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hello and welcometo lecture number 12 in our continuing series ondrugs and human behavior. today we're going to talk aboutantidepressant medications. i want to preface thisdiscussion with the caveat that i think it's reallyimportant to carefully evaluate, whether or not thesemedications are for a patient or for yourself orfor a family member, they're certainly notwithout controversy and they're certainlynot without side effects.

that being, said depressionis something that is treatable and early interventionoftentimes appears to be an importantpart of limited treatment. these drugs are not,i don't think, meant to be taken for lifetimes. they should be taken forbrief periods of time and then stepped off under thesupervision of a physician. their benefits, orpotential benefits, really are related tothe ways in which they

affect and can mitigate theeffects of stress on the brain. and that's one of the biggestproblems with depression, as it seems to oftentimesbe triggered by stress. and so if someone's goingthrough a high stress time period, it's potentiallya reasonable medication to add to try to bufferthe effects of that stress. research still needs to becontinued in these areas, and, again, i think it'ssomething-- everyone should consider what's the bestoption for themselves

and their loved ones and notsimply take pills because they seem to be the magic answer. i think these are things to beconsidered and thought about. so what we're going to talkabout today is talk about sort of what the hope forantidepressant drugs, or the claims about theiruse, are and then we'll introduce depression, talkabout the pathophysiology of depression, do aquick introduction to the types ofantidepressants we're

going to be talking about. then we'll break it down tosort of three different classes, the early antidepressantmedications, which include the tricyclics,the monoamine oxidase inhibitors and what arecalled atypical antidepressant medications. talk about selectiveserotonin reuptake inhibitors, which is the primary classof antidepressant treatment currently.

and then talk about somedual action antidepressants, some of which work fordepression, some of which work for otherthings, but all fall into the selectiveserotonin reuptake inhibitor or norepinephrinereuptake inhibitor category. finally, summarizesome of the efficacy of antidepressant medicationsand talk a little bit about what's instore for the future. so here's whatantidepressant drugs we hope

do, is, first of all,to alleviate the signs, symptoms, anddistress associated with clinical depression. so not just the sadness,but the anxiety, even pain can beinvolved in depression. so it's a pretty difficultthing to live with. certainly plenty of peopleare at risk for depression. women seem to be at greaterrisk for depression, but certainly men are atrisk for depression as well.

obviously, the ultimateproblem with depression is it could lead to suicide. men are far more likely tosuccessfully commit suicide and are at thegreatest risk for that. and it's certainlyan area where we need to be paying more attention. the number of us veteranscommitting suicide every year is beyond epidemic proportions. so we need tostart to understand

how to treat depressionand how to prevent it in the first place. so antidepressant drugs areto alleviate depression, but also to relieve anxiety,either as a single diagnosis or as part of comorbidanxiety depression situation, to try to improvethe lives of persons with debilitating depression andto repair the neuronal damage associated with depression. and that's one of the thingswe're going to talk quite a bit

about and i think,for me, that's one of the benefitsof some of these drugs is they have the potentialto try to stave off some of the damage caused bydepression and by high periods of stress. so here's the biggestthing about depression is these drugs areeffective for some people, but mostly forsevere depression. these drugs are not for themildly sad, slightly depressed.

they're probably not goingto help those people. but some exercise, somecognitive behavioral therapy is probably really bestfor that class of people. these drugs are forthe severely depressed. so if you look at the bluecircles in this graph, and you can see the blue line. the hdrs score is adepression inventory. the vertical axis is showinghow much they've changed and how much they've improved.

what you can seeis for those that have an hdrs scoreabove 25, there's pretty marked improvement withthese drugs for the most part. obviously, not all ofthem, but certainly, we start to see a pretty greatseparation between placebo and the antidepressantsat that point. so it starts to separateout at the greater the level of depression. and so the higher the levelof depression, the more likely

these drugs are to work. but these drugs are noteffective for somebody who has a mild case of depression. so what is depression? well depression, or majordepressive disorder, is a chronic, recurring,and potentially life threatening illness. 4.5% of the totalworldwide burden of disease in disabilityadjusted life years

is caused by depression. 70% of psychiatrichospitalization and 40% of suicidesare depression related. this is a really severe disease. about 9% to 10% ofthe us population suffers fromdepression each year. 10% of men andabout 25% of women will experience depressionin their lifetime. and only about afifth of those cases

are adequatelytreated every year. so we've got to do moreto treat these cases, find out what thebest treatments are. and again, i want tomake it very clear, these drugs are potentiallyuseful for many people, but not everyone and there are certainlyalternatives available. so i think this is aconversation to have, for sure. so what are thecharacteristics of depression? it's an affective disorder withalterations of emotion or mood,

substantialdecreases in interest in pleasurable activitiesor am inability to even express pleasure. oftentimes, sleepdifficulties, clear fatigue or loss ofenergy, feelings of worthlessnessor excessive guilt and possible thoughtsof death or suicide. from the diagnosticand statistical manual of mental disorder,the symptoms are as follows.

you have to have five or moreof these symptoms present during the same two weekperiod and represent a change and at least one of the symptomsis depressed mood or loss of interest or pleasure. so depressed mood most ofthe day, nearly every day, as indicated by eithersubjective report or other report, markedlydiminished interest or pleasure in all or most all ofactivities, significant weight loss when not dietingor significant weight

gain, insomnia orhypersomnia nearly every day, psychomotor agitation orretardation nearly every day, fatigue or loss of energynearly everyday, feelings of worthlessness orexcessive or inappropriate guilt, diminished abilityto think or concentrate or indecisivenessnearly every day, recurrent thoughts of death--not just fear of dying, but thoughts of death--recurrent suicidal ideation without a specific planor a suicide attempt

or specific plan forcommitting suicide. these symptoms must causeclinically significant distress or impairment. and the episode isnot attributable to the physiologicaleffects of substance use or some othermedical condition. so these are the symptomsassociated with depression and you can see why they canbe incredibly disruptive-- the loss of theability to concentrate,

inability to sleep,fatigue-- all of these are associated with depression. one of the important thingsto understand about depression is it's also associated withincreased levels of cortisol. and cortisol isa steroid hormone that is particularlydamaging to parts of the brain, particularlythe hippocampus and so we're going totalk about the potential for antidepressantsto help stave off

the effects of thatincrease in cortisol. we know that depressionis often caused by some sort of high orsudden stress occurrence. so it's oftentimes a triggerfor manic depressive disorder. so what is causing depression? that is, what is the underlyingpathophysiology of depression? well the classictheory of depression is simply that it's a deficiencyinvolving neurotransmitters-- in particular, serotonin,norephinephrine, and

or dopamine. and the idea was thatif we could restore to normal the moodstate by prolonging the presence of theseneurotransmitters in the synapse, wecan treat depression. so that was the idea, thatwe could increase mood by increasingneurotransmitter levels. the delay in clinicalantidepressant effect, according to thisclassic theory,

was due to changes inreceptor sensitivity, caused by chronic increaseof neurotransmitter synaptic levels. there has to be a changein receptor sensitivity, according to this view. well this is the classic theory. it's just simply a disruptionof neurotransmission. but what we reallythink is going on is a disruption in what'scalled neurogenesis.

so this is the neurogenictheory of depression. existing neurons are able torepair or remodel themselves and the brain is actuallycapable of making new neurons. we call thisneurogenesis and this is a brand new-- withinthe last 10 or 15 years-- discovery about the brain. so a variety ofstimuli can actually damage neurons anddecrease neurogenesis-- in particular, stressdamages hippocampal neurons.

we also know thatseveral factors are known to repair neuronsand increase neurogenesis. among them areantidepressant drugs. and so the idea is thatantidepressants aren't there to just increaseneurotransmitter levels, but actually to help repairand increase neurogenesis and so actually get the brainfunctioning better once again. so there's been some attempt toidentify the cellular processes in the hippocampusand the frontal cortex

that are responsible forthe protective effects of antidepressants. so this is a major focusof research in this area. one of these areasis looking at what's called cyclic ampresponse-element-binding protein, or creb, whichunfortunately has nothing to do with krebs cycle,but it is the cyclic amp response-element-bindingprotein. this activatesgenes that control

the production ofprotein, called brain-derived neurotrophicfactor, or bdnf. bdnf is an important factorthe has been recently talked about in a variety ofareas about its role in important normalhealth and development of the nervous system. so you'll probably hear a lotabout bdnf in other classes. so the criticalimportance of bdnf is it prevents neuronaldeath and protects neurons.

we know that chronicstress can reduce brain-derivedneurotrophic factor. the blood levels of bdnf arelower in depressed patients. and so by trying to solvethis piece of the puzzle, we think we canactually stave off some of the damage causedby chronic depression. so here's the basic idea. stress, injury, orillness may cause loss of neurons and somereduction in neurogenesis.

so this can be due todeath of a loved one, loss of a job, othersignificant stress, even birth of a child,marriage, all sorts of things can cause this kind ofstress, or even just some sort of injury, headinjury, traumatic brain injury. so antidepressants then increasebrain-derived neurotrophin factor, decrease thoseglucocorticoids that are responsible for partof that stress response, and then they increaseneurogenesis and neuronal

survival. so that's part of the puzzle. an open question iswhat are the genetic and what we call epigeneticfactors in depression? so somebody'sunderlying genetics, there certainly is heritabilitycomponents of depression. and then the epigeneticfactors are, you know, has stress or substanceabuse or brain injury cause some alteration inthe genetic expression

which then results indepression or results in neuronal injury or death. are some people moreresilient to these effects? are they less resilient? are they more susceptible? what are the genetic factors? and these are some reallyimportant questions that hopefully we'll havethe answer to sometime soon. depression is a consequenceof some sort of stress event.

stress damages the brain andweakens its ability to recover. antidepressants thenrelieve depressed mood by acting at the cellular levelto promote neuronal survival and reverse stressinduced neuronal damage. the immediate effectsof depressants is to modulate neurotransmittersynaptic levels, but the ultimate targetsare intracellular molecules, responsible for maintenance ofneuronal health and plasticity. so the idea is tohelp repair the brain.

so what are theseantidepressants? well, the tricyclicantidepressants are so named simply becauseof their chemical structure. we've talked aboutthis previously, but often the old schoolway of talking about drugs was by talking abouttheir molecular formulas. monoamine oxidase inhibitorsinhibit the enzyme monoamine oxidase, therebyincreasing the levels of dopamine and serotoninin the synaptic cleft.

the atypicalantidepressants, which would probably most of themnow be called dual action antidepressants. the ssris, or the selectiveserotonin reuptake inhibitors, do exactly what they describe. they block thereuptake of serotonin into the presynaptic neuron. then there are dualaction antidepressants. those primarily affectnorepinephrine and serotonin

and then those that simplyaffect norepinephrine reuptake inhibitors. and so these are thedifferent classes of drugs that we aregoing to talk about. the tricyclic antidepressants--so in this section, we're going to talk aboutthe tricyclics, the maois, and the atypicalsbecause they're kind of an older classof antidepressants that are prescribed far less, butare still available and may be

appropriate for some people--almost certainly much cheaper than thessris-- but they are associated with prettysignificant side effect profiles. so these tricyclicsare a class of drugs that all have thischaracteristic three ring molecular core. probably the mostwell known of these is amitriptyline,imipramine, and et cetera.

these are all fairly similarin their overall profile. the tricyclics cause twopharmacologic actions that account for both theirtherapeutic effects and most of their side effects. so they act by blocking thepresynaptic norepinephrine and serotonin reuptaketransporter proteins. so this is theirmechanism of action. this is what providestheir beneficial effects. unfortunately, they also blockthe histamine and acetylcholine

receptors, which is responsiblefor most of their side effects. so we get sedation and cognitivedysfunction that might occur. the anticholinergicactions in these drugs can be somewherebetween bothersome and incredibly toxic. the nortriptyline anddesipramine seem to be best. they seem to have theleast anticholinergic and antihistaminic properties. all tricyclicantidepressants have

three significantclinical limitations. they have very slowonset of action. they have significantside effects and in overdose,they are cardiotoxic and potentially fatal. and so providingsomebody who's depressed with a drug that cankill them-- probably not the best course of action. now if this is a drugthat they respond well to

and they can betrusted with them and the side effectsaren't too bad, it's certainly somethingto think about. so some of the side effects ofthese tricyclic antidepressants occur because they'reanticholinergic and antihistaminic anda little bit from their antiadrenergic actions. so there are certainlycognitive and memory effects. that's theanticholinergic effects,

the neurological effects,cardiovascular effects, gastrointestinal effects,sexual side effects, endocrine effects, allergicreactions, et cetera. so what to concludeabout the tricyclics? they're no moreefficacious than ssris. the potential sideeffects and toxicity are certainly much greaterthan ssris and ssris have a higher rate of patientcomfort and compliance. maois, or monoamine oxidaseinhibitors-- monoamine oxidase

is an enzyme thatregulates the amount of monoamine neurotransmitters,norepinephrine, dopamine, and serotonin inthe body and brain. three classic maois weredeveloped in the mid 1950s. their use is limited bypotentially fatal interactions when taken with certainfoods and medicines. you probably all looked atcough medicine or almost any over the counterdrug and it says do not take if you're takingmonoamine oxidase inhibitors.

so any drugs that areadrenaline-like that might be found in a nasal sprayor anti-asthma medications or cold medicines arepotentially fatal and any foods that contain tyramineare also potentially fatal in combinationwith monoamine oxidase. despite all that, interestin maois has remained strong. they can be as safe as ssris. they can work in manypatients who respond poorly to either tricyclics orssris, so they are potentially

a good choice for some people. they're particularlyeffective drugs for the treatment of awide range of depression. so people who arenon-responders to ssris, these might be a good choice. the atypicalantidepressants include maprotoline and amoxapine--the maprotoline-- sorry-- offers few therapeuticadvantages, can cause seizures and can be fatal in overdose.

the amoxapine may produceparkinsonian-like effects as a result of postsynapticdopamine receptor blockade. not generally a firstchoice and overdose can certainly be fatal. the other atypicalantidepressants i want to talk briefly aboutare trazodone, clomipramine, and buproprion. buproprion is used quitea bit in our modern times. so trazodone is asefficacious as the tricyclics.

it has a unique mechanism. unfortunately, it can causedrowsiness and priapism, which is an erection thatlasts for more than four hours. it is less anticholinergicand therefore causes less cognitive dysfunction. a new formulationwas approved in 2010 for treatment of majordepressive disorder in adults. the daytime sedation issometimes problematic, so it can be taken at night.

clomipramine is a tricyclicantidepressant treatment that inhibits mainlyserotonin reuptake with some norepinephrinepotentiating effects. it's classically indicated forobsessive compulsive disorder and seems to be equal totricyclics, but again, limited by its side effects. buproprion, which iswelbutrin or zyban, primarily effects thedopamine reuptake inhibition. it certainly affects thedopamine transporter.

it has an anti-cravingaction, so that's good. it has been tried fortreatment for people who are quitting somedrugs like cocaine and it's certainlybeen approved for use for people who aretrying to quit smoking, which is what zyban is for. it can cause anxiety,restlessness, tremor, and insomnia. it's used to treat depression,attention deficit hyperactivity

disorder, nicotine dependency. unfortunately, it cancause anxiety and seizures, but it can potentiallyimprove sexual function and it's certainly noteffective for panic disorder. so next we'll spendsome time talking about the selective serotoninreuptake inhibitors. this is the class ofantidepressant drugs that are primarily usedat this particular time. these are all potent blockersof the presynaptic transporter

for serotonin reuptake. so they blockreuptake or inhibit the reuptake of serotonin. the degree ofblocking of reuptake for other neurotransmittersvaries greatly. these include fluoxetine,sertraline, paroxetine, fluvoxamine, citalopram,escitalopram. so these are allselective serotonin number reuptake inhibitors.

we'll talk aboutthese individually. prozac's obviously the oldestand most commonly prescribed. paxil is oftenused for treatment of generalized anxietydisorder and panic disorder and has a pretty significantaffective blunting effect in some people. and then citalopramand escitalopram seem to be sort of thenewer go to antidepressants in this class.

there are two newer ssristhat are kind of too new to discuss in great detail. vilazodone has a dualserotonin action, doesn't appear to haveany therapeutic advantages over other agents. vortioxetine is a multimodalantidepressant, which inhibits serotonin reuptake,is an agonist to serotonin-1a, a partial agonistto serotonin-1b and an antagonist to5-ht3, 1d, and 7 receptors.

so keep an eye out for those. they may demonstratesome efficacy. one of the bigproblems with ssris is they inhibit some of thecytochrome p450 enzymes. so we get thisenzyme inhibition. so it's an importantclinical consideration for people who are takingother medications, things like other cytochromep inhibitors, hydrocodone, or birth control.

all these drugs canhave some effects on-- some of these drugscan have some effects on those otherdrugs so you always want to check and see whatkind of drug interactions there might be. in particular, fluoxetine, seemsto have the most significant cytochrome p inhibitioneffects as does fluvoxamine. citalopram and escitalopramhave very few cytochrome p enzyme inhibition or very littlecytochrome p enzyme inhibition.

in particular, you can seethat cytochrome p450 2dg is the mostsignificantly affected by this class ofdrugs, which is also the enzyme which is necessaryfor converting hydrocodone into codine. the clinical differencesamongst these individual ssris appear to be minimal. they appear to be aboutas equally effective and are about as effectiveas older antidepressants.

importantly, ssris arenot fatal in overdose. there are some concernswith ssri therapy, which include plenty of peoplewho are treatment resistant and the potential for what'scalled serotonin syndrome. potential side effectsof all these drugs include sedation, some apathy,some sleep disturbance, possible cognitive impairment,physiological symptoms, possible weight gain, somehave sexual side effects including inability to obtainan erection or an inability

to orgasm-- which doesn't seemto help anyone's depression. some people reportit as a benefit, that is that delayedorgasm seems to be somewhat of a benefit for some people. so keep in mind that that'spotential side effects. people who are at risk forbipolar disorder, these may trigger manic episodes. and certainly drugs like paxilhave significant withdrawal effects.

all these drugs containa black box warning about the potentialfor suicidal ideation in children andadolescents, on which we will talk aboutin more detail when we get to talking aboutadolescence psychopharmacology. quick warning about serotoninsyndrome-- high doses or combinations of drugs canproduce exaggerated responses to these drugs. these include alteredcognition, which

can include disorientation,confusion, hypomania, delusions, sort offeelings of losing it, some behavioralalterations, including agitation and restlessness,some autonomic symptoms, including fever, chills,sweat, diarrhea, hypertension, and tachycardia, someneuromuscular impairment, including ataxiaand hyperreflexia. and this usually can resolvewithin 24 to 48 hours, provided that they reduce whateveramount of drug they've taken.

one problem withtaking these drugs is they're associatedwith what's called serotonindiscontinuation syndrome. there are six core somaticsets of the symptoms that the acronym finishwill help you remember. they include flu-like symptoms,fatigue, lethargy, myalgias, chills, and headache, insomnia,gastrointestinal symptoms, including vomiting and diarrhea,potential imbalance, so dizziness, vertigo, ataxia,sensory disturbances, sensation

of electrical shocksin the arms, leg, or head, and hyperarousal,so anxiety or agitation. i can tell you, i wasout of my antidepressant. i take escitalopram, or lexapro,and ran out at some point and i can tell you, theflu-like symptoms and imbalance, all of that reallyare problematic. and once i got back on them,it resolved that issue. so i'm hoping toeventually step off them. you have to step off thesedrugs slowly or just simply

power through the serotonindiscontinuation syndrome. so ssris and suicide-- here'swhere we get some question about whether or not theyimprove or don't improve risk for suicide. you certainly getreductions in the thoughts of death, which are animportant part of reducing risk you see there isn't muchreduction in suicidal ideation. i mean, there's a little bit. and there is justsimply not much room

to move the needle onattempts or completion. it's the same thingwith suicidal ideation. it reduces fromabout 4% down to 0%, so that's a significantimprovement, but without treatment, it getsit almost to zero as well. so it probablydepends, of course, on the level ofdepression, et cetera. but at least reducingthose thoughts of death seemed to be animportant part of this.

so let's take a lookat some specific ssris. prozac, or fluoxetine, is thefirst ssri-type antidepressant and the first non-tricyclicantidepressant that's considered a firstline antidepressant. has similar efficaciesto tricyclics and is often the firstto be prescribed. in fact, oftentimes,insurance companies insist that it's thefirst to be prescribed. it has a two tothree day half life,

but it has an activemetabolite that has a half life of six to 10 days. so it takes almost threemonths to reach steady state. so this is one of the biggestproblems with this class of drugs, is it takes so longto get the point that you're taking in as much asyou're putting back out. and so you oftentimes have tostay on these drugs for quite a while to determine whetheror not they're effective, which can be problematic.

side effects include serotoninsyndrome, anxiety, insomnia, and sexual dysfunction--particularly, inability to obtain an erection. sertraline, or zoloft-- it'sfour to five times more potent and selective than prozac. reaches steady state muchquicker, four to seven days, is shorter acting andless-- has a shorter acting and less active metabolite. appears to be effective intreating depression, dysthymia,

and some anxiety disorders. it's reportedly effectivein comorbid ptsd and alcohol dependence and hasfew anticholinergic, antihistaminic, and adversecardiovascular effects as well as low risk oftoxicity and overdose. a pretty goodchoice for those who are having a prettysevere depression. this is a prettysafe drug for them. paroxetine, or paxil--personally, this

is one of those drugs thati think works very well for people who have verydisruptive anxiety disorders, but it would not be my firstchoice for major depression because it does seem to havesome serious affective blunting in some people. so it's fda approvedfor treating depression, obsessive compulsivedisorder, and panic disorder. it should not be usedduring pregnancy at all. it seems to be moreselective than prozac

and, again, has abouta 24 hour half life. fluvoxamine is aderivative of fluoxetine. it's available for treatment ofobsessive compulsive disorder. appears to be aneffective antidepressant, but again, appears to be bestin ocd, ptsd, panic disorder, social anxiety disorder. these are off-label uses, butthey are used in those areas. citalopram, or celexa, it's beenavailable in the us since 1998, used for treating majordepressive disorder,

social phobia, obsessivecompulsive disorder, and panic disorder. has about a 33 hourhalf life, which is much longer in the elderly. same effects as allother ssris, but does not include the drug interactionsbecause it does not inhibit the hepaticdrug-metabolizing enzymes. so this may be animportant consideration for people whoare on other drugs

that you don't want tohave interactions with. escitalopram, or lexapro--this is an active isomer of citalopram. it's twice as potent, soyou can use half the dose. seems to be equivalentin treating panic attacks in the elderly, but again,careful with prescriptions for in the elderly becauseof that extended half life. the dual actionantidepressants expand actions at twodifferent synaptic sites

to improve or maintain efficacywhile limiting side effects. nefazodone has been withdrawn,so we won't talk about it. milnacipran, venlafaxine,duloxetine, and mirtazapine are drugs that arecurrently available. so let's start withtalking about milnacipran. it blocks norepinephrineand serotonin reuptake, blocks the ndma-type glutamatereceptors in the spinal cord, contributing to itsanalgesic action. so it is approvedonly for that use.

the fda has approved this drugfor treatment of fibromyalgia, but not as an antidepressant. so it is primarilyfor chronic pain. effexor is a mixedserotonin-norepinephrine 5-ht and norepinephrinereuptake inhibitor. it's not anticholinergicor antihistaminic, has little to no cognitivedysfunction or sedation, but can cause increasein blood pressure. and there is alonger acting version

of this for treatment ofgeneralized anxiety disorder. pristiq was approved in2008 for the treatment of major depressive disorderhas an 11 our half life. there was some attempt to getthis approved for treatment of hot flashes in postmenopausalwomen, but that was refused. cymbalta appears to reduceboth depression and anxiety. also seems to work well toreduce the physical symptoms of pain, back ache, joint andmuscle pain, back and shoulder pain-- particularly thoseassociated with depression.

depression does-- it has likean achey component to it. there is potentialfor this to be used for pain and depressionthat occur comorbidly and can be used for generalizedanxiety disorder and has a half lifeof about 12 hours. fortunately, weight gain, sexualdysfunction, and hypertension have not been reportedas major problems with this particular drug. remeron increases norepinephrineand 5-ht transition

via a complicatedpresynaptic mechanism, causes a pretty highhistamine blockade, so it's highly sedative. keep in mind, when we talkabout histamine blockades, benadryl is primarilyhistamine blocker. if you think about whatbenadryl's like to take, it makes you verysleepy and that's what these drugs are like. so just keep that in mind.

this drug has been associatedwith increases in appetite and body weight and haspretty long half life of about 20 to 40 hours. strattera is a drug we'll talkabout when we talk about adhd. it is a norepinephrinereuptake inhibitor. it's used for adhd inchildren and adults, has been used as anadjunct in fibromyalgia, appears to be antidepressantand analgesic, and has shown to beeffective in ptsd.

primarily, it's used foradhd and comorbid depression. so how good are antidepressants? that is, how efficaciousare they really? well there's a very largestudy called the star d study. the goal was to determine theeffectiveness of depression treatment for majordepressive disorder in primary and specialtytreatment centers. talking about 3,000participants at 41 clinics. about two thirds ofparticipants were

able to achieveremission if they did not withdraw from the study. unfortunately, the dropoutrates were between 21% and 42%. so you have to considerthat the people who remained in thestudy are probably the ones who weregetting the most out of these antidepressants. so while we're talkingabout a two thirds reduction in depression forthose that stayed in,

keep in mind 20% to 40% of theoriginal group dropped out. so we're probably talking about50% efficacy rate, somewhere in there. overall there didn'tappear to be any that was any superior to others. one the biggest problems inconducting studies on these is there a very largeplacebo effects. we talked about this previously,about how to design studies and one of things you have todo is a placebo run in period.

and what's done inthose is you give people placebo for a first time periodand anybody who gets better is dropped from thestudy because you know that they're going torespond only to placebo. and then you can actually get amuch better determination as to whether or notantidepressants are effective by gettingthe people who don't respond to just the placebo. so where do we go from here?

well, we certainly needto develop the genetics in this area. so can we use geneticsto help guide therapy? we certainly need more effectivemedications with a reduced side effect burden. i think it's really important tobe mindful of the side effects that these drugs can cause. these are not, again, notdrugs to be taken lightly. so you want to be very cautiousand think about whether or not

these are for you. but again, i want toalso make it very clear, these can be veryeffective for some people and certainly living withdepression is not the answer. so these are probablybetter for some people than just simplyliving through it. there are other alternativetreatments you can explore too, but no depressionshould go untreated. i want to make that very clear.

so what can genetic testing do? well genetic testing mightbe able to help us identify deficits in drug metabolism thatpredict drug interactions that occur with many antidepressants. recent interest has centeredon how genetic alterations may influence the clinicalresponse or a lack of response to these medications. there are plenty of people whodon't respond at all to ssris and so we're going to exploresome alternative treatments

in the next set of discussions. so in the future, augmentingagents might be used, so drugs like modafinil. it's a nonstimulantwakefulness-promoting drug used to combat daytime fatiguein patients with narcolepsy. also been shown toimprove working memory and fluid intelligence. aromodafinil is a sortof longer lasting isomer formulation of modafinil.

lamotrigine is an anticonvulsantand mood stabilizer, which might help. two atypical antipsychotics,abilify and seroquel, have been demonstrated tohave antidepressant activity for, again, people whoare non-responsive. they are now approved by thefda for treatment of treatment resistant depression. so if you look atplacebo versus abilify, the minimal ornon-responses came mostly

in the placebo condition andabout twice as many people had a robust response toabilify as to placebo. and again, you startgetting increases in differences between placeboand abilify in the stronger responses. but again, you should alsonotice that about 40% of people still did notrespond to abilify. ziprasidone, again,over a period six weeks, seemed to improvecompared to placebo.

there are somenatural substances that may haveantidepressant properties. omega 3 fatty acids,epa, or dha, all of these have potentialneurogenic effects. certainly, dha has been shownto be an important component for neural development in kids. folate-- this is controversialas a treatment for depression. sam-e, its efficacy appears tobe similar to the tricyclics. st. john's wort-- carefulwith st. john's wort.

certainly, don'ttake if you're going to take it withother antidepressants and make sure you discussthis with your doctor because it does have anumber of drug interactions and so be verycareful of this one. there are other options too. dhea, ordehydroepiandrosterone-- we're going to talk moreabout that when we get to talkingabout older adults,

but this may be effectivein hiv-related depression. there are some studiesthat demonstrate its potential efficacy for that. so what do we conclude? well there is certainly needfor significant resources to come up withbetter alternatives to investigate the geneticand neurogenic issues in depression. depression shouldnever go untreated.

we just need to findthe best treatment. so we need tocertainly-- we certainly need more funding in this area. the best research inthis area is always done by people who have noskin in the game, as it were. so that is who have nofinancial incentives. so this is where ithink it's important that we get funding forindependent research. again, there are manynonpharmacological treatments

for depression in useand under investigation. these include things likeelectroconvulsive therapy, transcranialmagnetic stimulation, electric cortical stimulation. so these arepotentially areas where we can have nonpharmacologicinterventions and these certainlyhave demonstrated to be effective for peoplewho are non-responders. certainly not somethingto be done lightly,

but a number ofpeople have talked about how these alternativeshave been life savers for them. so we'll be discussingthat in our next series.