Prozac 5 mg vs higher doses

[firedoor]

I have been unable to find the exact reference, but I recall once reading that 5 mg of fluoxetine was shown to be comparable in effectiveness to 20 mg in Lilly's initial studies for the FDA (for MDD), but that the 20 mg dose was approved as the recommended starting dose in order to account for outliers. (Perhaps someone can clarify this).

Relatedly:

"The results of three dose-effect studies... [demonstrated that] a dose of 5 mg per day was as effective as any of the higher doses." N Engl J Med 1994; 331:1354-1361.

5 mg helped 54% with major depression; 20 mg helped 64%. Fewer adverse effects with the 5 mg dose. Conclusion: "No lower limit for an effective dose of this potent serotonin uptake inhibitor has been demonstrated in moderately depressed outpatients. Psychopharmacology Bulletin 1998:

In the 5 mg, 20 mg, and 40 mg fixed-dose study, there were no differences in effectiveness between the active treatment groups, all of which were superior to placebo. Side effect dropouts increased significantly with dosage....With endpoint analysis, numerically, 5 mg/day outperformed 40 mg/day which outperformed 20 mg/day...These data point to 5 mg/day as optimal, although there is no evidence that doses below 5 mg/day are not equally effective."
Journal of Clinical Psychiatry, 1992

"We conclude that starting fluoxetine at doses lower than 20 mg is a useful strategy because of the substantial fraction of patients who cannot tolerate a 20-mg dose but appear to benefit from lower doses.... Patients often benefitted clinically from treatment at lower doses, and failure to tolerate 20 mg/day of fluoxetine should not be taken as evidence that the agent cannot be used efficaciously in these patients.
Journal of Clinical Psychiatry, 1993

I am curious of others' thoughts regarding the dosing of Prozac. Might it have the reputation of being "(perhaps overly) stimulating/anxiogenic" and hence not the best choice with regard to anxiety (primary or iatrogenic) due to an inappropriately high recommended starting dose (20mg)? It is, after all indicated for panic disorder and OCD.

It seems that there is a significant disparity between 5-80mg/dy, and I'm curious as to the clinical relevance of this vis-a-vis treating various disorders (i.e. anxiety vs. eating vs. depressive disorders).

Lastly, while Prozac is known to be unique among the SSRI's with regard to its 5-HT2C antagonism (which increases dopamine and norepinephrine in the prefrontal cortex and nucleus accumbens), my understanding is that this may only be clinically relevant at the higher end of the dosing spectrum (if at all). Is this accurate, and how does the 5-HTC antagonism correlate clinically? For example, might the related potential increase in dopaminergic activity be especially helpful for anhedonia or perhaps confer a lower propensity for sexual dysfunction or SSRI-related apathy?

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[whopper]

Might Prozac have the reputation of being "(perhaps overly) stimulating/anxiogenic" and hence not the best choice with regard to anxiety (primary or iatrogenic) due to an inappropriately high recommended starting dose? It is, after all indicated for panic disorder and OCD.

Very curious and thought provoking. I've been operating on STAR*D data showing that increased amounts of antidepressant usually correlate to higher efficacy, but that was largely based on the results of the use of Citalopram.

Fluoxetine certainly is a different beast. With it's extremely long half-life (Half-life: 4-6 days (fluoxetine), 9.3 days (norfluoxetine), it certainly does give some food for thought that perhaps lower dosages (e.g. 5 mg) may build up in the system. For you medstudents, other antidepressants have half-lives of usually around 1-2 days.

Anectdotally, I've never tried to test if 5 mg QAM did as well as 20 mg or 40 mg QAM. I have had several patients that were put on Prozac by their PCP at 20-40, it didn't work or work as well an needed, I increased the dosage and they got better.

how does the 5-HT2C antagonism correlate clinically?

Activation of that receptor inhibits dopamine and NE release. Antagonism does the opposite. Pharmacological agents that block that receptor have been found to have antidepressant properties.

It's too easy, IMHO, to simply state to expect similar effects you'd expect with increasing dopamine and norepinephrine. As we all should know (by residency), medications, while often catalogued simply for one main effect, have multiple effects on multiple receptors. It could be that the higher dosage that antagonizes the 5-HT2C and thus would release dopamine and NE may be somehow offset and cancelled out by another effect.

(E.g. Strattera is a norepinphrine reuptake inhibitor, yet it showed no to little benefit as an antidepressant. Why? I sure as heck do not know. Pharmacological theory alone, that receptor action should've caused some benefit. Does it have benefits in chronic pain? Maybe so based on the receptor action but who knows what it would yield in a study.)

An article specfically addressed this concern:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC20038/?tool=pmcentrez
But clinically I have not seen anyone address the benefits of exploiting this mechanism.

Might it have the reputation of being "(perhaps overly) stimulating/anxiogenic" and hence not the best choice with regard to anxiety (primary or iatrogenic) due to an inappropriately high recommended starting dose?

Perhaps. There are several documented mentions that Prozac may not be the best SSRI for anxiety because it could be anxiogenic. I can tell you plenty of anectdotal mentions that it is stimulating (perhaps because of the DA release from 5-HT2C?). My fellowship director told me that "in the old days when Prozac was the only SSRI in town" patients in need of it that could not tolerate a TCA, but had excessive anxiety for the first few hours of Prozac ingestion had to take "Cranzac". It was liquid Prozac put into a large cup of cranberry juice and the patient had to very slowly ingest it.

 

[billypilgrim37]

...but had excessive anxiety for the first few hours of Prozac ingestion had to take "Cranzac". It was liquid Prozac put into a large cup of cranberry juice and the patient had to very slowly ingest it.

Our headache clinic still does this, but they just open up a 20mg capsule and dump it into 200ml cranberry juice (or I think 5 capsules in a 32 oz bottle... close enough.) 1mg/10cc Cranzac!

 

[OldPsychDoc]

...(E.g. Strattera is a norepinphrine reuptake inhibitor, yet it showed no to little benefit as an antidepressant. Why? I sure as heck do not know. Pharmacological theory alone, that receptor action should've caused some benefit. Does it have benefits in chronic pain? Maybe so based on the receptor action but who knows what it would yield in a study.)....

Methinks these studies were never done as the holders of the atomoxetine patent were not interested in marketing Strattera as a competitor to another product they were rolling out to the depression and chronic pain niche: duloxetine.

But then again, I'm just a cynic...

 

[nitemagi]

My experience is that the worsening anxiety/akathisia is more common early on with SSRI's, but that this can be minimized by starting the patient on baby doses such as 5mg of prozac or celexa until they've acclimated. I then titrate up q1-2 weeks as tolerated. This strategy has almost always been successful with my extremely anxious pt's that I worry won't be able to handle SSRI's d/t anxiety and/or somatizing concerns.

Stahl talks about multiple possible mechanisms including presynaptic 1A/1D receptors, or 2A projections to the raphe or basal ganglia, all being activated early. Over time the anxiolytic effects of serotonin kick in and override the worsening anxiety. It seems to take up to a week.

My theory is that this early worsening anxiety is responsible for the increase SI we think about, especially with adolescents.

 

[whopper]

Methinks these studies were never done as the holders of the atomoxetine patent were not interested in marketing Strattera as a competitor to another product they were rolling out to the depression and chronic pain niche: duloxetine.

I read somewhere, and I didn't save the article, tha Strattera was originally intended to be an antidepressant but the company's own studies showed no benefit in that area. They happened to find an incidental ADHD benefit with it and decided that all was not lost...after all a non-stimulant ADHD med!?!?

Norepinephrine reuptake inhibition should reduce chronic pain. Wellbutrin, and Effexor have that benefit in several studies but they never got the FDA approval for it. I put plenty of patients on Wellbutrin and their chronic pain went down. I get several doctors scratching their heads because the friendly hot-babe drug rep didn't teach them that Wellbutrin did that.
E.g.
http://www.ncbi.nlm.nih.gov/pubmed/15771151

NRIs also have a benefit in ADHD. Effexor has studies supporting that. That makes me suspect Cymbalta would do the same but I've never seen good data supporting it. I cite an article below, but that's not strong support.
http://www.ncbi.nlm.nih.gov/pubmed/20694126

A problem with using too much theoretical psychopharm is that, as I wrote, meds have multiple effects on multiple receptors and depending on the dosage, those effects could differ. A med with an NRI mechanism could have other mechanisms that cancel it out. Cheeseburgers have some enzymes that cause weight loss but the fat and carbs overried those enzymes significantly. Overall cheeseburgers still cause weight gain.

I've seen too many doctors give out meds simply on theory without seeing if an actual study backed it up. Not a problem if nothing else worked, but it is a problem when doctors try this first, second, third or even fouth-line. I would never give out Cymbalta to treat ADHD unless I saw a specific study backing it up or nothing else worked. When we give meds, it's not like we're giving a black vs white agent. IT's a diverse mechanism with several greys.

Another example I brought up in other threads is I somtimes give out Gabapentin to treat anxiety. I usually only do that if SSRIs, SNRIs, and Buspirone have failed in multiple trials, and only if the patient is experiencing a benefit from the Gabapentin. No benefit? I stop the Gabapentin.

The "it works in theory" approach when there's little other data should only be done when there are few other options.

 

[firedoor]

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