Tuesday, April 02, 2013

Does Antidepressant Dose Matter?

One of the great myths about antidepressants is that higher doses are more effective than lower doses. That's not how these drugs work, though. Most studies show a flat dose-response "curve" with SSRIs. More isn't better.

This is an important point to understand, because antidepressants quite often don't work for a given patient on the first try, and then it's necessary to do some "adjusting," which means either increasing the dose, switching to another drug, or adding a second med. Fredman et al. found that among 432 attendees at a psychopharmacology course, asked what they would do for a non-responsive patient on SSRIs, most chose raising the dose as the best next-step option. But that's the wrong answer.

In "Dose-response relationship of recent antidepressants in the short-term treatment of depression," Dialogues Clin Neurosci. 2005 September; 7(3): 249–262, (full article here) Patricia Berney of Unité de Psychopharmacologie Clinique, Hôpitaux Universitaires de Genève, Chêne-Bourg, Switzerland, examines a large number of clinical trials to discover the extent to which dosage matters in antidepressant therapy. It's worth going through her discussion drug-by-drug, because if you're taking one of these drugs and your doctor suggests a higher dose, you may want to consider whether it's going to be worth the time and expense. Usually it's not.

Citalopram (Celexa)
"The short-term studies with citalopram did not show significant differences In terms of clinical efficacy across a dose range of 20 to 60 mg/day. Even a dose of 10 mg/day was effective compared with placebo. The results of the maintenance study by Montgomery et al. and the meta-analysis by the same authors support these findings. Therefore, for the majority of patients, there Is no advantage of increasing the dose of citalopram above 20 mg/day."

Escitalopram (Lexapro)
This drug is the S-stereoisomer of citalopram (Celexa), meaning that it's structurally no different from half of what's in citalopram. (Citalopram is a so-called racemic mixture of left- and right-handed versions of the same molecule.) According to Berney: "The only fixed-dose-response study with escitalopram indicates that 10 mg/day was equally as effective as 20 mg/day."

Fluoxetine (Prozac)
"The studies with fluoxetine did not show significant differences in terms of clinical efficacy across a dose range of 20 to 60 mg/day. Even a dose of 5 mg/day was effective compared with placebo. Therefore, for the majority of patients, there is no advantage of increasing the dose of fluoxetine above 20 mg/day. It might even be the case that the higher dose of 60 mg/day is less effective in major depressive disorder." The latter refers to a study by Wernicke: "Fluoxetine 20 and 40 mg/day were statistically superior to 60 mg/day." One study (Dunlop) involving 372 patients found: "Fluoxetine 20, 40, and 60 mg/day each produced an improvement that was no different from placebo on change in the HAMD total score in 355 ITT patients with LOCF at the end of 6 weeks." (ITT = Intent to Treat, LOCF = Last Observation Carried Forward.) The result with completer-case analysis, which is to say just considering the 214 patients who finished the study, was that changes in the HAMD total score "were similar to those of the ITT-LOCF analysis."

Fluvoxetine (Luvox)
"In this fixed-dose study on a large sample, only fluvoxamine 100 mg/day showed a significant therapeutic benefit over placebo at end-point analysis (on LOCF) on modified HAMD 13 items final score at the end of 6 weeks at fixed dose. Significant differences were not seen between fluvoxamine 25, 50, or 150 mg/day or placebo. On the HAMD 13-items responder analysis, the differences were significant for fluvoxamine 100 and 150 mg/day compared with placebo, but not between these two dosages on visual inspection of the figures in the publication on completer cases analysis."

Paroxetine (Paxil)
"In the publication by Dunner and Dunbar, there is a short description of a study involving 460 patients. The paroxetine 10 mg/day dose was no more effective than placebo, even on the HAMD depressed mood item. The authors reported also on a pooled analysis from a worldwide database, involving 1091 patients who remained on a fixed dose of paroxetine or placebo for at least 4 weeks, which showed no differences in terms of clinical efficacy across a dose range of 20 to 40 mg/day paroxetine. Therefore, for the majority of patients, there is no advantage in increasing the dose of paroxetine above 20 mg/day."

Note: It's also worth looking at a more recent study by Ruhé et al., "Evidence why paroxetine dose escalation is not effective in major depressive disorder: a randomized controlled trial with assessment of serotonin transporter occupancy," Neuropsychopharmacology 2009 Mar;34(4):999-1010, in which unipolar depressed patients on Paxil or placebo (double-blind) were scanned for SERT occupancy by single-photon emission-computed tomography (SPECT). The overall finding: "Paroxetine dose escalation in depressed patients has no clinical benefit over placebo dose escalation."

Sertraline (Zoloft)
"In the study by Fabre and Putman, sertraline 50 mg/day, but not 100 and 200 mg/day, was more effective than placebo at end-point analysis on change on the HAMD 17 items total score on ITT-LOCF at 6 weeks. There was no statistical analysis performed between the different doses, but inspection of the data in the publication suggests no differences."

Milnacipran (Savella)
This SNRI is approved for treating depression outside the U.S., but inside the U.S. it is approved only for fibromyalgia. Four studies were analyzed. They showed "flat dose-response relationship between 100 and 300 mg/day," with 50 mg/day being less effective than placebo.

Venlaxafine (Effexor)
This SNRI (inhibiting reuptake of both serotonin and norepinephrine) is a Top Ten antidepressant in the U.S. Patricia Berney's finding from reading the clinical trials:
In the venlafaxine studies, doses varied between 25 and 375 mg/day. A positive dose-response curve was only demonstrated with trend analysis. However, the difference between the higher dose range and placebo was not pronounced. Better efficacy could be obtained with a dose of venlafaxine above 75 mg/day in terms of remission rate. In a review concerning all aspects of antidepressant use, Preskorn mentioned an ascending then descending dose-response curve for venlafaxine in an evaluation comparing 7 dose levels between 25 and 375 mg/day with placebo, coming from fixed and flexible-dose studies. However, the major difference in terms of mean HAMD score change, ie, 2 points, was between a group of patients receiving 175 mg/day and another receiving 182 mg/day, hardly a different dose! This suggests a calculation artifact rather than a pharmacological dose-response curve.

For the majority of patients, a dose of venlafaxine 75 mg/day should be adequate.

Reboxetine (Edronax, Norebox, Prolift, Solvex, Davedax, Vestra)
A norepinephrine reuptake inhibitor, reboxetine is approved for depression outside the U.S. Said Berney: "Despite availability of several short clinical trials, we cannot comment on the dose-response relationship for reboxetine."

"No positive dose-response relationship has been found for 40 to 120 mg/day."

The common thread here is obvious. Antidepressants, when they work at all, tend to work about as well whether you take a large dose or a small dose. The dose-response curve for most of these drugs is a straight horizontal line. That's the main takeaway not only from Berney's meta-analysis but a separate meta-analysis by Baker et al.,"Evidence that the SSRI dose response in treating major depression should be reassessed," Depression and Anxiety, (2003), 17(1):1-9. It's also the conclusion reached in yet another meta-analysis by Hansen et al., Med Decision Making January/February 2009, 29(1):91-103 (Said the Hansen group: "Dose was not a statistically significant predictor of categorical HAM-D response. Among comparative trials with nonequivalent doses, trends favored higher dose categories but generally were not statistically significant.")

The lack of a dose-response relationship above a certain minimum effect dose doesn't necessarily mean the drugs are doing nothing. It means that once you've achieved an in vivo concentration of the drug sufficient to saturate whatever transporter protein(s) or receptors the drug in question targets, there's nothing left for the drug to attach to. Thus any excess goes unused.

It's important to note, though, that these drugs do tend to show a strong dose-response relationship when it comes to side effects. (One 2010 meta-analysis found that across 9 different studies, "Higher doses of SSRIs were associated with significantly higher proportion of dropouts due to side-effects.")

Bottom line: Upping your dose, on any of the major antidepressants listed above, isn't a good strategy. It may worsen side effects, but it's unlikely to change your therapeutic outcome. If a particular drug isn't working for you, a far better strategy than upping the dose is to try a different drug and/or add talk therapy to the mix (if you're not already doing it).

Likewise: If you are seeing good therapeutic effect from a drug but side effects are causing problems, you should ask your doctor or nurse practitioner about dialing back the dosage to the minimum therapeutic dose, so as to keep side effects from swamping the therapeutic effect.


  1. Interesting post. 2 remarks though:
    1) Reboxetine seems to be useless (regardless of dose):Eyding et al (2010). Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials BMJ, 341 (oct12 1)
    2) This seems restricted to one specific use of antidepressants (just for depressive disorder). So what about the supposed much higher efficacy of these medications for OCD for instance, when at higher (commonly 2x or 3x the standard dose)?
    (and i'm no advocate of psychopharmacology; i trust good psychotherapy better)

  2. Anonymous9:58 AM

    They are all really useless according to the latest research by independent researchers, and they are quite dangerous.
    1 in 6 become manic (bipolar) by taking antidepressants and will be wrongly diagnosed as suffering from bipolar disorder. They will then be told they need medication for life and given antipsychotics, lithium and antiepileptics (mood stabilizers) in cocktails that have never been researched.
    In the longest and largest antidepressant study conducted (STAR-D) only 3 percent had effect after one year of treatment with several antidepressants.
    7 out of 10 get their sex lives destroyed by these pills
    Suicide risk may increase with up to 600%, especially in young people.
    Once you have started on antidepressants you have an 85% risk of becoming chronically depressed. Without antidepressants, your risk for chronic depression is only 15%
    Antidepressants can both stimulate and numb feelings and thoughts so as to make people do strange and often violent things. Very honest and good people may suddenly steal, embezzle money and even commit murder.
    Many people have extreme side effects when they try to stop. They usually think it is depression and anxiety coming back, and don’t dare to try stopping again.
    Most doctors reduce medication too quickly when patients want to stop. You should never try to reduce more than 10% of the medication every 2 weeks. That means a minimum tapering period of 20 weeks. Rule of thumb: use one month to withdraw for every year you have been on the medication. 10 years of use=10 months tapering.
    In research, antidepressants don’t work better than sugar pills, even in the short run. So they are medications with extreme risks and no benefit.
    There are many treatments that work. Simply taking a quick walk for 20 minutes 3 times a week has better effect in research than an antidepressant. Cognitive therapy works better than antidepressants, and have lasting effects.
    Google on Breggin and Whitaker to find more info and references to all of this research.

    1. Once you have started on antidepressants you have an 85% risk of becoming chronically depressed. Without antidepressants, your risk for chronic depression is only 15%

      source, please...

  3. Brian S2:01 PM

    I wanted to thank you for this post, and the others. I don't have the scientific knowledge demonstrated by the previous commenters, but your posts made me dig into some of the issues I have with - surprising, to me - results.

    I've gained 60 pounds in three years. I've been in a mental fugue state for three years; I used to be regarded as extremely competent at my job, and right now I'm barely hanging on to it. I'm physically and mentally exhausted. At some points, I've slept twenty hours a day. I'm a type 1 diabetic (insulin dependent) and have been for 28 years, but in the past three years my control has slid into dangerous areas.

    When I previously looked at side effects, I read the packaging and the Walgreens insert. I tended to think that covered everything.

    I see, on a regular basis, an endocrinologist, a urologist, a psychiatrist, a psychologist, a general practitioner, and a pulmonary specialist. All of these doctors have my complete medical history and medication digest available to them.

    For three years I have been begging them to help me with my exhaustion. It's crippling. How can you stay on top of a tech industry when reading a book puts you to sleep? How can you solve problems when you can't keep all the details in mind at once? I found I had low testosterone, and had high hopes that might help. And it did - I went to sleeping 12 to 15 hours instead of 20. But my doctors mostly told me, "You're fat, lose weight." or "Exercise, you'll feel better." No concept of the body numbing fatigue I was experiencing, no examination of possible root causes.

    No doctor ever mentioned to me that weight gain, exhaustion, fugue, bone pain were all side effects of Zoloft. Worse, I had only been placed on Zoloft three years ago when my insurance company demanded I see an independent psychiatrist in order to remove my use of brand name drugs; the 2nd psychiatrist put me on Zoloft.

    I've been considering disability because I am so physically and mentally tired. I had the backing of two doctors if I chose to pursue that.

    I was diagnosed as bipolar before I started the SSRI, and I believe I'm truly bipolar -- my entire life has been scattered with incidents of bipolar swings. Lithium carbonate has saved my ass there and I will never dispute that. (Put another way, without Lithium I'd probably be in prison for life.)

    But the addition of Zoloft has nearly destroyed my life and only because I read your posts did I start to dig deeper. I went off Zoloft last week cold turkey (very bad idea, I admit, but my psychiatrist was disputing my claims) and within a few days I was doing yard work, I worked out on my Bowflex that had been unused for three years, I had read two books and I slept 8 hours an evening. If it weren't for the insomnia and psychotic rage that accompanied the cold turkey state, I'd still be off it. As it stands, I'm on a rapid weaning. (Faster than advised before, but I'll keep the comment above in mind while I progress.)

    At this point I want to remove the SSRI from my medication and stay off. I want nothing more to do with them.

  4. Very well written article mate, thank you for the valuable and useful information. Keep up the good work! FYI, please check these depression, stress and anxiety related articles:

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    10 Things That Really Won’t Cure My Depression

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