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Slide 1: Rates in Different Subpopulations With Major Depressive Disorder Administered Venlafaxine, SSRI’s, or Placebo -AKA Effexor vs.. SSRI’s for remission -JCP 2001 -by Entaush, Ph.D., Huang, MS (both are employees of Wyeth), Thase, MD (considered the savior of Effexor) -presented by Corey Scott Yilmaz, MD
Slide 2: Disclaimers  VFX= Effexor     I have not ties to Wyeth or any other pharmaceutical companies I hate the Effexor pen (Zocor makes the best) AD or A-D= Anti-depressant PCB=Placebo – Anything stated in this article still does not outweigh meta analysis’ that have been done to show that all AD choices are equally effective in general – This article does not contradict the important point that it’s not so much what you do (pick a AD based on SEs, find a FH, prior response), but that you keep doing it, so focusing on compliance and minimizing SEs is important – Response=50% reduction in Ham-D, Remission<7 on Ham-D
Slide 3: Depression  Information is from the Medical Journal of Australiawww.mja.com.au  5% of pts will present with MDD, 5% will have a less severe form of depression, so making the Dx of MDD is important for treatment decisions (psychiatrists agree on a Dx of MDD only about 60-70% of the time) The disability caused by MDD is underestimated by the medical profession – Dysthymic d/o and Adjustment d/o w depressed mood are +/- in their response to A-Ds – Guidelines stress A-Ds, not necessarily an equal emphasis on psychological treatments, despite the importance in most psychiatric disorders  – Depressed pts report more impairment of quality of life than those with common medical problems (so is MDD worse than HTN/DM- probably) – Depressed pts use more general medical resources, causing almost a double in health care dollars, 2400$ vs.. 1400$
Slide 4: Depression and GPs      GP prescribe 2/3 A-Ds – Should we actively seek out referrals or consultation from primary care centers for those with BAD, psychotic MDD, +SI, no response to 1-2 Rx’s, or who may need ECT? – Should we partner with some GP’s to see their pts at least once in consultation? MDD pts reporting to GPs have shorter episodes, meet fewer diagnostic criteria (easier cases?) Severity is the best predictor of persistence, or lack of remission (and Venlafaxine may be better in ensuring remissiontherefore being better in severe MDD) GPs prescribe TCAs at lower doses than needed (90% prescribe them at doses<125mg, only 17% of psychiatrists do this), so a referral may need a therapeutic dose GPs often do not give adequate trials (40% prescribed for less than the recommended trial or continuation period, only 7% of psychiatrists do this), so a referral may need a good evaluation of trials in terms of duration and dose
Slide 5: Depression and Referrals Our augmentation strategies are important (adding Lithium or VPA if we suspect BAD from a strong FH, the presence of a severe or psychotic depression, mania induced by a SSRI) (adding a stimulant if there is melancholia- severe anhedonia, PMR/PMA, reduced emotional reactivity), or switching or adding a SNRI/Buproprion/TCA or adding Pindolol (blocks 5HT1a receptors) May people switch to VFX or Buproprion based on the dual transmitter theory, despite the sometimes <10% action on the other NT at low doses and little evidence supporting this so far(we will see with the A-D version of CATIE) We may get a referral for a psychotic depression or a Bipolar depression and we may need to rerefer for an evaluation for ECT) (are we so clever when we pick a A-D seemingly at random? Probably not) Despite what we may think about ourselves, picking a AD is a guessing game no matter what anyone says and should be based on a thorough history of any response from an AD in any distant or close relative and prior response, OR a thorough discussion of the SE’s of all SSRI’s and the pt then decides, which may increase compliance and commitment to treatment  STL>FXT in tolerance, CLX better than other SSRI’s in SEs?
Slide 6: Depression Severity and Antidepressants (A-Ds) Work! (50-55% response rate, NOT REMISSION vs.. 30% for PCB (not bad for almost the same as no treatment) for MDD not Minor Depression  Mild to moderate depression responds equally to psychological treatments or A-D – Ham-D scores from 12 to 17 are MILD depressiondon’t prescribe A-D as they respond to ‘problem solving’ best (NNT=3 for problem solving vs.. 10 for SSRI’s vs.. 5 for CBT vs.. 4? For Remeron)  Moderate to severe depression responds best to Therapy and A-D – Ham-D scores>17 is MODERATE depressionprescribe A-D and therapy – many patients just get medication management  so make sure your pts are seeing a competent therapist if you only do medication management  In severe depression (Ham-D >24), it may be more important to ensure remission, so VFX may be important, but is probably less important in garden variety MDD – It is probably much more important to find a family history of response or prior patient response – Recommendations are to discuss all the options with patients and let them decide based on SEs and comorbidity as this will increase compliance 
Slide 7: Depression Severity and Antidepressants (A-Ds), cont’d TCA’s may be better at severe forms of MDD, so augmentation with HS NTL may help with the types of MDD that a psychiatrist sees (NTL and DSP preferred b/c of low sedation and anticholinergic SEs as well as the ability to measure levels/measure compliance) – Interpersonal therapy + NTL =75% success rate in acute phase  Depressed elderly- stimulant medications are often underutilized when considered in s highly selective subgroup of pts that don’t respond to monotherapy, even though their safety in evaluating BP and in cardiac conditions is well documented and their low abuse potential in the elderly. Their routine use is not recommended. (Dr. Burke)  Light therapy in seasonal effective disorder can have a rapid onset (4-7 days)  Consider dual diagnosis beyond prior response history and family history (everyone must have a distant cousin or someone that was on an AD that helped- psychiatrists must be willing to do the homework to find that information by making probably only one phone call)- examples might be buproprion if you suspect ADD or ADHD (now or in childhood) or the pt is willing to try to quit smoking, lower doses for panic disorder – Effexor for everyone is probably a poor decision and doesn’t distinguish us from PMDs 
Slide 8: Depression and Length of Treatment  Response at 8 weeks with no response at 4 and 6 weeks is 20% and 7% – Should we even wait 6 weeks if no response, or is 4 better? – Should we try for 4 to 6 weeks, not 6 weeks? Treat for 1 year after 1st episode and make sure the pt FU’s at intervals of 3 months, as the recurrence rate is 50% after a 1st episode  Maintenance Rx for 2+years if 2-3 episodes, FH of recurrent depression, or any suspicion that relapse is likelytreat for longer when in doubt  A trial of 4 weeks of a A-D will give you a good idea whether the pt will ever respond  – 36% with no improvement after 2 weeks of FXT responded at 8 weeks (for FXT, 8 weeks is the max as opposed to 6 weeks for other Ads)
Slide 9: Supportive Therapy and Managing SI  Explain the nature of MDD, its prognosis, treatment, raising hope and possibly PCB response, Support the pt’s reasons for living Advise the pt to call the doctor and make yourself very available if SI becomes stronger (different than a safety contract?)  Advise pts to DC ETOH and all drugs if they truly want to enhance their recovery  See pt’s weekly if SI is present, and only prescribe meds for 1 week at a time to ensure close FU  – Consider Dysthymic d/o in pts where a personality disorder is suspected as the “personality disorder” may remit with adequate treatment Call at least one family member to tell them how to respond if SI returns or increases (and ask them about any family’s response to ADs)  Document and ask that all guns be removed  Psychiatrists are superior than GPs in identifying stressors, diagnosing comorbidity, not necessarily in choosing an AD  – 15 minutes per visit more frequently is better than 1 hour less frequently
Slide 10: Background  MDD 2:1 female to male        There are 2 peaks at 30 and at 50 for both Women peak at 30yo then decreases at 45yo For men>50yo, check a testosterone level Comorbidity with women is usually anxiety Comorbidity with men is usually substance Women tend to overeat, gain weight or oversleep more than men Elderly pts with MM problems are at greater risk (and stimulants are considered very safe) – Menarche and Menopause are pivotal changes that contribute to this vulnerability in women
Slide 11: Background      Early Onset MDD is associated with a FH (due to genetic causes), while late onset is associated with CVA, neurodegenerative events Young women are less likely to respond to TCAs Severely depressed elderly pts are less responsive to SSRIs than TCAs (10N pt on TCA) – NTL may be more effective in this case due to noradrenergic effects Does vulnerability effect who will respond to ADs? – There are important differences in hormones, drug absorption, volume of distribution, hepatic fxn, body fat %, renal clearance VFX had a higher remission rate in an initial meta analysis of 2045 pts (pretty impressive), although this data per the Carlat report may have had a selection bias against SSRI’s as the pts were SSRI non responders
Slide 12: Methods           8 phase 2 or 3 trials for VFX were included Data on File at Wyeth Each study was randomized, double-blind with up to 8 weeks of treatment Minimum score of 20 on the Ham-D (>17 is moderate depression, >24 is severe) so these are our patients There was no > than 20% decrease in symptoms, so these were nonresponders (partial response is >25%) Excluded those with CV, Renal, Hepatic, SZ, abnormal PE or EKG findings, ETOH or substance abuse, any A-P use, MAOI use, OR anxiolytic or sedative hypnotic use within 7 daysso these are our patients Pts had been randomly assigned to VFX XR or IR, an SSRI (Prozac, Paxil or Luvox) or PCB Ham-D was given an frequent intervals Response=>50% reduction in Ham-D from baseline There was other statistical analysis that were done that I can’t begin to comprehend
Slide 13: Results       2072 pts were in the original studies randomly assigned Women were 64% of all pts There was no difference in the baseline Ham-D Most common SEs (‘adverse events’) were N, HA, Insomnia, Dizziness – Men had fewer HA w VFX than SSRI’s, Women had HA that was = to SSRIs, N> with SSRIs – For <40yo, N, Dizziness, Insomnia were > w VFX <3% of pts experienced changes in BP (is the DBP increase w VFX overstated like the SZ risk with Buproprion?) Bottom line- these results are not powered and are in low numbers, and there was no difference in attrition b/w VFX and SSRIs
Slide 14: Results, page 2      In 3/4 age groups except 41-54, RESPONSE rate was not significantly different but higher with VFX (61-79%) vs.. SSRIs (51-62%) – For age 41-54, the RESPONSE rate was significantly higher for VFX (63%) vs.. SSRIs (53%) – This slide is not shown b/c it was not significant in 3/4 age groups or it did not target remission or absence of depressed mood? For age <54, REMISSION was 46/44% for VFX vs.. 37/33% for SSRIs, but NOT for age >54 (is depression in the elderly not as responsive to VFX?) For 3/4 age groups (not age>65), ONSET of REMISSION occurred SOONER at week 4 than week 8 for SSRI’s For pt’s <54, ONSET of RESPONSE occurred SOONER at week 2 than week 4 for SSRI’s For only age <40yo, ABSENCE of depressed mood (1 item in the ham-D) was higher with VFX (39%) than SSRIs (31%) [Onset was not different]
Slide 15: Results, page 3    REMISSION rates were higher for VFX in both men and women At week 8 there were no differences in rates of RESPONSE b/w sexes In men, REMISSION after 3 weeks was higher for VFX (17%) than SSRIs (10%) – In women, this was also seen, but later at 4 weeks  In both, ONSET of RESPONSE occurred sooner in VFX than w SSRIs (25 to 20% for women)
Slide 16: Discussion     Remission, response, and absence of depressed mood did NOT differ between men and women of different ages Efficacy advantages favoring VFX was not limited to a particular sub group defined by age or gender groups Meta-analysis allows more conclusive evidence to be gathered and stronger conclusions to be made And if you account for anti-SSRI selection bias, this difference in remission is 41% vs. 35%, NOT 45% vs. 35%, so there is still a difference, but the ITT is much different 10 versus 20, so the clinical significance diminishes
Slide 17: Discussion, page 3    Not including pts that DC’d treatment may have underestimated the benefits of treatment, as most reasons for DC such as lack of efficacy or SEs can be dealt with clinically SE data was not sufficiently powered to compare groups A disproportionately large # of SSRI pts were on Prozac, and none were on Zoloft or Celexa (but there is little difference in efficacy in this classis there such a thing as Prozac ineffectiveness with time?)
Slide 18: Discussion, page 4 Pts with chronic depression are less likely to have a PCB response, so differences among medications may be more important  Are all classes of SSRIs really equal in effectiveness? 
Slide 19: Discussion, page 2    Differences in study design or methods can affect the validity of the meta analysis This meta analysis is much better than most b/c it uses similar patient selection and evaluation as it was all done by Wyeth Not including our pts (ETOH, anxiety d/o’s, GMC’s), aka more complicated pts would have resulted in overall lower response and remission rates, but probably would have effected both the SSRI groups and VFX equally, still resulting in a difference
Slide 20: VFX  SE’s are important: likely due to it’s short half life (as with Paxil), there is a significant w/d syndrome, which we must tell pts about – – Sexual SEs can be a major downer- remember 2.7% of pts on Prozac volunteered that as a SE, whereas it is more likely 30%+ Does Celexa have the fewest SEs and equal clinical efficacy to VFX?    If you believe the 45% vs.. 35% remission rate with VFX vs. SSRI’s, that means you need to treat 10 people (b/c of the 10% difference) to create one more remission (intent to treat) If you think it’s more like 41% to 35% (which it may be due to selection bias against SSRI nonresponders), you need to treat 20 people to create one more remission (b/c of the ~5% difference) Is this just a statistically significant difference, or something of marginal clinical significance? – – – – – For 1st line treatment, all pills work For treatment refractory pts, augmentation strategies are important as well as probably using VFX For 2nd line treatment, switching to a TCA, ?Buproprion? or VFX is a good choice Should we use the Ham-D at the same time as the BDI? But always remember- “It’s not so much what you do, but that you keep doing it”
Slide 21: VFX The general opinion is that there is less to be gained from the selection of a particular AD vs.. ensuring good compliance (to ensure an adequate trial has been done) and ensuring the pt has a good competent therapist (to maximize the success rates of dual treatment)  Age may be a factor in choosing VFX (no elderly), but not sex  Selecting a AD is not a one size fits all decision (VFX for everyone) but a decisions based on a thorough investigation into any FH response and prior response as well as whether treatment was actually a full trial or not (10N pt on Triavil 2-10, 10mg of Amitriptyline, 2mg of Trilafon)  – The most important factor is to try to increase compliance and to make an appointment for the pt to a competent therapist