Antidepressants And Antixiolytics.docx

Major depressive disorder is one of the most common cause of disability in the developed world with 17% lifetime prevalence in US. Atleast some of the recent growth in antidepressant use stems from their application for a variety of other conditions including generalized anxiety disorder, ptsd, ocd and the list goes on and on Ssri and snri are first line agents for many of these conditions and they have become some if the most prescribes classes of medications in the us. So in essence they put u in a good mood, they help u relax, they take you to your happy place.  Ssri- selective serotonin reuptake inhibitors o Fluoxetine o Paroxetine o Sertraline o Citalopram o Ssris work by inhibiting the serotonin transporter (sert), thereby increasing the concentration of serotonin at the synapse.  Ssri inhibit the presynaptic reuptake of serotonin (5HT).  Snri – serotonin norepinephrine reuptake inhibitor o Venlafaxine o Duloxetine o Inhibit the presynaptic reuptake of norepinephrine and serotonin  On the exam, u can recognize the symptoms of depression by using the mnemonic sigecapswhich include specific symptoms related to sleep, interest, guilt, energy, concentration, apetite, psychomotor, suicidal ideation. Both ssri and snri are first line agents used for the treatment of major depressive disorder (MDD). Acute episodes of mdd can last 6-14 months if untreated and many times they last for years. After their first trial on a new antidepressant, about a 3rd of pt will achieve remission, once an adequate response is achieved, the therapy is continued for a minimum of 6-12 months to prevent relapse. Ssri and snri can even be used as long term maintenance to prevent future mdd episodes. Ssri and snri treat depression by enhancing serotinergic neurotransmission in the cns. Infact all currently available antidepressants exert many of their clinical and toxic effects by increasing the availability of monoamines at the synapse usually serotonin and norepinephrine  Lets illustrate a few more scenarios in which either ssri or snri are your first line agents of treatment. After mdd, anxiety disorders represent the most common applicationof antidepressants. Many of the ssri and snri have been approved for all of the major anxiety disorders including GAD, panic, PTSD and ocd. Lets go through them one by one. o Gad- recall from the bens diner sketch, the drugs from the sedative hypnotic class are still occationally used for the treatment of anxiety disorders. Benzodiazepines for example provide much more rapid relief from gad symptoms than any antidepressant. Ssri and snri however have been shown to be as or more effective than benzodiazepines for the long term treatment of anxiety. Not only that, ssri and snri do not carry the same

risk of dependence and addiction that occur with the benzos. Ssri and snri are your go to drugs. o Panic disorders- while generalized anxiety disorder involves a chronic state of worry that inhibits daily activity, panic disorders are characterized by recurrent episodes of brief overwhelming anxiety which often occur without a triggering factor. Pt often fear having an attack and avoid situations in which they might have an attack. Ssri and snri treat panic disorder. o Ptsd- ssri and snri are both first line treatment for ptsd. This condition manifests when a traumatic event results in recurrent intrusive thoughts or imagery, hypervigilance, nightmares and avoidance of situations that remind the pt of the trauma. Ssri and snri can benefit a number of the symptoms of ptsd including anxiety and hypervigilance though other treatments such as psychotherapy are usually required as well. o OCD- is characterized by obsessions which are repetitive anxiety provoking thoughts or compulsions which are repetitive behaviors that reduce anxiety. Several of the ssri are approved for the treatment of ocd that’s why its close to ssri desk  For the rest of the clinical scenarios I want you to think of ssri rather than snri o Bolemia- ssri have been helpful in bolemia. Bolemia is characterized by episodic binge on food followed by ritualistic purging either through emesis or laxatives or some other method. I wanna emphasize that anorexia is different > anorexia involves distorted body image and reduced food intake causing weight loss that is atleast 15% below ideal body weight. Ssri are not useful for anorexia, though refeeding, family therapy, and cbt can be used for treatment o Social anxiety disorder- common condition in which pt experience severe debilitating anxiety during social interactions impairing their job performance for example. Several of ssri have been shown to be effective for the treatment of social anxiety  It turns out that the snri but not the ssri are useful for the treatment for certain pain condition. Drugs that posess both norepinephrine and 5ht reuptake blocking property can be useful in treating pain disorder. o Diabetic neuropathy - For example both duloxetine and venlafaxine can be used to treat diabetic neuropathy o Chronic pain- Keep in mind that duloxetine has been shown to be useful for managing all kinds of chronic pain conditions including low back pain and osteoarthritis.(vis says both snri) o Fibromyalgia – Duloxetine (vid says both snri) has also been shown to be effective in the treatment of fibromyalgia- a condition that involves widespread pain in muscles, joints and soft tissue locations all in the absence of distinct lab or physical exam finding  When treating your pt with ssri or snri, you gotta keep in mind that these drug are not for the management of acute symptoms – ssri and snri take about 1-2 months to achieve their maximum effect, and that can be a long time when your pt is waiting for the symptomatic relief of chronic pain or anxiety syndrome. Recall when treating depression, about a third of pt can achieve remission. However when your pt comes to clinic and continues to describe depressive symptoms, keep in mind that u gotta give that ssri some time to work. A trial therapy should last

at least 8-12 weeks before u can definitively assess an inadequate treatment response after which the therapy can be switched to another agent or augmented with the addition of another drug  Long term treatment of numerous anxiety disorders are achieved with ssri and snri. Remember tho , if u need immediate symptoms relief, an ssri isn’t gonna cut it , they are for long term maintenance therapy only. A benzo for example provides much more rapid relief for both generealized anxiety and panic  Lets discuss side effects. o Ssri Siadh- a rare side effect of ssri – this causes hyponatremia.  Diminished sexual function and interest – as a result atleast 30-40% of pt report reduced libido, disrupted arousal, anorgasmia and increased ejaculation latency  Weight gain- ssri can cause weight gain  Drowsiness- ssri can cause drowsiness as well  Ssri can cause insomnia as well so your pt may report some daytime sedation and diminished mental energy  Ssri AND snri- can cause serotonin syndrome – drugs that inhibit serotonin reuptake such as ssri and snri can potentially lead to excessive levels of synaptic serotonin , this leads to a potentially fatal syndrome that u must immediately recognize on exam. Serotonin syndrome shares many of the same features as neuroleptic malignant syndrome (NMS)> which is a separate condition that can be precipitated by dopamine blocking agents such as antipsychotics. There is a subtle distinction however, just like in nms, serotonin syndrome can present with autonomic instability, agitation, hyperthermia and hypertension. But heres what ud clue u into serotonin syndrome specifically , look for hyperreflexia and clonus whereas in nms u are more likely to see rigidity and hyporeflexia. Bouncing ankle clonus is a classic sign of hyperereflexia that they love to use on exam. It turns out that serotonin syndrome can occur with overdose of a single drug or concurrent use of multiple drugs that increase cns serotenergic transmission such as ssri + tca/MAO. The management of serotonin syndrome involves discontinuation of all serotenergic agents , stabilizing vital signs and possible administration of serotonin antagonist  Cyproheptadine – blocks 5-HT2 o Snri- snri have many of the same serotenergic adverse effects accociated with ssri??. But the n in snri means that they increase they increase noradrenergic transmission so u might see some increased bp and hr as well as cns activation including insomnia and agitation  Withdrawal- sudden discontinuation of a short half life ssri (paroxetine , or sertraline) or snri can lead to discontinuation syndrome. It involves flu like symps such as dizziness, fatigue, headache and nausea 1-2 days after stopping the medication . so remember to taper pt off the ssri or snri

  



Tca- By now whenever u think of treating depression, I want you to think of enhacing synaptic availability of MOA. One of the leading hypothesis out there concerning the pathophysiology of depression is the MOA hypothesis which suggests that depression is related to a deficiency in central serotonin, norepinephrine , dopamine. So recall ssri and snri inhibit reuptake thereby increasing moa availability In the cns and TCA are no different. Imipramine ( and its derivatives desipramine and clomipramine) – Amitriptyline and nortriptyline Tcas work kind of like the snri – they inhibit reuptake (into presynaptic neuron) of norepinephrine and serotonin reuptake by blocking the activity of norepinephrine transporter (NET) and the serotonin transporter (SERT) leading to increased levels of moa in the synapse . well that sounds like itd be useful for treating depression, but the truth is tcas are now releagated to 2nd or 3rd line treatment for major depressive disorder disorder. Cuz tca are potentially lethal in overdose, have serious drug interactions , cause numerous adverse effects so as a consequence tcas are now reserved for pt whose depression is unresponsive to other agents (resistant depression). Keep in mind that tcas are pretty much used for treatment resistant depression only. I know they are called antidepressants and all but I want u to focus on their off label uses of tca o Lets start with treatment of pain disorders. o Tcas have been used in the treatment of neuropathic and other pain conditions since the 1960s . just like with the snri, the analgesic properties of tca are likely associated with their action as serotonin and norepinephrine reuptake inhibitors . so both the snri and tca can be used to treat diabetic neuropathy for example. Their role as antidepressants may also come into play as well because chronic pain conditions are also associated with major depression.  Tca treat chronic pain eg neuropathic pain o The tca antidepressant are also used for migraine prevention (prophylaxes) amitriptyline is the only tca that has proven efficacy for migranes- though other tca might also have benefit. o Recall from our ssri sitcom that ocd is known to respond to serotonergic antidepressants. In addition to ssri , one of the tca – clomipramine- has been shown to be effective in reducing the symptoms of ocd . though these are generally less well tolerated than ssri and are not first line.  Clomipramine (tca) treats ocd ( ssri first line). o On the exam, the emphasis will be placed on characterizing these classic adverse effects that has relegated these to 2nd 3rd line for most clinical conditions  Sexual dysfunction – reduced libido, anorgasmia, increased ejaculation latency.  Anticholinergic activity- most common adverse effect of the tca are direct manifestation of their potent anticholinergic properties. Anticholinergic toxicity results from the inhibition of central and peripheral muscarinic ach receptors kind of like how atropine works. Tcas commonly cause many of the classic anticholinergic side effects such as dry mouth, constipation, blurred vision, urinary retention and confusion.it turns out among the tcas, amitriptyline has

o

o

o

the most potent cholinergic effects, while the secondary amines – nortriptyline and desipramine – has the least . so the anticholinergic effects like dry mouth, constipation and urinary retension can be reduced by using these secondary amine agents instead of amitriptyline > this can be esp important in the elderly as these pt are at an increased risk of side effects due to comorbid conditions, decreased hepatic and renal clearance of medication and higher burden of concurrent medication that can interact with tcas .  Tca are relatively contraindicated in elderly pt due to an increased risk of sedation, delirium and falls > (severe anticholinergic and antihistamine and antialpha)  When that elderly pt presents to the er confused and mad as a hatter, it could be any number of medications causing toxicity. One of the clues that will point u towards anticholinergic toxicity specifically is the urinary retention . o Maybe hes confused , dry and ahd to stick a foley in him to empty a litre of urine from his bladder > start thinking of drugs with anticholinergic effects such as antihistamines and tcas. Tca are also ass with h1 rec antagonism . ( tca block h1 rec ) . recall that central blockade of h1 receptors can cause increased apetite and weight gain, as well as sedation. So far tca have caused anticholinergic activities, histamine blockade, so why not some peripheral antagonism of alpha 1 adrenergic receptors ( tca block alpha 1 receptors )  It turns out that tca can exert potent alpha blocking effects leading to peripheral vasodilation and orthostatic hypotension so remember to watch out for falls in elderly. Not only that, refractory hypotension due to peripheral dilation can contribute to a fatal decrease in cardiac output Sure pt suffering from tca overdose will be experiencing some antimuscuranic, antihistaminic and anti alpha symptoms however, it’s the inhibition of myocardial fast sodium channels that can lead to fatal cardiac arrhythmias. The most common cause of death in pt with tca overdose is fatal cardiac arrhythmia. Blockage of fast sodium channels has deleterious effects on the cardiac conduction system causing qrs and qt prolongation and fatal cardiac arrhythmias. Contractility is also depressed contributoing to refractory and potentially fatal hypotension. Just like with type 1 antiarrythmatics, blockade of fast sodium channel decrease the slope of cardiac action potential thereby slowing action potential conduction through the myocardium. On the ecg this is seen as a widened qrs complex due to increased ventricular depolarization time. The qt interval may be prolonged as well which may precipitate a torsades de pointes arrhythmia and syncope . if a pt on tca presents with a widened qrs or ventricular arrhythmia > they have gotta get sodium bicarb therapy. Sodium bicarbonate increases serum ph which favors the non ionized form of the drug making it less accessible to bind to sodium channels. Sodium bicarb also increases ecf sodium which helps overcome the competitive rapid sodium channel blockade induced by tcas



o

o

Tca induced cardiotoxicity eg fatal cardiac arrhythmias is the mcc id death in overdose  Tca can widen the qrs complex on ecg  Tca can induce torsades de pointes  Sodium bicarb treats widened qrs and ventricular arrhythmia caused by tca overdose Students often remember the 3 C when thinking about the adverse effect of tca  Cardiac,  Coma,(antihistamine)  Convulsions  Tca poisoning can induce seizures likely due to antagonist effect of tca on the gaba a receptor Also serotonin syndrome must be considered in any pt suspected of antidepressant overdose since may of them including tca affect serotonin reuptake potentially causing too much serotonin to build up at the synapse esp when drug are used in combination.

Mao inhibitors Im definitely picking on some kind of theme here. We started with serotonin and norepinephrine reuptake inhibitors great for depression and anxiety states. Then we went on the tca, which also inhibit both serotonin and norepinephrine reuptake inhibition though our main focus there was treating neuropathic pain and now we are continuing the chapter with moa inhibitors. Monoamines ofc include norepinephrine and serotonin and so again we are going to be increasing the noradrenergic and serotenergic transmission both in the periphery and in the cns. This time tho we will also be enhancing the activity of another monoamine, dopamine – and that means we will be treating parkinsons . that’s about it I guess since moa inhibitors aren’t really used any more in clinical situation. One of the first classes of antidepressant introduced in the 1950s – moa inhibitors were historically used for depression and anxiety but fell out of use due to toxicity and lethal food and drug interactions. They are now primarily used to treat depression unresponsive to other medication.  Moa inhibitors act by blocking the activity of monoamine oxidase thus preventing the breakdown of monoamine neurotransmitters and increasing their availability. There are 2 isoform of monoamine oxidase: mao A and mao B o Mao A- prefentially deaminates serotonin, norepinephrine, dopamine  Mao a is responsible for catalizing the oxidative deamination of amines such as dopamine, norepinephrine and serotonin > thereby decreasing the content of monoamines in peripheral and cns neurons o Moa B- only metabolizes dopamine  Mao Inhibitors prevent breakdown of monoamines leading to increase noradrenergic, serotenergic and dopaminergic transmission in the periphery and cns  Most mao inhibitors available in the us are non selective and irreversible  Tranylcypromine (mao inhibitor)

 Phenelzine (mao inhibitor)  Isocarboxazid (mao inhibitor)  Because both tcas and Mao inhibitor are potentially lethal in overdose, require careful titration ,have serious drug interaction and have many adverse effects – their clinical use is limited. Mao inhibitors increase the availability of serotonin and norepinephrine in the cns , which is useful in treating depression ( not first line tho) . but they have been reported to be particularly useful for treating atypical depression which includes which includes certain features such as hyperphagia, hypersomnia and leaden paralysis. Though the utility of diagnosing major depression with atypical features has been called into question ??. now mao inhibitors are reserved for pt whose anxiety or depression has been unresponsive to other agents- so mao inhibitors are useful in treatment resistant depression.  Selegiline – a selective irreversible inhibitor of mao B . inhibits the breakdown of dopamine and this is esp useful in cns as it increases dopamine levels. The motor features of parkinsonism are treated with levodopa and other dopamine agonist that restore central dopaminergic transmission and a selective mao b inhibitor like selegiline can be used as adjunctive therapy for pt with declining or fluctuating responses to levodopa  Side effects o Generally these are not 1st or even 2nd line antidepressant due to their side effect profile. And because they inhibit the breakdown of serotonin , youd expect the same kind of side effects as those casued by ssri and they do . infact the most common adverse effects of mao inhibitors are orthostatic hypotension , weight gain and these agents ass with highest rates of sexual side effects of all the antidepressant. o Tyramine is a naturally occurring monoamine compound found in aged meats, alcoholic beverages and fermented dairy products like this cheese . tyramine acts as a chatecholamine releasing agent in the body but normally before it gets into the general circulation , its metabolized in the gi tract by mao. But if u inhibit mao tho, all that tyramine gets to flow in the general circulation where it acts as a sympathomimetic agent displacing norepinephrine from neuronal storage vesicles? > this can precipitate a pressor response (htn crises- htn, blurry vision, diaphoresis) consisting of vasoconstriction, tachycardia and htn. Not only that , pt on mao inhibitor who injest large amount of diatary tyramine may experience malignant htn leading to stroke or mi. therefore these pt must adhere to a low tyramine diet o And just ike with other serotenergic drugs, ssri snri tca , mao inhibitors are associated with serotonin syndrome- a potentially fatal syndrome caused by excessive levels of synaptic serotonin and presents with autonomic instability , agitation and hyperthermia and htn and remember to look for hyperreflexia and clonus as well  Mao inhibitors should be avoided with other drugs that increase serotonin levels eg tca, ssri, snri > cause serotonin syndrome.  Keep in mind that most serotinergic antidepressant should be discontinued atleaset 2 weeks before starting an mao inhibitor

o

Phentolamine (alpha1 and alpha 2 blocker) can be used to manage hypertensive symptoms of tyramine toxicity.

Buproprion, mirtazapine, trazodone There are a number of antidepressant that do not fit neatly into the other classes we have covered so far. We have seen the ssri, snri, tca, mao inhibitors. But then there is this special set of agents called the atypical antidepressants which will be the focus of this sketch. In addition we will mention 1 agent that is in its own class of serotonin modulators. these drugs are frequently used in pt with major depression who have had inadequate responses or intolerable side effects with another first line treatment. Because of their efficacy and tolerability, ssri are considered first line agents for initial treatments for unipolar depression. Yaa the atypical antidepressant and serotonin modulators are relegated to 2 or 3d line but they do have some unique properties as well bumping up them to first line when the pt is looking for certain desirable characteristics. Whenever u think of treating depression, I want u to think of enhancing the synaptic availability of monoamines.  Bupropion (atypical antidepressant) is an antidepressant drug with the chemical structure similar to that of amphetamines that works by inhibiting the reuptake of norepinephrine and dopamine. It basically inhibits norepinephrine transporter (NET) and dopamine transporter (DAT) > these 2 transporters are responsible for the reuptake. So synaptic levels of norepinephrine and dopamine is increased. But remember, unlike the previous drugs, bupropion has no effect on serotonin. Because bupropion resembles amphetamines in chemical structures, it exerts cns activating effects, this makes bupriopon useful in treating depression associated with hypersomnolence and low energy. Bupriopon can also be used to treat tobacco dependence. Its not clear why bupropion reduces the urge to smoke, nonetheless, it seems to be about as effective as nicotine patches. Keep this in mind when your pt comes in seeking treatment for depressive symptoms as well as nicotine dependence. Though, other antidepressants may also have a role in smoking sessation. o The most significant side effect of bupropion is seizures. Seizures are even more common when bupropioin is given in high doses and is contraindicated in any pt with a history of seizures. The risk of seizures is even greater in pt with a history of eating disorder- so bupropion is contraindicated in pt with a history of bulimia and anorexia nervosa because it lowers the seizures threshold in these pt o Remember that bupropion is not a typical antidepressant and so it actually has a few added benefits that make it the preffered agent for treating major depression in certain pt. first of all remember is different from the other antidepressant and that it dosent effect serotonin and unlike agents such as ssri, bupropion does not cause sexual dysfunction. Remember ssri can cause sexual dysfunction in upto 50% of pt, and if your pt is distressed from decreased libido and impaired sexual performance, consider transitioning to bupropion instead

o

Lastly bupropion may also be preffered because it causes less weight gain than other antidepressant. It turns out bupropion can help with weight mainitainence or it can also be associated with mild weight loss  Mirtazapine ( atypical antidepressant ) – if u recall, mirtazapine is the alpha 2 blocker. Mirtazapines has the ability to block presynaptic alpha 2 receptors. Inhibition of presynaptic alpha 2 auto receptor causes an increase in presynaptic catecholamine( serotonin , norepi) release. Mirtazapines pharmacology is actually quite complex and receptors affected by these drugs don’t stop there . miratazapine can even antagonize 5ht2 and 5ht3 serotonin receptors. Mirtazapine is also a potent h1 receptor antagonist, this antagonism of h1 can cause sedation> this side effect can actually be used therapeutically making mirtazapine one of the first line option for pt with major depression and insomnia. Mirtaazipine can also be used as an adjunctive treatment with the more activating antidepressants like bupropion to balance out the effect. o Unline bupropion mitazapine is associated with weight gain, though its often an unwanted side effect , this too maybe desirable for some pt including the elderly or pt with MDD + anorexia. o Like bupropion, mirtazapine may be preferred as a first line treatment for major depression because of its lack of sexual side effects.  Trazodone: (serotonin modulator in other words it antagonizes postsynaptic serotonin receptors (5ht 2 receptors) while also weakly inhibiting serotonin reuptake. I want to emphasize that trazodone has minimal effects on dopamine and norepinephrine. o Trazodone also antagonizes alpha 1 receptor. Alpha 1 blockade can cause major vasodilation which leads to a rare but serious effect of trazodone therapy called priapism. Priapism is a persistant erection lasting lasting more than 4 hours that is not associated with sexual excitement – nickname is trazobone lolz. Priapism is most common in young adult men and is medical emergency and can result in permanent damage to penile tissue and erectile dysfunction if left untreated .  Furthermore trazodone should be used in caution in pt with condition that predispose priapism such as sickle cell, multiple myeloma  Other side of alpha 1 antagonism is postural hypotension( orthostatic hypotention). o Trazodone is also a potent h1 receptor antagonist and the ensuing effects of trazodone can actually be quite pronounced. We save trazodone for last because it is not a first line treatment for depression having been supplanted by the ssri , rather because of its hypnotic effects, its main therapeutic its for pt with insomnia and depression . because of its sedative effects, trazodone should be avoided in elderly and should not be used with other cns depressants including benzos and barbiturates. Trazodone is a sedating antidepressant most often used as a hypnotic to treat insomnia associated with depression or with antidepressant treatment. o Although its less common compared to other antidepressant that effects serotonin like ssri, trazodone can cause sexual dysfunction

o

Can cause Serotonin syndrome- the weak inhibition of serotonin uptake with trazodone means we should keep this side effect in mind here too