Antidepressant. Med

8/3/2019 Antidepressant. Med.

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Antidepressant

Wesam R Kadhum



D epressionD epression is a heterogeneous disorder thathas been characterized and classified in avariety of ways.Major depression and dysthymia (minor) arepure depressive syndromes, whereas bipolardisorder and cyclothymic disorder signify

depression in association with mania.



D epression is a serious disorder that afflictsapproximately 14 million adults in the United Stateseach year.The lifetime prevalence rate of depression in theUnited States has been estimated to include 16percent of adults ( 21 percent of women, 13 percent of men), or more than 32 million people .The symptom s of depre ss ion are intense feelings of sadness , hopelessness , and despair , as well as theinability to experience pleasure in usual activities ,changes in sleep patterns and appetite , loss of energy ,and su icidal tho ug ht s.



M ania is characterized by theopposite behavior that is,enthusiasm , rapid thought

and speech patterns , extremeself-confidence , and impaired

judgment .D epression and mania aredifferent from schizophrenia,which produces disturbancesin thought.



A simplified classification based on presumed

origin is as follows:1. "reactive" or "secondary" depression (most

common), occurring in response to realstimuli such as grief, illness, etc;

2. "endogenous" depression, a geneticallydetermined biochemical disorder manifestedby inability to experience ordinary pleasureor to cope with ordinary life events.

3. D epression associated with bipolar affective(manic-depressive) disorder.





A ntidepre ss antagent s



M echani sm of A ntidepre ss ant Dr ugs

Most clinically usefulantidepressant drugs potentiate,either directly or indirectly, theactions of norepinephrine and/orserotonin in the brain.T

his, along with other evidence, ledto the biogenic amine theory , whichproposes that depression is due toa deficienc y of monoamine s, su chas norepinephrine and serotonin ,at certain ke y site s in the brain .Conversely, the theory envisionsthat mania is caused by anoverproduction of theseneurotransmitters.



1. Selective Serotonin Reuptake Inhibitors

The primary indication for SSRIs is depre ss ion ,for which they are as effective as the tricyclicantidepressants .

A number of other psychiatric disorders alsorespond favorably to SSRIs, includingobsessive-compulsive disorder , panic disorder ,generalized anxiety disorder, posttraumaticstress disorder, social anxiety disorder,premenstrual dysphoric disorder, and bulimianervosa .



P harmacokinetics

All of the SSRIs are well absorbed after oraladministration.P

eak levels are seen in approximately 2 to 8hours on average.Food has little effect on absorption (exceptwith sertraline, for which food increases itsabsorption).



Adverse effects of

selective serotonin re-uptake inhibitors





Venlafaxine

Venlafaxine is a potent inhibitor of serotoninreuptake and, at medi um to hi gher do ses, isan inhibitor of norepinephrine re-uptake.

It is also a mild inhibitor of dopaminereuptake at high doses.Venlafaxine has minimal inhibition of the

cytochrome P450 isoenzymes and is asubstrate of the CYP 2D6 isoenzyme.



D uloxetine

D uloxetine inhibits serotonin and norepinephrinereuptake at all do se s.It is exten sivel y metabolized in the liver to numerousmetabolites.D

uloxetine sho uld not be admini stered to patientswith hepatic insufficiency.Metabolites are excreted in the urine , and the use of duloxetine is not recommended in patients with end-stage renal disease.

Food dela ys the absorption of the drug.The half-life is approximately 12 hours.D uloxetine is highly bo und to pla sma protein .



The most common side effects of venlafaxine are

nausea, headache, sexual dysfunction, dizziness,insomnia, sedation, and constipation .At high doses, there may be an increase in bloodpressure and heart rate.

Gastrointestinal side effects are common withduloxetine , including nausea, dry mouth, andconstipation . D iarrhea and vomiting are seen lessoften. Insomnia, dizziness, somnolence, andsweating are also seen.Sexual dysfunction also occurs along with thepossible risk for an increase in either bloodpressure or heart rate.



3. Atypical Antidepressants

The atypical antidepressants are a mixedgro up of a gent s that have actions at severaldifferent sites.This group includes bupropion, mirtazapine,nefazodone, and trazodone.The y are not an y more efficacio us than thetric yclic antidepre ss ant s or SSRIs, but theirside effect profiles are different.



B upropion

This drug acts as a weak dopamine andnorepinephrine reuptake inhibitor to alleviate thesymptoms of depression.B upropion is unique in that it assists in decreasingthe craving and attenuating the withdrawalsymptom s for nicotine in tobacco us er s tr ying toquit smokin g.Side effect s may include dry mouth, sweating,nervousness, tremor, a very low incidence of sexual dysfunction, and an increased risk forseizures at high doses.



Mirtazapine

This drug enhances serotonin and norepinephrineneurotransmission via mechanisms related to its abilityto block presynaptic 2 receptors.Additionally, it may owe at least some of itsantidepressant activity to its ability to block 5 -HT 2receptors.It is a sedative because of its potent antihistaminicactivity, but it doe s not cause the antimuscarinic sideeffects of the tricyclic antidepressants, or interfere withsexual functioning , as do the SSRIs.Increased appetite and weight gain frequently occur.M irtazapine i s markedl y sedatin g, which ma y be us edto advanta ge in depre ss ed patient s havin g diffic u lt ysleepin g.



Nefazodone and trazodone

These drugs are weak inhibitors of serotoninreuptake.Their therapeutic benefit appears to be related totheir abilit y to block po st synaptic 5-H T 2A

receptor s. With chronic use, these agents maydesensitize 5 -HT 1A presynaptic autoreceptors and,thereby, increase serotonin release.B oth agents are sedatin g, probably because of their potent H

1-blocking activity.

Trazodone has been associated with causingpriapi sm , and nefazodone has been associatedwith the risk for hepatotoxicit y.



4 . Tricyclic AntidepressantsTherape utic us e sThe TC As are effective in treating moderate to severemajor depre ss ion .Some patient s with panic di sorder also respond to TC As.Imipramine has been used to control bed-wettin g inchildren (older than 6 years) by causing contraction of theinternal sphincter of the bladder.A t pre sent , it i s us ed ca utio us ly because of theinducement of cardiac arrhythmias and other seriouscardiovascular problems.The TC As, particularly amitript yline , have been used totreat mi graine headache and chronic pain syndromes in anumber of conditions for which the cause of the pain isunclear.



D rug-interaction

Drugs interactin g with tric yclic antidepre ss ant s. CNS = centralnervo us sys tem; MAO = monoamine oxida se .



P reca u tion s

TC As (like all antidepressants) should be used withca u tion in known manic-depre ss ive patient s , evenduring their depressed state, because antidepressantsmay cause a switch to manic behavior.The TC As have a narrow therape utic index ; forexample, five- to six-fold the maximal daily dose of imipramine can be lethal.D epressed patients who are su icidal should be givenonly limited quantities of these drugs and bemonitored closely.The TC As may exacerbate certain medical conditions,such as unstable angina , benign prostatic hyperplasia ,epilepsy , and patients with preexisting arrhythmias .



Adverse effects



5 . Monoamine Oxidase Inhibitors

Therape utic us e sThe MAO inhibitors are indicated for depressedpatients who are unresponsive or allergic to TC Asor who experience strong anxiety.These drugs are also useful in the treatment of phobic states .D espite their efficacy in treating depression,because of their risk for drug-drug and drug-foodinteractions, the MAO inhibitors are consideredto be la st-line a gent s in man y treatment venues.



P harmacokinetics and mechanism of actionThese drugs are well absorbed after

oral administration, but antidepressanteffects require at least 2 to 4 weeks of treatment.E nzyme re generation , when(irrever sibly) inactivated, varies, but itusually occurs several weeks after

termination of the drug.Thus, when switchin g antidepre ssantagent s, a minim um of 2 week s of dela y m us t be allowed aftertermination of MAO inhibitor therapyand the initiation of another

antidepressant from any other class.MAO inhibitors are metabolized andexcreted rapidly in the urine .



Side effectsSide effects of treatment withMAO inhibitorsincludedrowsiness,orthostatichypotension,blurred vision, drymouth, dysuria,and constipation.



B ipolar Affective D isorder

Nature of B ipolar Affective D isorder:

B ipolar affective (manic-depressive) disorder is a

frequently diagnosed and very serious psychiatricdisorder.P atients with cyclic attacks of mania have manysymptoms of paranoid schizophrenia ( grandio sity,

bellico sit y, paranoid tho ug ht s, and overactivit y).





Lithi um salt s are used prophylactically fortreating manic-depressive patients and in thetreatment of manic episodes and, thus, isconsidered a mood stabilizer .

Lithium is effective in treating 60 to 80percent of patient s exhibitin g mania andhypomania.

Although many cellular processes are alteredby treatment with lithium salts, the mode of action i s u nknown .



Lithium is given orall y, and the ion is excretedby the kidney.Lithium salts can be toxic.

Their safety factor and therapeutic index areextremely low comparable to those of digitalis.





Carbamazepine has also been recognized aseffective in some groups of manic-depressivepatients despite not bein g formall y approvedfor such use.V

alproate has recently been approved for thetreatment of mania and is being evaluated asa mood stabilizer.A t ypical antip sychotic s, beginning witholanzapine, are being investigated andapproved as antimanic agents and potentialmood stabilizers









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Antidepressant. Med