IF AN SSRI.. WHICH ONE FIRST

Transcription

1 IF AN SSRI.. WHICH ONE FIRST By Dan Egli, Ph.D. Accredited for Continuing Education By Psy Broadcasting Corporation (PsyBC) This paper can be downloaded from the PsyBC library

2 Continuing Education Information: - Overview and Educational Objectives - Learning Objectives - Instructions for accessing PsyBC s automated testing center 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 the U.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 not to use this class of medications at all, and if so, to decide which one might be the "best" SSRI to start with for a particular patient. In some cases, one might be deemed preferable, and this paper is designed to help clinicians decided this in selected cases where this is possible. The paper starts fromthe assumption that the five agents are more similar than different. Value: 3 continuing education credits Learning Objectives for If an SSR Which one First? 1. To gain an understanding of the similarities and differences between the five selective serotonin 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 of antidepressants (e.g. older TCA's and other newer non-ssri's). 5. To better understand the pros and cons of using each individual SSRI 6. To be better able to interact with pharmaceutical representatives and their literature in a more informed manner. Accessing PsyBC s Automated Testing Center PsyBC is now using an automated system that will allow you to take your test for continuing education credits, fill out the course evaluation form, pay the fee, and print out your certificate of completion all online. INSTRUCTIONS: 1) Go to the PsyBC website < 2) Click on "Testing Center" in the navigation bar at the top.

3 3) Register (only necessary if this is the first time you have used the system). 4) Click "Login" 5) Click on "Buy Credits" in the top navigation bar and purchase the number of credits for which this symposia is valued. 6) Click on "Testing Area" 7) Find the symposium for which you wish to receive credit and click on "go to test". 8) Take the test and fill out the evaluation form. After clicking on "submit" you will receive your test results. If you have not passed the test you will be given another opportunity to take the test. 9) After successfully completing the test click on "My Profile" at the top navigation bar. There you will be able to retrieve and print out your certificate. 3

4 IF AN SSRI.. WHICH ONE FIRST? Dan Egli, Ph.D. Given the rise in popularity of the antidepressant class known as the selective serotonin reuptake inhibitors (SSRIs) this article will attempt to address the question that this author frequently gets asked in the context of psychopharmacology collaboration and consultation, that being Which SSRI is the best one? or Which SSRI should be used first? By way of simple review, there are currently 23 antidepressants available in the United States, 14 of which are older and not used as widely. The other 9 are the newer antidepressants, 5 of which are SSRIs which will be the focus of this article and the other 4 being Remeron /Remeron SolTab, Serzone, Wellbutrin /Wellbutrin-SR, and Effexor /Effexor-XR. The 14 older antidepressants are mostly defined by the tricyclic antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs). These older agents are rarely the first-line agents in major depression and are typically only used in cases of severe, treatment-resistant major depression when numerous newer 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. market): 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 are essentially 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 similarity in many other domains. In this article we will try to examine in more detail some of their similarities and differences in order to help clinicians formulate an intelligent answer 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 five SSRIs along those 26 domains in order to help clinicians better distinguish between the 5 SSRIs and to be able to choose between them in cases where one agent might be seen as more preferable to another within this class. In order to assist in the learning process, two figures are provided. Figure 1, which is blank, is to be completed as the topic is discussed. Figure 2 has been completed. I am neither advocating the use of this class of antidepressants, nor the use of a particular SSRI. However, I want clinicians to be informed about SSRIs in case they

5 decide to use them as the drug of first choice for a particular patient. Every case needs to be individualized and tailored to that patient's personal needs and the first-line agent needs to be determined based on a complex interaction of issues not limited to, but including, 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 new antidepressants) have essentially taken over the anxiolytic market. These are all broad-spectrum efficacy agents that typically have panicolytic, anti-obsessional, and anti-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. In addition, 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 not apply to pediatric, adolescent, or geriatric populations. It is not that these agents are avoided for these age groups; it is simply that there is little data and no formal indication (FDA-approval) for use in these populations. Fluoxetine s depression indication does, however, include geriatric outpatients. Where severity warrants, widespread use of these agents off-label in all three age groups is common and 5

6 standard clinical practice. With that as a backdrop, let s now proceed to take a look at each 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 is approximately one month. Various authors cite figures such as 3 to 5 weeks, 4 to 6 weeks, 3 to 6 weeks, but in this authors office we consistently let people know that they should not look for any of the SSRIs to kick in before a month. Obviously there are individuals that are early responders and individuals that are delayed responders but this can not be determined until the particular SSRI is started. The only way one would know if someone was an early or delayed responder is by history. If the patient had previous episodes of depression, what was the typical response to antidepressants? It is this author s opinion that all 23 currently available 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 of LOOOA. (2) TERATOGEN RATING The current teratogen (impact on fetus from effects of psychotropic drugs) ratings by the FDA are: Category A (minimal to no problem), Category B (mild), Category C (moderate), Category D (severe), and Category X (extreme danger). All five SSRIs have a teratogen rating of C. Although all five SSRIs have the same teratogen rating, the only consistent data on any of the five SSRIs appears to be with fluoxetine. In spite of Lilly s protest the FDA downgraded Prozac s teratogen rating from a B to a C, thus equalizing and leveling the playing field for this particular domain. (3) HALF-LIFE (t _ ) Half-life is the time it takes for the plasma drug concentration to drop to half its peak level. During the second half-life the drug level falls to 25% during the third half-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 1 day. 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, and the half-life of the active, non-inert metabolite norfluoxetine is 7 to 15 days. The half-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, and 35 hours for citalopram. The fact that a particular agent has a short or long halflife is neither a disadvantage nor an advantage, but both. We could cite examples where the long half-life of Prozac (and its metabolite) would be a benefit (in cases of missing a dose) and where the long half-life is a disadvantage (switching to a MAOI). Likewise, one could cite both the disadvantages of the short half-life SSRIs (discontinuation syndrome) as well as advantages (e.g. briefer time to be able to start MAOI). The pharmacologic rule, sometimes referred to as the Law of 4 or 5 refers to the fact that if one multiplies the half-life of the drug by 4 or 5, 6

7 one can roughly determine how long it will take for the drug to completely be out of one s system. (4) TYPICAL ADULT RANGE Although some adults who are hypersensitive to side-effects or who ruminate about the possibility of side-effects need to start at lower-than-typical doses, dosage ranges for the five SSRIs are as follows: Prozac (mg) Zoloft (mg) Paxil (mg) Luvox (mg) Celexa (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-therapeutic doses. Prior to exceeding the ceiling doses, obtain the patient's informed consent. (5) INDICATIONS The five SSRIs have the following indications (FDA approval): Prozac : major depressive episode (MDE), obsessive-compulsive disorder (OCD), bulimia, and pre-menstrual dysphoric disorder (PMDD), Zoloft : MDE, OCD, panic disorder, and post-traumatic stress disorder (PTSD), Paxil : MDE, OCD, panic disorder, social phobia/social anxiety disorder, PTSD, and generalized anxiety disorder (GAD), Luvox : OCD Celexa : MDE It is important to remember that because an SSRI has a particular indication, this has ABSOLUETLY NOTHING to do with preferential efficacy. It simply means that the manufacturer spent the money to prove that it worked more effectively than placebo. Conversely, the fact that a particular SSRI is not indicated for something (e.g. Celexa is not indicated for OCD) does not mean that it might not be equally efficacious. In fact, it usually is. In fact, it simply represents that the manufacturer has decided not to spend the millions of dollars in doing the studies given that there are already a large market share of prescribers using the drug for that particular off-label indication. In fact, this author has used all five SSRIs with both major depression and each of the major anxiety disorders with approximate equal efficacy. As another example, because Luvox is only approved for OCD, does not mean that it works preferentially well in adults with OCD. It simply means that the drug company only chose to spend the money on that particular indication. 7

8 (6) LIQUID FORMULATION (YES/NO) Prozac, Zoloft, Paxil, and Celexa are available in a liquid formulation while Luvox is not. Of the four SSRIs that come in a liquid formulation, Celexa and Paxil 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 enough for it to be contraindicated with Antabuse, and in the other two it is minimal. Liquid formulations are typically considered in individuals who have trouble swallowing tablets/capsules or in individuals (pediatric or geriatric populations) who are responsive to extremely low (e.g. 2mg) doses of an SSRI. Because of the bad taste of liquid Prozac that some patients complain of, we simple have them mix it with cranberry juice so that they can have their daily dose of Cranzac. Y/N Y Y Y NY % alcohol 0.23%* 12%** 0% -- 0% mg/ml 20mg/5ml 20mg/ml 10mg/5ml -- 10mg/5ml oz. Bottle 120ml (4 oz.)60ml (2 oz.) 250ml (8.3 oz.) -- 4 oz. flavor(s) mint -- orange -- peppermint scent mint menthol citrus -- mint color clear clear orange -- clear * inert 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 for the following diagnoses: (one s where SSRIs are frequently employed:) OC-spectrum disorder (paraphilias, trichotillomania, body dysmorphic disorder [BDD], kleptomania, and gambling) Child and adolescent major depression (8) P450 (Drug-drug interaction potential) P450 refers to the interaction of an SSRI with other drugs. I believe that that the drug manufacturers have emphasized P450 for marketing purposes rather than for clinical importance. In my 20 years of practice, not one of my patients has had any serious P450 problems. Of course, a good clinical interview should be conducted before prescribing any medication. P450 is of more concern in geriatric populations because those patients are taking many more prescription medications. I will, however, address the particular isoenzyme of concern to the SSRI of choice, and there are now numerous sources where the P450 drug-drug interaction profiles are updated and reviewed on a regular (often semi-annually) basis so that drug-drug interaction problems can be minimized. Depending on whether the drug is an inhibitor or inducer, the resultant drug-drug interaction will be one of either raising 8

9 or lowering the blood level thereby causing potential toxicity or lack of loss of efficacy. For Prozac the isoenzyme pathway of concern would be 2D6. An example of a class of drugs, which would be of concern to co-administer with the SSRIs, would be the TCAs. Because of the pharmacokinetic interactions of these two classes, one could potentially see extremely high/toxic blood levels of the TCA combining these two classes. That is not to say that is never done, or shouldn't done in cases of severe, treatment-refractory major depression. In such cases careful therapeutic monitoring of the blood plasma level of the TCA should be done. In addition, any titration schedule of the TCA would be done extremely slowly. The isoenzyme of concern with Zoloft would also be the 2D6 hepatic isoenzyme, though probably only at the higher range of the therapeutic dose. 2D6 would also be the isoenzyme of concern with Paxil. Luvox, is the SSRI with the most drug-drug interactions and/or contraindications because both 1A2 and 3A4 are of concern. This is what lead the manufacturer to emphasize various drug-drug cautions and contraindications, some of which were with drugs that have, heretofore, been withdrawn because of the possibility of serious (lethal) cardiac side-effects. Other psychotropic classes of concern and caution include Clozaril and the benzodiazepines. Contraindicated agents that have since been withdrawn included several 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 very limited 2D6 concerns. In cases where an SSRI is added to other medications that are on board or where other medications are being added to the regimen of someone who is already on an SSRI, we do extensive literature reviews of any potential combination, seek a second opinion, review the P450 literature, etc. before proceeding. By following this 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 formulation known as Prozac Weekly and Serafem (for PMDD). Just as Wellbutrin and Zyban are both bupropion, so Serafem and Prozac are fluoxetine. I believe that the 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 for additional sales. Again, the alternate name of the drug has nothing to do with either additional or lesser efficacy and is simply a marketing strategy of the drug company/manufacturer. (10) GENERIC AVAILABLE (YES/NO) Of the five SSRIs, only fluoxetine is available generically. Lilly, the manufacturer of Prozac, unsuccessfully fought against four different generic manufacturers (Teva, Barr, Par, and Geneva). I would expect all five manufacturers to do whatever they had to extend their patent life so as to maximize their sales and profit. According to the FDA, the generic manufacturers must prove 9

10 bioequivalence such that (theoretically) the generic formulations would be equally effective to the trade compound. I am sure that each of us have stories of someone who when switched over ( a requirement of their mangled care plan ) to generic Prozac (and because of a real or perceived lessening of efficacy,) went back into a depression. It is this author s best guess (at this early stage) that for most people fluoxetine is probably bioequivalent to Prozac. For bioequivalence a generics manufacturer must show that it s drug is comparable to the innovator drug in dosage form, strength, route of administration, quality, performance characteristics and intended use (Saklad, 2002). The main concern is bioequivalence and, in particular, bioavailability (does the drug deliver the same dose of active ingredient into the bloodstream in the same amount of time). Extent and rate of absorption are the main pharmacokinetic outcomes measured. (11) IN-THE-PIPELINE Each of the five manufacturers is talking about possible moves in the future. Examples would be obtaining pediatric and/or adolescent major depression indications for each of the five drugs. Luvox might be interested in developing a controlled-release (CR) formulation because it is the SSRI with the shortest halflife thereby requiring a b.i.d. (twice a day) dosing, which sometimes causes more of a problem with compliance than the one-a-day (qd) dosing SSRI s. Another possible development would be an I.V. formulation of Celexa, which like I.V. formulations of other psychotropics (most notably the neuroleptics) would result in more rapid absorption and considerably shorten the latency of onset of action. These in-the-pipeline decisions will be made by the manufacturer based on marketability and profit rather than on patient need. Obviously, if a certain drug is already being used off-label for a particular disorder (not FDA-approved but widely used in standard clinical practice) the drug company is not likely to spend the money to seek an indication for alternative diagnoses (e.g. Luvox for depression). Other discussions revolve around other racemic (having to do with the handedness of the drug chemically), formulations similar to what is being discussed in the field of ADD/ADHD with methylphenidate. A soon-to-be approved example of this is the (left-handed) racemic formulation of citalopram known as escitalopram. Whether this is just a marketing ploy by the manufacturer or a genuine attempt to improve efficacy remains unclear. In general, I do not see any of these future moves to be a real surprise or to dramatically improve the current levels of efficacy. (12) SEXUAL DYSFUNCTION LIKELY (YES/NO) Simply stated, yes! - for all five SSRIs. This is clearly the primary complaint from this class of drugs. I do not see any of the five consistently providing lesser relief from the sexual dysfunction that occurs for both men and women and for which there is little-to-no (in this author s opinion) good solution. In addition this sideeffect generally does not remit. Drug holidays from the short half-life SSRIs certainly eliminates the sexual dysfunction side-effects but may also put the person back in a state of clinical depression. I have not recommended this procedure to a single patient and those who have done so, after being informed of the 10

11 consequences, have only done so once, vowing never to do it again. To enumerate the various pharmacologic strategies to treat SSRI-induced sexual dysfunction is beyond the scope of this discussion and furthermore, would not show anything to be consistently effective. Decreased libido, delayed orgasm, and anorgasmia are not uncommon. This is not to say that every patient will experience sexual dysfunction. Very infrequently, some patients will even have pro-sexual sideeffects. The antidepressant with the least amount of sexual side-effects is Wellbutrin /Wellbutrin-SR. (13) MOST SEDATING (SIMPLY CHECK ONE BOX) This author s extensive use of all five SSRIs suggests Paxil is the most sedating for the most people. Is this an advantage? Yes and no. Is this a disadvantage? Yes and no. For someone with an agitated major depression with significant insomnia this might be a significant advantage. For someone with a depression involving significant hypersomnia, this would be a distinct disadvantage. The fact that the other SSRIs are probably less sedating (for large groups of people,) is also neither a pure 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. If patients 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 an SNRI (serotonin norepinephrine reuptake inhibitor) rather than remaining a pure SSRI. At these higher doses, its histaminic properties increase. Blockade of histaminic (H 1 or H 2 ) receptors is typically associated with drowsiness and weight gain. (14) MOST ACTIVATING (SIMPLY CHECK ONE BOX) Although any of the five SSRI can be activating, I have found Prozac to be more consistently activating than the others. Again, this is neither a pure advantage nor a pure disadvantage. There are times when activation for someone with a significant anergic depression is desirable as long as the activation does not approach chronic levels of restlessness. Conversely, the activation is a problem in patients with agitated depressions, with co-morbid ADD/ADHD, or who tried taking the drug at night. Obviously, if someone is benefiting from the drug, but experiencing activation, we will have them take it qam (every morning). Activation in its most severe form could resemble a neuroleptic-like akathisia. If this occurs, immediately discontinue the drug and switch either to another SSRI or another class. Sedation or activation from one SSRI does not automatically imply a similar response with a second SSRI. The same statement is true with regards to efficacy and side-effects as 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 the second SSRI. One might get a particular side-effect from SSRI #1 and not get that side-effect at all from SSRI #2 or conversely not have a particular side-effect with SSRI #1 and have a significant amount of that side-effect from SSRI #2. We cannot predict the response to a drug until it has been administered. (15) INDUCE CYCLING (YES/NO) 11

12 Simply stated, yes to all five SSRIs. All five of these agents are equally likely, in large groups, to induce cycling. Giving an SSRI to someone who was presumed to be unipolar but who is latently bipolar (Type I or Type II) may induce a manic or hypomanic state. If this happens, the pharmacologist would immediately discontinue the SSRI, reevaluate the diagnosis as a probable cycling mood disorder and think in terms of a mood stabilizer. The fact that a person has not had a previous history of mania or hypomania would not rule out the possibility of bipolarity nor would the absence of bipolarity in the family history. Even in the face of what I consider to be a through clinical interview process, and additionally getting to know the patient in psychotherapy over time, I have still made the mistake of assuming the person had unipolar major depression, start an SSRI, only to have the patient flip up into a high. I educate my patients about the symptoms of mania or hypomania. Should such symptoms develop, patients are to immediately call their prescriber who immediately will discontinue the drug. In this 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 is Prozac. Norfluoxetine is at least as potent as the parent compound and contributes to its antidepressant/panicolytic/anti-obsessional, and anti-compulsive properties. Sertraline's metabolite desmethylsertraline is of negligible clinical significance being approximately only 1/25 as potent as the parent compound. Paxil and Luvox are thought not to have clinically measurable metabolites while the metabolite of Celexa is also thought to be of negligible contribution being less than 1/10 as potent as the parent compound. As discussed above, the significance of Prozac s metabolite probably has less to do with efficacy and more to do with issues related to its half-life. (17) CARDIOTOXICITY (YES/NO [ESSENTIALLY NONE]) Since all five SSRIs are relatively/essentially non-cardiotoxic, this domain differentiates the SSRIs from the older agents. For the vast majority of patients, the SSRIs are relatively safe. Where there are questions, we simply obtain a cardiology consultation. Cardiotoxicity is more an issue when an SSRI is added to a regimen of other medications or other medications are added to the regimen of an SSRI such that the pharmacokinetic and/or pharmacodynamic interaction causes a more significant cardiac side-effect. Cardiotoxicity is one of the major concerns of the older tricyclics (TCAs) and was a leading concern when there were sudden deaths of children on desipramine. For patients without pre-existing cardiac disease, I do not see prescribers routinely recommending baseline EKGs, obtaining cardiac 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 equal reliability that all five SSRIs are relatively non-lethal in overdose. That is not to 12

13 say that it would be impossible for patients to take their life with an overdose of an SSRI alone, but it would take a boat load of that SSRI to do so. The reason is that the TCAs have a narrow therapeutic index (small difference between therapeutic and lethal dose) whereas the SSRIs have a very wide therapeutic index (extremely large difference between therapeutic and lethal dose). The vast majority of suicide completers who had an SSRI in their toxicology reports, also had numerous other drugs on board and, to date, the number of deaths world-wide from an aggressive, 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 all five SSRIs have a very good safety record. (19) COST Using the AWP (average wholesale price) data for a one-month supply of this class of medication would indicate that they are fairly pricey. The following prices were 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, it appears 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 price to 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. The saving is very little. Each SSRI manufacturer has a program that supplies the drug free to indigent patients. (physician recommendation is required.) This author s strategy over the past 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 in that patients name after obtaining consent of physician and patient. I have not had a single patient who has had to discontinue an SSRI because of the cost. Because each drug rep is competing with four other drug reps for an essentially similar product, they are always pleased to have a call from me requesting that their product be the one that is delivered in person to the physician s office for a particular patient. They are happy to do so and usually rush to get it done. One savings 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, give twice as many milligrams for the price. Also, when floxetine s generic exclusivity is lost in February 2002 the number of generic manufacturers is likely to expand and hopefully drive down the price. (20) WASH-OUT TO MAOI (WEEKS) 13

14 This dimension refers to the length of time between discontinuing the SSRI and starting an MAOI. With the exception of Prozac, an MAOI may be started two weeks after the discontinuation of the SSRIs. Because of the long half-life of the metabolite of Prozac (norfluoxetine), the most conservative figure is to wait five weeks between discontinuing Prozac and starting an MAOI. This will be true for all three of the MAOIs currently available in the United States (Nardil, Parnate, and Marplan ). To avoid inducing a serotonin syndrome wait two-weeks after discontinuing Zoloft, Paxil, Luvox, and Celexa (after) at least five-weeks after discontinuing Prozac before starting an MAOI. MAOIs are, however, not usually used except in cases of severe, treatmentrefractory major depression and where there is a high degree of likelihood that the patient can understand and comply with the complex dietary restrictions. Because of 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 redeveloping a major depression or significant symptoms of the anxiety disorder for which they are being treated. (21) COADMINISTER WITH MAOI (YES/NO) Simply stated, no! The risk for the development of a serotonin syndrome when combining 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 the introduction of the antibiotic linezolid (Zyvox), which is a reversible MAOI (RIMA). Prescribers are unsure how to manage the antidepressant choice for patients on it, as there is now one case report of a patient developing serotonin syndrome 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 is not developed such that the drug monitoring of the SSRI plasma levels is considered to be cost-effective or accurate. Accordingly, TDM is not done in routine clinical practice during the administration of any of the five SSRIs. TDM was more routinely practiced with various TCAs in the past and is still done with certain 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 and patient assessment of symptom reduction as a way of determining whether or not to raise, 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 an SSRI to achieve efficacy nor do we know who are the slow metabolizers who with sub-therapeutic doses might develop a therapeutic response to the drug. This is purely trial-and-error and, as such, most prescribers follow the start low, go slow, work up rule as far as titrating the dose. (23) EFFICACY TO TCAs 14

15 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 major depression. Choosing an SSRI as a first-line agent, then, would not be based on greater efficacy but rather on other dimensions such as the greater efficacy with comorbid 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 the manufacturers of the 23 currently available antidepressants in the United States can claim greater efficacy either individually or as a class over any other drug or any other class (in regards to major depression). Efficacy is not what differentiates them 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. Linear pharmacokinetics basically means a change in drug dose results in a proportional change in drug concentration. I am not sure there is a huge practical clinical benefit to this information. The drug reps from the companies of SSRIs with linear pharmacokinetic will make a big deal of this aspect. Linear pharmacokinetics might be clinically useful if therapeutic drug monitoring reliably predicted blood plasma level with Zoloft and Celexa when the dose is raised. We simply need to be aware that when raising the dose of SSRIs that have non-linear pharmacokinetics, the blood plasma levels of (Prozac, Paxil, and Luvox ) might swing wider than with the other two. I have not seen or experienced nonlinearity to be a clinical problem. Perhaps this is more of a theoretical or academic interest. (25) POOP OUT (YES/NO) Simply stated, all five SSRIs are equally likely to show the possibility of poop out. Poop out is a term used by many patients when a drug that was previously working either seems to stop working all together or begins to work less well. I would 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/clinical decision 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 reachieved. If that does not work we will increase the dose even further (if it is being tolerated fairly well) or switch to a different SSRI. Even if poop out occurs in the context of apparent therapeutic levels of the drug, if the drug is being tolerated reasonably well we would still proceed in a similar manner by typically increasing the dose another 10 or 20mg. The reason for this phenomena is unknown. (26) DISCONTINUATION SYNDROME (YES/NO) 15

16 All four of the short half-life SSRIs can present with a discontinuation syndrome if the drugs (Zoloft, Paxil, Luvox, or Celexa ) are abruptly discontinued. This is never recommended. We taper slowly so as to avoid the discontinuation syndrome. I think that the word discontinuation syndrome is preferred over withdrawal syndrome because the latter term is reserved for drugs that are addicting/habituating. Because of the long half-life of both the parent compound and it metabolite, Prozac is the only drug of its class that does not cause a discontinuation syndrome. The discontinuation syndrome can be quite annoying and 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 of the discontinuation syndrome. The mnemonic is as follows: Flu-like (fatigue, myalgia, loose stools, and nausea), Lightheadedness/dizziness Uneasiness/restlessness Sleep and sensory disturbances Headache The three major risk factors for this syndrome are the time on the drug, potency of the drug, and half-life of the drug. In fact, some prescribers administer low doses of Prozac to off-set the symptoms of the discontinuation syndrome that is brought on by a patient stopping a short half-life SSRI too quickly. Obviously, then, the way to avoid this problem is to taper and discontinue the drug more slowly and over a longer period of time. I have not seen one case of discontinuation syndrome in any patient who follows this directive. In some cases when we switch from one antidepressant to another in a hurry, we alert the patients to what the discontinuation syndrome will be, and how long they are likely to experience it. We sometimes see the rapid discontinuation as the lesser of two evils in the process of getting patients quickly into another antidepressant protocol. That is to say, we can live with the possibility of a discontinuation syndrome over the possibility of a relapse. In summary, considering these 26 variables across the five SSRIs, we conclude that there 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, and that helps to maintain a state of euthymia (no mood disorder) once the drug is discontinued. At this time, we cannot determine which SSRI will do that for an individual 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 as well. Because one SSRI might be more activating than the others more of the time does not mean it should not be chosen as a first-line SSRI. Because one SSRI might be more sedating than the others for most people does not mean it should not be chosen 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 be consistently chosen as the first-line SSRI. 16

17 As a class, the SSRIs have been an important addition to the antidepressant arena. I think that the similarities are far greater than the differences and as a clinician who has used all five SSRIs consistently for many years, I will not hesitate to continue to use all five as a first-line agent and generally still find myself not agreeing with the drug rep from each of respective manufacturers about the supposed significant clinical differences between them. Although I realize that a particular patient may have a differential response to a specific SSRI, I do not believe this is true for most people or for large groups. This list of 26 items is not meant to be comprehensive. An example of a category that certainly needs to be additionally factored in would be propensity for weight 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. Protein binding, 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 ask why, the reasons given are rarely ones that would lead me to believe that the particular SSRI among the five would be the one that I would consistently choose first for every patient. What I would recommend is that the readers become familiar with all five agents, use all five in appropriate situations, and individualize treatment so that many factors are used to determine which SSRI might be chosen first. Although in some cases it might be more clear cut (e.g. previous personal history of a robust response to a particular agent in a previous episode of depression), my suspicion is that for many patients any one of the five as a first-line agent would work fairly well. In cases of clear-cut treatment resistance (inadequate response after adequate dose and adequate duration), 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 this widely used class of medication. The opinions expressed are those of the author alone and should not be construed as a substitute for medication decisions that can and should only be made in the context of a good prescriber-patient relationship. Unless a Level III prescribing psychologist (DOD/PDP grad), Level II collaboration should be guided by State Board of Psychology guidelines. Although this paper is unsupported by any pharmaceutical company grants, Dr. Egli is either on the Visiting Faculty or has received education grants from all five of the manufacturers of the SSRIs (Eli Lilly, Pfizer, Glaxo SmithKline, Upjohn/Solvay, and Forest Pharmaceutical). Dr. Egli s CM/CME Programming has met criteria for an unrestricted educational grant according 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 of the 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. 17

18 REFERENCES Barr, L. C., Goodman, W. K. & Price, L. H. Physical symptoms associated with paroxetine discontinuation. American Journal of Psychiatry, 1994, 151, 289. Drug Topics Red Book, 104 th edition, Medical Economics Co., Montvale, N.J. April, Egli, Dan, Citalopram: 5 th Edition or Valuable Addition? American Journal of Pharmacopsychology, Vol. 2, Issue 1, pp Keuthen, N. J., Cyr, P., Ricciardi, J. A., Minichiello, W. E., Buttolph, M. L., & Jenike, M.A. Medication withdrawal symptoms in obsessive-compulsive disorder patients treated with paroxetine. Journal of Clinical Psychopharmacology, 1994, 14, Preskorn, Sheldon H. Outpatient Management of Depression: A Guide for the Primary Care Practitioner: 2 nd Edition. Professional Communications, Inc., Caddo, OK., 1999, Saklad, Stephen R. The Psychopharmacology Desktop Reference: 2 nd Edition. 2002, Providence, R.I., Manisses Communications Group, Inc., p