (MAOIs)– Nonselective and irreversible– Selective and/or reversible (RIMAs)
Tricyclic Antidepressants (TCAs)
•Amytriptiline•Imipramine•Desipramine•Nortriptyline•Protryptyline•Doxepin.• clomiperamine
N
HCl
HN
HCl
Tricyclic Antidepressants (TCAs)
Mechanism of Action:Inhibition of NT reuptake:
Immediate action = > NE and 5-HT in synapse.
After chronic treatment (2 - 4 weeks):
and 5-HT2 Receptors
Desesitization of 2 and D2 Autoreceptors
cAMP TCAs do not block dopamine transport: Differ from
CNS stimulants
TCAs
Tricyclic Antidepressants (TCAs)
Tricyclic Antidepressants (TCAs)
Characteristic three ring nucleus.
Most are incompletely absorbed,and 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.
Individual variance as high as 10-30 folds to a given dose is due to genetic control of hepatic microsomal oxidative enzymes
High protein binding, high lipid solubility.Takes up to 4 weeks for all TCA antidepressants to have an effect despite their fast inhibitory effect on NT reuptake:
This delay of theraputic effects remain unexplained
Tricyclic Antidepressants (TCAs)
/ CH3 / H
N N
\CH3 \ CH3
tertiary amine secondary amine
3o => 2o
Tricyclic Antidepressants (TCAs)
3°Amines: Imipramine, Amitriptyline
2°Amines: Desipramine, Nortriptyline
Selectivity 3o Amines – 5-HT > NE
2o Amines -- NE > 5-HT
Other effects (con’t):• Metabolism is affected by: Smoking, Barbiturates, SSRIs and
other 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
• Fatal in overdose
Tricyclic Antidepressants (TCAs)
X. MAO INHIBITORS
• Tranylcypromine• Isocarboxacid• Phenelzine
MAO-A NE, 5-HT, Tyramine
MAO-B DA
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.
May have active metabolites, phenelzine is metabolized by acetylation and may have and may vary in different individuals.
Effects persist even after these drugs are no longer detectable in plasma (1-3 weeks).
Mechanism of action: 1) Irreversible MAO inhibitors
Phenelzine and isocarboxazid => hydrazides.
Tranylcypromine => non-hydrazide Decrease metabolism of most biogenic amines NE, 5HT,
DA, tyramine
2) Reversible MAOA inhibitors
Brofaromine, Moclobemide
Delayed mechanisms
Delay in beginning of treatment
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
X. MAO INHIBITORS
Drug-Drug Interactions:•Tricyclic Antidepressants: Hyperpyrexia, Seizures •Fluoxetine, Sertraline, Paroxetine: Hyperthermia, Diaphoreis, Seizures, Delirium •Sympathomimetic Drugs (e.g. amphetamine, phenylephrine, phenylpropanolamine, guanethidine, reserpine): Hypertensive Crisis, •CNS Depressants: Additive Effects •Opioid Analgesics (particularly meperidine: Hypertensive crisis; circulatory collapse •Buspirone: Hypertension •General Anesthetics: Prolonged hypotensive and CNS depressive effects
Other side effects:
• Hypotension
• Hepatotoxicity
• Sedation.
Selective MAOAI are less likely to potentiate pressor actions of tyramine and other indirect sympathomymetic amines than Non selective MAOIs
X. MAO INHIBITORS
So MAOIs are drug of late choice:
selective benefits: phobias and anxiety
XI. SSRIs
•Fluoxetine
•Sertraline
•Paroxetine
•Fluvoxamine
SSRIs are preferred to TCAs:
• Lower anticholinergic effects
• Lower sedation
• Lower weight gain
• Lower cardiovascular effects
XI. SSRIs
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 Increase NE
» ………….
XI. SSRIs
XI. SSRIs
XII. Heterocyclics2nd Generation heterocyclics
• amoxapine
• maprotiline
• trazodone
• bupropionThird Generation heterocyclics
• mirtazapine
• venlafaxine
• nefazodone
fewer side effects reduced dangers of drug-drug interactions are less likely to exacerbate other illnesses and are less toxic in over dosage
XII. Heterocyclics
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, and trazodone3) Alteration of NE & DA output
bupropion, amoxapine
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 & 5-HT & DA reuptake inhibitor.
Maprotiline: A tetracyclic drug, 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 and 5-HT1A autoreceptors.
Unpredictable efficacy in depression.
Highly sedative (hypnotic), but minimal antimuscarinic action.
priapism is an important side effect.
Bupropion:
Resembles amphetamine.
Blocks DA & NE reuptake.
Causes CNS stimulation.
Inhibits appetite.
Aggravates psychosis.
Minimum sexual disorders
XII. Heterocyclics
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
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.
Psychological Treatment ECT (Electroconvulsive therapy) St. John’s Wort (Hypericum)
• peripheral neuropathy: TCAs• Chronic neuralgia / chronic pain syndrome• Obsessive-compulsive disorder: SSRIs and clomipramine• Attention-deficit hyperactive disorder(ADHD): TCAs• Panic and phobia disorders• Nocturnal enuresis: Imiperamine(Ephedrine, DDAVP)• Eating disorders: specially Fluoxetine• Generalized anxiety: TCAs
Other Medical uses of antidepressants
Class/Generic NamesAmitriptylineImipramineDoxepinDesipramineNortriptylineTrimipramineProtriptylineClomipramineMaprotilineMirtazapineFluoxetineSertralineParoxetineFluvoxamineCitalopram
Reboxetine*
Amoxapine
TrazodoneNefazodone
Bupropion
Venlafaxine
Alprazolam
IsocarboxazidPhenelzineTranylcypromine
Oral Dosage Range (mg/day)75-30075-30075-30075-30075-30075-20020-60100-25075-22515-455-8025-20010-50100-30020-40
2-4
200-600
150-600100-600
300-450
75-375
1-4.5
10-3015-9030-60
TRICYCLICS
TETRACYCLICS
SEROTONIN REUPTAKE INHIBITORS
NOREPINEPHRINE REUPTAKE INHIBITORS
AMINOKETONES
TRIAZOLOPYRIDINES
DIBENZOXAZEPINE
PHEYLETHYLAMINES
TRIAZOLOBENZODIAZEPINES
MONOAMINE OXIDASE INHIBITORS
Trade NameElavilTofranilSinequanNorpraminPamelorSurmontilVivactilAnafranilLudiomilRemeronProzacZoloftPaxilLuvoxCelexa
Vestra
Ascendin
DesyrelSerzone
Wellbutrin
Effexor
Xanax
MarplanNardilParnate
* Not Available in US
TABLE 1: ANTIDEPRESSANTS
CardiacOrthostasis,
hypertension,heart block,tachycardia
UrogenitalErectile dysfunction,ejaculation disorder,
anorgasmia, priapism
Central Nervous SystemDizziness, cognitive impairment,
sedation, light-headedness,somnolence, nervousness,
insomnia, headache, tremor,changes in satiety and appetite
GastrointestinalNausea, constipation,vomiting, dyspepsia,
diarrhea
Autonomic Nervous SystemDry mouth, urinary retention,
blurred vision, sweating
Potential Side Effects of Antidepressant Therapy
Tricyclic Antidepressants (TCAs)
Side Effects:
• Atropine-like side effects: • dry mouth, paradoxical excessive perspiration, constipation,
blurred vision, mydriasis, metallic taste, urine retention, cofusion, delirium => muscarinic blockade.
• Orthostatic hypotension => 1and possibly 2 blockade.
• Drowsiness, sedation and weight gain => Histamine-Receptor blockade.
• Vomiting and sexual effects:
5-HT beside 5-HT3
As many other drugs antidepressants are metabolized more rapidly by children and more slowly by patients over 60 years old Dose adjustment require
Pro-Arrhythmic Effects (Class I Antiarrytmic type) Pro-Arrhythmic Effects (Class I Antiarrytmic type) 1.Sinus Tachycardia 2.Supraventricular Tachycardia 3.Ventricular Tachycardia 4.Ventricular Fibrillation 5.5.Prolongation of PR, QRS or Prolongation of PR, QRS or QT Interval 6.6.ST Segment and ST Segment and T Wave changes changes 7.7.Bundle branch block or complete heart block Bundle branch block or complete heart block
Tricyclic Antidepressants (TCAs)
DRUGS SEDATION ANTICHOLINERGIC ORTHOSTATTICHYPOTENSION
CARDIACEFFECTS
Dibenzoxapines AmoxapinePhenylpiperazine Trazadone NefazodoneAminoketones BupropionSerotonin andNorepinephrineReuptake Inhibitors VenlafaxineSerotonin andNorepinephrineReuptake Activity MirtazapineMonoamineOxidase Inhibitors Isocarboxazid Phenelzine Tranylcypromine
Low
HighLow
High
Low
Moderate
LowLowHigh
Low
LowLow
Very Low
Very Low
Low
NoneNoneVery Low
None
ModerateLow
Moderate
Very Low
Low
HighHighVery Low
None
LowLow
Low
Low
Low
NoneNoneNone
Adverse Effects of Antidepressants
pharmacology of antidepressants and mood stabilizers
DRUGS SEDATION ANTICHOLINERGIC ORTHOSTATICHYPOTENSION
CARDIACEFFECTS
Heterocyclics Amitriptyline Clomipramine Desipramine Doxepin Imipramine Maprotiline Nortriptyline Protriptyline TrimipramineSelective SerotoninReuptake Inhibitors Fluoxetine Paroxetine Sertraline
HighHighLowHighModerateModerateModerateLowHigh
LowLowLow
HighHighLowModerateModerateModerateModerateModerateHigh
NoneNoneNone
ModerateLowLowModerateHighLowLowLowModerate
NoneNoneNone
HighModerateModerateModerateHighModerateModerateModerateHigh
NoneNoneNone
pharmacology of antidepressants and mood stabilizers
Adverse Effects of Antidepressants
Side Effects (con’t):• Most serious side effect is cardiac toxicity(specially
with Imipramine) => Palpitations, tachycardia and arrhythmia
Accumulation of hydroxilated metabolites in the heart Blockade of Na channels
This side effects are less with secondary TCAs:
Nortryptyline, Desipramine
Tricyclic Antidepressants (TCAs)
• Pharmacodynamic – AD + sedatives - additive, esp.. alcohol
– AD + Sympathomimetics - hypertensive crisis
– MAOI + SSRIs - serotonin syndrome (may be lethal) SSRI + MAOI a “NO! NO!” Serotonin Syndrome
(akathisia, muscle twitches, shivering, seizure and coma)
• Pharmacokinetic– SSRIs or Some Tricyclics + Inhibitors of P450-2D6 and
P450-3A4 - arrhythmias (may be fatal)
– Increase in metabolism by carbamazepine and smoking
– Decrease in protein binding by phenytoin, ASA
DRUG INTERACTIONSDRUG INTERACTIONS
• Antidepressants and mood stabilizers may be inhibitors, inducers, or substrates of one or more cytochrome P450 isoenzymes
• Knowledge of their P450 profile is useful in predicting drug-drug interactions
• When some isoenzymes are absent or inhibited, others may offer a secondary metabolic pathway
• P450 1A2, 2C (subfamily), 2D6, and 3A4 are especially important to antidepressant metabolism and drug-drug interactions
Antidepressants and the Cytochrome P450 System
Venlafaxine, citaloprame and sertraline have minimal interaction with cytochrome P450 isoenzymes
Antidepressants and the Cytochrome P450 System
Some of important interactions:
Fluvoxamine:
increase in BZDs, clozapine, Theophyline, Warfarine concentration
Fluoxetine and Trazodone:
increase in Astemizole and Terfenadine and TCAs concentration
Nefazodone:
can potentiate the effects of BZDs
Factors Influencing Choice
Features of illness, e.g. agitation, hypersomia
Suicide riskOther therapyOther illness.Side effectsCostSpecial problems e.g.
Age, driving, pregnancy
Mania
Mania alone is rare (10%) and most frequently cycles with Major/endogenous depression (Manic-Depressive Disease, Bipolar Disorder).
exact opposite symptoms of depression
elation (full of energy and fun)
decreased need for sleep
Talkative, go on-and-on about the things they will do.
Flight of ideas
Excessive involvement in pleasurable activities
spending excessive amounts of money
hypersexual Mechanism of disease:
Increase In catecholamines and ……..???
XVI. Anti-Manic Drugs
Lithium (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 (Haloperidole)
2) Anticonvulsive: Valproic acid & Carbamazepine
Li+
Mechanism of action• 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.
• Alters the coupling of the receptors with their second messengers by reducing coupling of G-proteins.
• Can reduce release of NTs (DA & NE except 5-HT).
• Change in the distribution of Na+
XVI. Anti-Manic Drugs
PIP
PIP2
G IP3
IP2
IP1
InositolPI
XLi+
PLC
XVI. Anti-Manic Drugs
X
Receptor
DAG
Li+
Li+ is effective in the treatment of acute mania and maintenance
Other uses include:
• Improve the notrophile count in chemotherapy
• Prophylaxy of cluster headache(a periodical headache in men)
• Bulimia
• Syndrom of inappropriate secretion of ADH
• Hyperthyroidism
XVI. Anti-Manic Drugs
Li+
• This drug has a low theraputic index and patient should be monitored
• Inhibits ADH => diuresis.
• May decrease thyroid function.
• Tremor, ataxia, aphasia
• Polydipsia, polyuria(ADH)
• Decrease in Na: increase in Li uptake in tubules
• Not to be taken with thiazide diuretics (e.g. chlorthiazide): Lithium renal clearance is reduced by 25%.
• Useful in refractory depression when added to SSRIs or TCAs, but not a good antidepressant alone.
XVI. Anti-Manic Drugs
• Na+
• use of diuretics
• change in renal function
• pregnancy
Li+ overdosage
XVI. Anti-Manic Drugs
Hemodyalisis is the prefer way to decrease Li+ concentration
Valproic Acid:A 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: ???
XVI. Anti-Manic Drugs
CarbamazepineEffective as an antimania medication
Mechanism of action:
May be due to decrease overexcitability of neurons (anticonvulsive effect).
Olanzepine and ClonazepamAre use as adjuvant in the acute or refractory mania
XVI. Anti-Manic Drugs
All neuroleptics (with the exception of clozapine), produce more severe extrapyramidal syndromes when combined with lithium.
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