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IF AN SSRI . WHICH ONE FIRST
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Overview for If an SSRI … Which One First?
This program will provide an overview of the similarities and differences between the five (5)currently available selective serotonin reuptake inhibitors (SSRIs) that are available in theU.S.
The overview is designed to give clinicians an overview of the five agents across twenty-six(26) different variables so as to assist in making the best possible decision as to whether or notto use this class of medications at all, and if so, to decide which one might be the "best" SSRIto start with for a particular patient. In some cases, one might be deemed preferable, and thispaper is designed to help clinicians decided this in selected cases where this is possible. Thepaper starts fromthe assumption that the five agents are more similar than different.
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Learning Objectives for If an SSR … Which one First?
1. To gain an understanding of the similarities and differences between the five selectiveserotonin reuptake inhibitors (SSRI's)2. To be able to make informed collaborative decisions regarding which SSRI to use first.
3. To be able to understand the factors leading to being able to decide which SSRI to use first.
4. To be able to better differentiate this new class of antidepressants from the other classes ofantidepressants (e.g.
older TCA's and other newer non-SSRI's).
5. To better understand the pros and cons of using each individual SSRI6. To be better able to interact with pharmaceutical representatives and their literature in amore informed manner.
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“IF AN SSRI . WHICH ONE FIRST?”
Given the rise in popularity of the antidepressant class known as the selectiveserotonin reuptake inhibitors (SSRIs) this article will attempt to address the questionthat this author frequently gets asked in the context of psychopharmacologycollaboration and consultation, that being “Which SSRI is the best one?” or “WhichSSRI should be used first?”
By way of simple review, there are currently 23 antidepressants available in the UnitedStates, 14 of which are older and not used as widely. The other 9 are the newerantidepressants, 5 of which are SSRIs which will be the focus of this article and theother 4 being Remeron®/Remeron SolTab, Serzone®, Wellbutrin®/Wellbutrin-SR®,and Effexor®/Effexor-XR®. The 14 older antidepressants are mostly defined by thetricyclic antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs).
These older agents are rarely the first-line agents in major depression and are typicallyonly used in cases of severe, treatment-resistant major depression when numerousnewer antidepressants have failed and/or in situations where they are used off-label(e.g. trazodone [Desyrel®] by non-psychiatrists, or for insomnia and pain syndromes(amitriptyline (Elavil®).
The 5 SSRI’s currently available are as follows (in order in introduction to the U.S.
fluoxetine (Prozac®) sertraline (Zoloft®) paroxetine (Paxil®) fluvoxamine (Luvox®) citalopram (Celexa®)
Based on previous articles by this author (Egli, 2000) I believe that these 5 agents areessentially more similar than different. In that earlier article I refer to them as“fraternal quintuplets” because of their similarity of efficacy as well as their similarityin many other domains. In this article we will try to examine in more detail some oftheir similarities and differences in order to help clinicians formulate an intelligentanswer to the question “which SSRI first?” for each individual patient.
In this article, I would like to take 26 different variables and compare each of the fiveSSRIs along those 26 domains in order to help clinicians better distinguish betweenthe 5 SSRIs and to be able to choose between them in cases where one agent might beseen as more preferable to another within this class. In order to assist in the learningprocess, two figures are provided. Figure 1, which is blank, is to be completed as thetopic is discussed. Figure 2 has been completed.
I am neither advocating the use of this class of antidepressants, nor the use of aparticular SSRI. However, I want clinicians to be informed about SSRIs in case they
decide to use them as the drug of first choice for a particular patient. Every case needsto be individualized and tailored to that patient's personal needs and the first-line agentneeds to be determined based on a complex interaction of issues not limited to, butincluding, such things as:
Co-morbid medical conditions Concurrent psychotropic medications Concurrent non-psychotropic medications Concurrent over-the-counter (OTC) and herbal/"natural” preparations Previous personal history of response to a particular agent Any family history of preferential response to an agent Cost Previous history (real or perceived) of non-response to a particular agent Previous family history of non-response to a particular agent Previous history of side-effect profile (good or bad) to a particular agent Concurrent substance abuse (drug or alcohol) Previous history of earlier or delayed response to a particular agent
The other major development with the SSRIs is that they (along with the other newantidepressants) have essentially taken over the anxiolytic market. These are allbroad-spectrum efficacy agents that typically have panicolytic, anti-obsessional, andanti-compulsive properties in addition to their obvious antidepressant properties.
At least one of these agents has received FDA approval for the treatment of anxiety
disorders such as social phobia, panic disorder, OCD, GAD, and PTSD.
all 5 of these agents are being used off-label for each and every one of these anxiety
disorders. The fact that they are neither CNS depressants nor addicting is sufficient to
explain the takeover of the anxiolytic market. Benzodiazepines are less commonly
used in even moderate doses for moderate lengths of time. Even the
hypnotic/insomnia market has essentially been taken over by non-benzodiazepine,
non-habituating antidepressants (e.g. trazodone [Desyrel] and mirtazapine [Remeron
SolTab®]). In some parts of the country, however, zolpidem (Ambien®) and zaleplon
(Sonata) are still in widespread use. Zopiclone® (the third “ZZZ” drug) marketed as
Imovane is not available in the United States. These are medications that have little
anticholinergic (drying) effects and yet low (non-antidepressant) levels of these
medications can be used to treat insomnia without the risk of addiction, without CNS
depressant effects, and without “morning hangover.” Even when morning “hangover”
occurs, it is usually very simple to treat by either slightly reducing the dose (slightly)
and/or changing the nighttime dose to an earlier hour.
Since these agents only have adult indications, the following information does notapply to pediatric, adolescent, or geriatric populations. It is not that these agents areavoided for these age groups; it is simply that there is little data and no formalindication (FDA-approval) for use in these populations. Fluoxetine’s depressionindication does, however, include geriatric outpatients. Where severity warrants,widespread use of these agents off-label in all three age groups is common and
standard clinical practice. With that as a backdrop, let’s now proceed to take a look ateach of the 26 domains so that we can begin to compare and contrast the 5 SSRIs.
(1) LATENCY OF ONSET OF ACTION (LOOOA)
Although there are individual exceptions, the LOOOA for all five SSRIs isapproximately one month. Various authors cite figures such as 3 to 5 weeks, 4 to 6weeks, 3 to 6 weeks, but in this authors office we consistently let people know thatthey should not look for any of the SSRIs to “kick in” before a month. Obviouslythere are individuals that are early responders and individuals that are delayedresponders but this can not be determined until the particular SSRI is started. Theonly way one would know if someone was an early or delayed responder is byhistory. If the patient had previous episodes of depression, what was the typicalresponse to antidepressants? It is this author’s opinion that all 23 currentlyavailable antidepressants in the United States have a similar LOOOA. Accordingly,none of the five antidepressants can be chosen as a first-line agent on the basis ofLOOOA.
(2) TERATOGEN RATING
The current teratogen (impact on fetus from effects of psychotropic drugs) ratingsby the FDA are: Category A (minimal to no problem), Category B (mild), CategoryC (moderate), Category D (severe), and Category X (extreme danger). All fiveSSRIs have a teratogen rating of C. Although all five SSRIs have the sameteratogen rating, the only consistent data on any of the five SSRIs appears to bewith fluoxetine. In spite of Lilly’s protest the FDA downgraded Prozac’s teratogenrating from a B to a C, thus equalizing and leveling the “playing field” for thisparticular domain.
(3) HALF-LIFE (t_)
Half-life is the time it takes for the plasma drug concentration to drop to half itspeak level. During the second half-life the drug level falls to 25% during the thirdhalf-life, and so on. After 6 half-lives, ~98.4% of the drug would be eliminated.
Essentially, all of the SSRIs except Prozac® have a half-life of approximately 1day. Only Prozac®, and its metabolite (norfluoxetine) have a much longer half-life.
The approximate half-life for fluoxetine (the parent compound) is 2 to 4 days, andthe half-life of the active, non-inert metabolite norfluoxetine is 7 to 15 days. Thehalf-lives of the four SSRIs, respectively (reading from left to right on Figure 1.)are 26 hours for sertraline, 21 hours for paroxetine, 15 hours for fluvoxamine, and35 hours for citalopram. The fact that a particular agent has a short or long half-life is neither a disadvantage nor an advantage, but both. We could cite exampleswhere the long half-life of Prozac® (and its metabolite) would be a benefit (in casesof missing a dose) and where the long half-life is a disadvantage (switching to aMAOI). Likewise, one could cite both the disadvantages of the short half-lifeSSRIs (discontinuation syndrome) as well as advantages (e.g. briefer time to beable to start MAOI). The pharmacologic rule, sometimes referred to as the “Lawof 4 or 5” refers to the fact that if one multiplies the half-life of the drug by 4 or 5,
one can roughly determine how long it will take for the drug to completely be outof one’s system.
(4) TYPICAL ADULT RANGE
Although some adults who are hypersensitive to side-effects or who ruminate aboutthe possibility of side-effects need to start at lower-than-typical doses, dosageranges for the five SSRIs are as follows:
Prozac® 20-60 (mg) Zoloft® 50-200 (mg) Paxil® 20-60 (mg) Luvox® 50-300 (mg) Celexa® 20-60 (mg)
Not only will some individuals need to start at lower than normal starting doses,but some may not achieve a therapeutic effect unless they have supra-therapeuticdoses. Prior to exceeding the ceiling doses, obtain the patient's informed consent.
The five SSRIs have the following indications (FDA approval):
Prozac®: major depressive episode (MDE),
bulimia, and pre-menstrual dysphoric disorder (PMDD),
Zoloft®: MDE, OCD, panic disorder, and post-traumatic stress disorder
Paxil®: MDE, OCD, panic disorder, social phobia/social anxiety
disorder, PTSD, and generalized anxiety disorder (GAD),
It is important to remember that because an SSRI has a particular indication, thishas ABSOLUETLY NOTHING to do with preferential efficacy. It simply meansthat the manufacturer spent the money to prove that it worked more effectivelythan placebo. Conversely, the fact that a particular SSRI is not indicated forsomething (e.g. Celexa® is not indicated for OCD) does not mean that it might notbe equally efficacious. In fact, it usually is. In fact, it simply represents that themanufacturer has decided not to spend the millions of dollars in doing the studiesgiven that there are already a large market share of prescribers using the drug forthat particular off-label indication. In fact, this author has used all five SSRIs withboth major depression and each of the major anxiety disorders with approximateequal efficacy. As another example, because Luvox® is only approved for OCD,does not mean that it works preferentially well in adults with OCD. It simplymeans that the drug company only chose to spend the money on that particularindication.
(6) LIQUID FORMULATION (YES/NO)
Prozac®, Zoloft®, Paxil®, and Celexa® are available in a liquid formulation whileLuvox® is not. Of the four SSRIs that come in a liquid formulation, Celexa® andPaxil® do not contain alcohol. The amount of alcohol content in Prozac is 0.23%while the amount of alcohol in the oral concentrate of Zoloft® is 12%, high enoughfor it to be contraindicated with Antabuse®, and in the other two it is minimal.
Liquid formulations are typically considered in individuals who have troubleswallowing tablets/capsules or in individuals (pediatric or geriatric populations)who are responsive to extremely low (e.g. 2mg) doses of an SSRI. Because of thebad taste of liquid Prozac that some patients complain of, we simple have them mixit with cranberry juice so that they can have their daily dose of “Cranzac.”
120ml (4 oz.)60ml (2 oz.) 250ml (8.3 oz.) --
* ÓinertÓ amount (i.e. inactive ingredient)** contraindicated if taking disulfiram (Antabuse¨) concurrently
(7) OFF-LABEL USAGE
Because all five SSRIs have very similar off-label usage profiles, they are used forthe following diagnoses: (one’s where SSRIs are frequently employed:)
OC-spectrum disorder (paraphilias, trichotillomania, body dysmorphic
disorder [BDD], kleptomania, and gambling)
(8) P450 (Drug-drug interaction potential)
P450 refers to the interaction of an SSRI with other drugs. I believe that that thedrug manufacturers have emphasized P450 for marketing purposes rather than forclinical importance. In my 20 years of practice, not one of my patients has had anyserious P450 problems. Of course, a good clinical interview should be conductedbefore prescribing any medication. P450 is of more concern in geriatric populationsbecause those patients are taking many more prescription medications. I will,however, address the particular isoenzyme of concern to the SSRI of choice, andthere are now numerous sources where the P450 drug-drug interaction profiles areupdated and reviewed on a regular (often semi-annually) basis so that drug-druginteraction problems can be minimized. Depending on whether the drug is aninhibitor or inducer, the resultant drug-drug interaction will be one of either raising
or lowering the blood level thereby causing potential toxicity or lack of loss ofefficacy.
For Prozac® the isoenzyme pathway of concern would be 2D6. An example of aclass of drugs, which would be of concern to co-administer with the SSRIs, wouldbe the TCAs. Because of the pharmacokinetic interactions of these two classes,one could potentially see extremely high/toxic blood levels of the TCA combiningthese two classes. That is not to say that is never done, or shouldn't done in casesof severe, treatment-refractory major depression. In such cases careful therapeuticmonitoring of the blood plasma level of the TCA should be done. In addition, anytitration schedule of the TCA would be done extremely slowly. The isoenzyme ofconcern with Zoloft® would also be the 2D6 hepatic isoenzyme, though probablyonly at the higher range of the therapeutic dose. 2D6 would also be the isoenzymeof concern with Paxil®. Luvox®, is the SSRI with the most drug-drug interactionsand/or contraindications because both 1A2 and 3A4 are of concern. This is whatlead the manufacturer to emphasize various drug-drug cautions andcontraindications, some of which were with drugs that have, heretofore, beenwithdrawn because of the possibility of serious (lethal) cardiac side-effects. Otherpsychotropic classes of concern and caution include Clozaril® and thebenzodiazepines. Contraindicated agents that have since been withdrawn includedseveral of the antihistamines and azole anti-fungals (e.g. ketoconazole). Celexa®may have the “cleanest” P450 profile of the five and may only have some verylimited 2D6 concerns.
In cases where an SSRI is added to other medications that are “on board” or whereother medications are being added to the regimen of someone who is already on anSSRI, we do extensive literature reviews of any potential combination, seek asecond opinion, review the P450 literature, etc. before proceeding. By followingthis procedure I have been able to avoid any lethal or toxic side-effects. Of course,some patients have experienced usual side-effects.
(9) ALTERNATE NAMES
Only Prozac® has two alternate names, those being a 90mg per week formulationknown as Prozac Weekly® and Serafem® (for PMDD). Just as Wellbutrin® andZyban® are both bupropion, so Serafem® and Prozac® are fluoxetine. I believe thatthe alternate names that drug companies choose are simply ways to (attempt to)extend the patent life of the drug and/or simply trying to rename the drug foradditional sales. Again, the alternate name of the drug has nothing to do witheither additional or lesser efficacy and is simply a marketing strategy of the drugcompany/manufacturer.
(10) GENERIC AVAILABLE (YES/NO)
Of the five SSRIs, only fluoxetine is available generically. Lilly, the manufacturerof Prozac, unsuccessfully fought against four different generic manufacturers(Teva, Barr, Par, and Geneva). I would expect all five manufacturers to dowhatever they had to extend their patent life so as to maximize their sales andprofit. According to the FDA, the generic manufacturers must prove
bioequivalence such that (theoretically) the generic formulations would be equallyeffective to the trade compound. I am sure that each of us have stories of someonewho when switched over (“a requirement of their mangled care plan”) to genericProzac (and because of a real or perceived lessening of efficacy,) went back into adepression. It is this author’s best guess (at this early stage) that for most peoplefluoxetine is probably bioequivalent to Prozac®. For bioequivalence a genericsmanufacturer must show that it’s drug is comparable to the innovator drug indosage form, strength, route of administration, quality, performance characteristicsand intended use (Saklad, 2002). The main concern is bioequivalence and, inparticular, bioavailability (does the drug deliver the same dose of active ingredientinto the bloodstream in the same amount of time). Extent and rate of absorptionare the main pharmacokinetic outcomes measured.
Each of the five manufacturers is talking about possible “moves” in the future.
Examples would be obtaining pediatric and/or adolescent major depressionindications for each of the five drugs. Luvox® might be interested in developing acontrolled-release (CR) formulation because it is the SSRI with the shortest half-life thereby requiring a b.i.d. (twice a day) dosing, which sometimes causes moreof a problem with compliance than the one-a-day (qd) dosing SSRI’s. Anotherpossible development would be an I.V. formulation of Celexa®, which like I.V.
formulations of other psychotropics (most notably the neuroleptics) would result inmore rapid absorption and considerably shorten the latency of onset of action.
These “in-the-pipeline” decisions will be made by the manufacturer based onmarketability and profit rather than on patient need. Obviously, if a certain drug isalready being used off-label for a particular disorder (not FDA-approved butwidely used in standard clinical practice) the drug company is not likely to spendthe money to seek an indication for alternative diagnoses (e.g. Luvox® fordepression). Other discussions revolve around other racemic (having to do withthe “handedness” of the drug chemically), formulations similar to what is beingdiscussed in the field of ADD/ADHD with methylphenidate. A soon-to-beapproved example of this is the (left-handed) racemic formulation of citalopramknown as escitalopram. Whether this is just a marketing ploy by the manufactureror a genuine attempt to improve efficacy remains unclear. In general, I do not seeany of these future moves to be a real surprise or to dramatically improve thecurrent levels of efficacy.
(12) SEXUAL DYSFUNCTION LIKELY (YES/NO)
Simply stated, yes! - for all five SSRIs. This is clearly the primary complaint fromthis class of drugs. I do not see any of the five consistently providing lesser relieffrom the sexual dysfunction that occurs for both men and women and for whichthere is little-to-no (in this author’s opinion) good solution. In addition this side-effect generally does not remit. Drug holidays from the short half-life SSRIscertainly eliminates the sexual dysfunction side-effects but may also put the personback in a state of clinical depression. I have not recommended this procedure to asingle patient and those who have done so, after being informed of the
consequences, have only done so once, vowing never to do it again. To enumeratethe various pharmacologic strategies to treat SSRI-induced sexual dysfunction isbeyond the scope of this discussion and furthermore, would not show anything tobe consistently effective. Decreased libido, delayed orgasm, and anorgasmia arenot uncommon. This is not to say that every patient will experience sexualdysfunction. Very infrequently, some patients will even have pro-sexual side-effects. The antidepressant with the least amount of sexual side-effects isWellbutrin®/Wellbutrin-SR®.
(13) MOST SEDATING (SIMPLY CHECK ONE BOX)
This author’s extensive use of all five SSRIs suggests Paxil® is the most sedatingfor the most people. Is this an advantage? Yes and no. Is this a disadvantage? Yesand no. For someone with an agitated major depression with significant insomniathis might be a significant advantage. For someone with a depression involvingsignificant hypersomnia, this would be a distinct disadvantage. The fact that theother SSRIs are probably less sedating (for large groups of people,) is also neither apure advantage nor a pure disadvantage. We allow the side-effect of sedation,activation, or neither to help determine the time of day the drug might be taken. Ifpatients experience sedation from an SSRI, they would take the drug at night.
Some people believe that, at least at higher doses, Paxil® may actually resemble anSNRI (serotonin – norepinephrine reuptake inhibitor) rather than remaining a pureSSRI. At these higher doses, its histaminic properties increase. Blockade ofhistaminic (H1 or H2) receptors is typically associated with drowsiness and weightgain.
(14) MOST ACTIVATING (SIMPLY CHECK ONE BOX)
Although any of the five SSRI can be activating, I have found Prozac to be moreconsistently activating than the others. Again, this is neither a pure advantage nor apure disadvantage. There are times when activation for someone with a significantanergic depression is desirable as long as the activation does not approach chroniclevels of restlessness. Conversely, the activation is a problem in patients withagitated depressions, with co-morbid ADD/ADHD, or who tried taking the drug atnight. Obviously, if someone is benefiting from the drug, but experiencingactivation, we will have them take it qAM (every morning). Activation in its mostsevere form could resemble a neuroleptic-like akathisia. If this occurs, immediatelydiscontinue the drug and switch either to another SSRI or another class. Sedation oractivation from one SSRI does not automatically imply a similar response with asecond SSRI. The same statement is true with regards to efficacy and side-effectsas well. That is to say, one may have efficacy from one SSRI and not another.
One may have a lack of response to one SSRI but get a robust response to thesecond SSRI. One might get a particular side-effect from SSRI #1 and not get thatside-effect at all from SSRI #2 or conversely not have a particular side-effect withSSRI #1 and have a significant amount of that side-effect from SSRI #2. Wecannot predict the response to a drug until it has been administered.
(15) INDUCE CYCLING (YES/NO)
Simply stated, yes to all five SSRIs. All five of these agents are equally likely, inlarge groups, to induce cycling. Giving an SSRI to someone who was presumed tobe unipolar but who is latently bipolar (Type I or Type II) may induce a manic orhypomanic state. If this happens, the pharmacologist would immediatelydiscontinue the SSRI, reevaluate the diagnosis as a probable cycling mood disorderand think in terms of a mood stabilizer. The fact that a person has not had aprevious history of mania or hypomania would not rule out the possibility ofbipolarity nor would the absence of bipolarity in the family history. Even in theface of what I consider to be a through clinical interview process, and additionallygetting to know the patient in psychotherapy over time, I have still made themistake of assuming the person had unipolar major depression, start an SSRI, onlyto have the patient “flip up” into a high. I educate my patients about the symptomsof mania or hypomania. Should such symptoms develop, patients are toimmediately call their prescriber who immediately will discontinue the drug. Inthis respect, none of the SSRIs is less likely to induce cycling than the other four.
(16) METABOLITE (S)
Essentially the only SSRI with a clinically significant (non-inert) metabolite isProzac®. Norfluoxetine is at least as potent as the parent compound andcontributes to its antidepressant/panicolytic/anti-obsessional, and anti-compulsiveproperties. Sertraline's metabolite desmethylsertraline is of negligible clinicalsignificance being approximately only 1/25 as potent as the parent compound.
Paxil® and Luvox® are thought not to have clinically measurable metabolites whilethe metabolite of Celexa® is also thought to be of negligible contribution being lessthan 1/10 as potent as the parent compound. As discussed above, the significanceof Prozac’s metabolite probably has less to do with efficacy and more to do withissues related to its half-life.
(17) CARDIOTOXICITY (YES/NO [ESSENTIALLY NONE])
Since all five SSRIs are relatively/essentially non-cardiotoxic, this domaindifferentiates the SSRIs from the older agents. For the vast majority of patients,the SSRIs are relatively safe. Where there are questions, we simply obtain acardiology consultation. Cardiotoxicity is more an issue when an SSRI is added toa regimen of other medications or other medications are added to the regimen of anSSRI such that the pharmacokinetic and/or pharmacodynamic interaction causes amore significant cardiac side-effect. Cardiotoxicity is one of the major concerns ofthe older tricyclics (TCAs) and was a leading concern when there were suddendeaths of children on desipramine. For patients without pre-existing cardiacdisease, I do not see prescribers routinely recommending baseline EKGs, obtainingcardiac consultations, or doing other cardiac workups (stress test, echocardiogram,etc.).
(18) LETHALITY IN OVERDOSE (YES/NO)
This domain is also primarily here to separate this class from the older tricyclics.
Given that the TCAs are extremely lethal in overdose, one can say with equalreliability that all five SSRIs are relatively non-lethal in overdose. That is not to
say that it would be impossible for patients to take their life with an overdose of anSSRI alone, but it would take a “boat load” of that SSRI to do so. The reason is thatthe TCAs have a narrow therapeutic index (small difference between therapeuticand lethal dose) whereas the SSRIs have a very wide therapeutic index (extremelylarge difference between therapeutic and lethal dose). The vast majority of suicidecompleters who had an SSRI in their toxicology reports, also had numerous otherdrugs “on board” and, to date, the number of deaths world-wide from anaggressive, huge overdose of an SSRI alone, is very few and rare. All five SSRIs,then, are equally likely to be non-lethal in overdose. Therefore, I believe that allfive SSRIs have a very good safety record.
Using the AWP (average wholesale price) data for a one-month supply of this classof medication would indicate that they are fairly “pricey.” The following priceswere quoted for the following daily doses:
Prozac® 20mg qd = $87.00/mo.
Generic Prozac 20mg qd = $80.00/mo. (!) Zoloft® 50mg qd = $72.00/mo.
Paxil® 20mg qd = $77.00/mo.
Celexa® 20mg qd = $66.00/mo.
As excited as people have been to have one of the SSRIs available generically, itappears that all four generics manufacturers are also looking to make huge profits.
The monthly price of the generic version of Prozac is surprisingly similar in priceto trade name Prozac®. If there were any questions at all about bioequivalence,cost issues alone would lead this author to stay with the trade name compound. Thesaving is very little.
Each SSRI manufacturer has a program that supplies the drug free to indigentpatients. (physician recommendation is required.) This author’s strategy over thepast 20 years has been to build relationships with pharmaceutical representative.
All of the reps have been very happy to drop off samples to a patient’s physician inthat patients name after obtaining consent of physician and patient. I have not hada single patient who has had to discontinue an SSRI because of the cost. Becauseeach drug rep is competing with four other drug reps for an essentially similarproduct, they are always pleased to have a call from me requesting that theirproduct be the one that is delivered in person to the physician’s office for aparticular patient. They are happy to do so and usually rush to get it done. Onesavings strategy is to remember that citalopram (Celexa®) and sertraline (Zoloft®)cost very little more for the larger dose sizes, which are scored and, as such, givetwice as many milligrams for the price. Also, when floxetine’s generic exclusivityis lost in February 2002 the number of generic manufacturers is likely to expandand hopefully drive down the price.
(20) WASH-OUT TO MAOI (WEEKS)
This dimension refers to the length of time between discontinuing the SSRI andstarting an MAOI. With the exception of Prozac®, an MAOI may be started twoweeks after the discontinuation of the SSRIs. Because of the long half-life of themetabolite of Prozac® (norfluoxetine), the most conservative figure is to wait fiveweeks between discontinuing Prozac® and starting an MAOI. This will be true forall three of the MAOIs currently available in the United States (Nardil®, Parnate®,and Marplan®). To avoid inducing a serotonin syndrome wait two-weeks afterdiscontinuing Zoloft®, Paxil®, Luvox®, and Celexa® (after) at least five-weeks afterdiscontinuing Prozac® before starting an MAOI.
MAOIs are, however, not usually used except in cases of severe, treatment-refractory major depression and where there is a high degree of likelihood that thepatient can understand and comply with the complex dietary restrictions. Becauseof the length of the “washout” required when going from Prozac® to an MAOI,there is usually an increased risk of patients decompensating and developing or re-developing a major depression or significant symptoms of the anxiety disorder forwhich they are being treated.
(21) COADMINISTER WITH MAOI (YES/NO)
Simply stated, no! The risk for the development of a serotonin syndrome whencombining any of the five SSRIs with an MAOI is both significant and severe.
Symptoms of the serotonin syndrome could include hypothermia, diaphoresis, G.I.
distress, significant mental status changes, and myoclonus. A new concern in theintroduction of the antibiotic linezolid (Zyvox), which is a reversible MAOI(RIMA). Prescribers are unsure how to manage the antidepressant choice forpatients on it, as there is now one case report of a patient developing serotoninsyndrome on the combination of linezolid and sertraline.
(22) THERAPEUTIC DRUG MONITORING (TDM) YES/NO
TDM is not done nor recommended for any of the five SSRIs. The technology isnot developed such that the drug monitoring of the SSRI plasma levels isconsidered to be cost-effective or accurate. Accordingly, TDM is not done inroutine clinical practice during the administration of any of the five SSRIs. TDMwas more routinely practiced with various TCAs in the past and is still done withcertain psychotropic medications (e.g. some of the mood stabilizers like Lithium®,Depakote®, and Tegretol®). Because of the cost and reliability/accuracy problem,TDM is not recommended with the SSRIs. One must then rely on clinician andpatient assessment of symptom reduction as a way of determining whether or not toraise, lower, or maintain the drug dose. We do not know in advance who are the“rapid metabolizers,” who might require higher or supra-therapeutic doses of anSSRI to achieve efficacy nor do we know who are the “slow metabolizers” whowith sub-therapeutic doses might develop a therapeutic response to the drug. Thisis purely trial-and-error and, as such, most prescribers follow the “start low, goslow, work up” rule as far as titrating the dose.
(23) EFFICACY TO TCAs
For major depression, all five SSRIs are as effective as the TCAs. That is to say,none of the five SSRIs are more effective than any of the older agents for majordepression. Choosing an SSRI as a first-line agent, then, would not be based ongreater efficacy but rather on other dimensions such as the greater efficacy withcomorbid anxiety disorders (OCD, social phobia, PTSD, GAD, and panic disorder)as well as the relative non-lethality in overdose, relatively non-cardiotoxicity, and,overall, fewer side-effects. For the treatment of depression, none of themanufacturers of the 23 currently available antidepressants in the United States canclaim greater efficacy either individually or as a class over any other drug or anyother class (in regards to major depression). Efficacy is not what differentiatesthem either from class to class or within class.
(24) PHARMACOKINETICS (LINEAR OR NON-LINEAR)
Only Zoloft® and Celexa® have linear pharmacokinetics while the other three(Prozac®, Paxil®, and Luvox®) have non-linear pharmacokinetics. Linearpharmacokinetics basically means a change in drug dose results in a proportionalchange in drug concentration. I am not sure there is a huge practical clinicalbenefit to this information. The drug reps from the companies of SSRIs with linearpharmacokinetic will make a big deal of this aspect. Linear pharmacokineticsmight be clinically useful if therapeutic drug monitoring reliably predicted bloodplasma level with Zoloft® and Celexa® when the dose is raised. We simply need tobe aware that when raising the dose of SSRIs that have non-linearpharmacokinetics, the blood plasma levels of (Prozac®, Paxil®, and Luvox®) might“swing” wider than with the other two. I have not seen or experienced non-linearity to be a clinical problem. Perhaps this is more of a theoretical or academicinterest.
(25) “POOP OUT”(YES/NO)
Simply stated, all five SSRIs are equally likely to show the possibility of “poopout.”
“Poop out” is a term used by many patients when a drug that was previouslyworking either seems to stop working all together or begins to work less well. Iwould not predict this routinely with any of the five SSRIs. More often than not,“poop out” is the result of the failure to titrate the dose up to therapeutic levels.
Non-compliance should also be ruled out as a possible cause. The solution/clinicaldecision is simply to “turn the dial up a notch” and increase the dose slightly.
Usually this takes care of the “poop out” effect once steady state has been re-achieved. If that does not work we will increase the dose even further (if it is beingtolerated fairly well) or switch to a different SSRI. Even if “poop out” occurs inthe context of apparent therapeutic levels of the drug, if the drug is being toleratedreasonably well we would still proceed in a similar manner by typically increasingthe dose another 10 or 20mg. The reason for this phenomena is unknown.
(26) DISCONTINUATION SYNDROME (YES/NO)
All four of the short half-life SSRIs can present with a discontinuation syndrome ifthe drugs (Zoloft®, Paxil®, Luvox®, or Celexa®) are abruptly discontinued. This isnever recommended. We taper slowly so as to avoid the discontinuation syndrome.
I think that the word discontinuation syndrome is preferred over withdrawalsyndrome because the latter term is reserved for drugs that areaddicting/habituating. Because of the long half-life of both the parent compoundand it metabolite, Prozac® is the only drug of its class that does not cause adiscontinuation syndrome. The discontinuation syndrome can be quite annoyingand is not unlike a flu-like syndrome lasting approximately 3 to 5 days. On author(Preskorn, 1999) uses the mnemonic FLUSH to remember the major symptoms ofthe discontinuation syndrome. The mnemonic is as follows:
lu-like (fatigue, myalgia, loose stools, and nausea),L
leep and sensory disturbancesH
The three major risk factors for this syndrome are the time on the drug, potency ofthe drug, and half-life of the drug.
In fact, some prescribers administer low doses of Prozac® to off-set the symptomsof the discontinuation syndrome that is brought on by a patient stopping a shorthalf-life SSRI too quickly. Obviously, then, the way to avoid this problem is totaper and discontinue the drug more slowly and over a longer period of time. Ihave not seen one case of discontinuation syndrome in any patient who follows thisdirective. In some cases when we switch from one antidepressant to another in ahurry, we alert the patients to what the discontinuation syndrome will be, and howlong they are likely to experience it. We sometimes see the rapid discontinuationas the “lesser of two evils” in the process of getting patients quickly into anotherantidepressant protocol. That is to say, we can live with the possibility of adiscontinuation syndrome over the possibility of a relapse.
In summary, considering these 26 variables across the five SSRIs, we conclude thatthere is no such thing as “the best SSRI.” The best SSRI is the one that works the best,by itself, with the greatest efficacy, with the fewest side-effects, at the lowest dose, andthat helps to maintain a state of euthymia (no mood disorder) once the drug isdiscontinued. At this time, we cannot determine which SSRI will do that for anindividual person until we select one of the five. Choosing one that works beautifully,for a specific patient does not mean that any other SSRI might not have worked aswell. Because one SSRI might be more activating than the others more of the timedoes not mean it should not be chosen as a first-line SSRI. Because one SSRI mightbe more sedating than the others for most people does not mean it should not bechosen as a first-line SSRI. Because one SSRI seems to have a better P450 profile(fewer drug-drug interactions) does not automatically mean that it should beconsistently chosen as the first-line SSRI.
As a class, the SSRIs have been an important addition to the antidepressant arena. Ithink that the similarities are far greater than the differences and as a clinician who hasused all five SSRIs consistently for many years, I will not hesitate to continue to useall five as a first-line agent and generally still find myself not agreeing with the drugrep from each of respective manufacturers about the supposed significant clinicaldifferences between them. Although I realize that a particular patient may have adifferential response to a specific SSRI, I do not believe this is true for most people orfor large groups. This list of 26 items is not meant to be comprehensive. An exampleof a category that certainly needs to be additionally factored in would be propensity forweight gain. In this respect, Paxil® would be the biggest culprit among the five.
Again, this alone would not be a reason to preclude its use as a first-line agent. Proteinbinding, incidence of EPS, and likelihood of rash might be other examples.
On occasion, I interact with prescribers who report having a favorite but when I askwhy, the reasons given are rarely ones that would lead me to believe that the particularSSRI among the five would be the one that I would consistently choose first for everypatient. What I would recommend is that the readers become familiar with all fiveagents, use all five in appropriate situations, and individualize treatment so that manyfactors are used to determine which SSRI might be chosen first. Although in somecases it might be more clear cut (e.g. previous personal history of a robust response toa particular agent in a previous episode of depression), my suspicion is that for manypatients any one of the five as a first-line agent would work fairly well. In cases ofclear-cut treatment resistance (inadequate response after adequate dose and adequateduration), the literature suggests trying a second SSRI before moving out of class.
I trust this summary will be helpful to the readers in becoming more familiar with thiswidely used class of medication.
The opinions expressed are those of the author alone and should not be construedas a substitute for medication decisions that can and should only be made in thecontext of a good prescriber-patient relationship. Unless a Level III prescribingpsychologist (DOD/PDP grad), Level II collaboration should be guided by StateBoard of Psychology guidelines. Although this paper is unsupported by anypharmaceutical company grants, Dr. Egli is either on the Visiting Faculty or hasreceived education grants from all five of the manufacturers of the SSRIs (Eli Lilly,Pfizer, Glaxo SmithKline, Upjohn/Solvay, and Forest Pharmaceutical). Dr. Egli’sCM/CME Programming has met criteria for an unrestricted educational grantaccording to the FDA, AMA, and ACCME guidelines.
Note: Figure 1. is designed as a fill-in post-test while, Figure 2. found at the back ofthe volume is the completed quiz.
The author expresses sincere appreciation for the helpful reviews and feedback
from: Jack Wiggins, Ph.D. ~ Reuben Silver, Ph.D. ~ James Jefferson, M.D.
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Multi-analyte assay of 23 Anti Epileptic Drugs (AEDs) in human plasma Renata Lagewaard, Ronald Vermunt, Toos de Mooy, Jos vd Elshout, Robert vd Wegen, Robert Wortelboer and Rudi Segers Introduction Until the early 1990s, the choice of antiepileptic medication was limited to traditional drugs such as phenobarbital, primidone, phenytoin, carbamazepine and valproate. Although th
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