Spare The Venlafaxine.....

Venlafaxine is a commonly prescribed second-generation antidepressant. It is well-known to psychiatrists because it is a second line medication if SSRIs fail and for many psychiatrists it is another first-line antidepressant. In some head-to-head comparisons with SSRIs venlafaxine has a more favorable side effect profile. It does have the risk of discontinuation symptoms and typical antidepressant side effects. I have noticed that the dose escalation with venlafaxine seems to be out of proportion with SSRIs, bupropion, and third-generation antidepressants.

Consider the following venlafaxine related scenarios:

1. A colleague comes into my office late in the day and asks me: “Have you ever heard of venlafaxine causing sedation at higher doses?” The patient in question was just increased from 187.5 mg to 225 mg - the suggested max dose according to the FDA approved package insert. 

2. I am asked to consult on patient who had extensive pharmacogenomic testing in a different facility where she was told that she may need to take 350 to 450 mg of venlafaxine per day based on that genetic profile. She wants to make sure that she gets an adequate dose of the antidepressant and is currently on 225 mg.  I reviewed the limitations of that approach with the patient and potential side effects and I let her know that the commonest side effect I see in people taking high-dose venlafaxine is excessive sedation or low energy in the daytime. As we start to follow the recommended dose increase she discloses that she has had sedation even at the 225 mg level. We decreased the dose to 150 mg and that side effect is gone.  Her depression is also gone.

3. I see a significant number of patients taking more than 300 mg per day of venlafaxine from the same geographic location in the United States. They all tell me that the target dose in that location is 350 mg per day and they are all experiencing numerous side effects. Many had dose escalations into that range in a week or two - much faster than any increase I have done.

What is wrong with this picture? Why are there a significant number of people taking more than the recommended dose of venlafaxine in some cases much more and appearing to have side effects? The roots of this prescribing behavior can be traced back to old-school psychopharmacology. Proponents of that approach suggests that there may always be a group of outliers that need to take higher-than-expected doses of medications - typically antidepressants but there has also been a history of excessive dosing of antipsychotic medications. People were generally more cautious with more toxic medications like tricyclic antidepressants, monoamine oxidase inhibitors, lithium, and various addictive compounds. They also seem to be more cautious with SSRI type medications at least initially. It took over a decade for me to see a dose of sertraline in excess of the maximum recommended dose.  While it is true that there are always outliers in terms of dose-response what is the best way to approach that problem.

I have attended medical education courses where the lecturer suggested titrating the medication to the point of toxicity and then reducing it back down to the next lowest dose. That particular lecture was focused on treating anxiety disorders with SSRIs. I don’t think that is the best approach. The best approach to me is one where the patient recovers from anxiety or depression and the process does not experience a single side effect. I know that can be done because I have been doing it for decades.

That also brings me to what I think is a good research article that looks at optimal dosage ranges. It is a very large meta-analysis of fixed dose randomized clinical trials that utilize the specific antidepressants - citalopram, escitalopram, fluoxetine, paroxetine, sertraline, venlafaxine, and mirtazapine.  The trials were identified by searching the literature and looking for unpublished studies specifically by searching national drug licensing agencies and requests directly to pharmaceutical manufacturers. Outcomes were noted at eight weeks of treatment and defined as a 50% reduction on an observer rated scale for depression.  Dose equivalence among medications was determined from previous studies and the recommendations of the manufacturer. The article is written by researchers that I consider to be world experts in meta-analyses and the analysis of large data sets in psychiatry.

77 studies were identified from a total of 24,524 published references and 4030 unpublished records.  27 were published, 21 or unpublished, and 29 were both published and unpublished. The study showed too hard when treatment groups across all of the medications of interest between the years 1986 and 2013.

The authors calculated dose response, dropouts due to adverse effects, and dropouts for any reason. Relative risks (RRs) were calculated for specific doses. The dose outcome relationships for venlafaxine are included in the figures below from the original article.  The Response figure shows the significant increase of up to about 150 mg and then a much more modest increase beyond that. The Dropout figure shows a similar increase up to the 150 mg range. The Dropout for any reason was less remarkable. The authors calculated that the 75-150 mg dose of venlafaxine was equivalent to 20 to 40 mg of fluoxetine (click to enlarge graphic)

The authors conclude that optimal acceptability of SSRIs and venlafaxine and and mirtazapine occurs within the lower end of the licensed dose range. They reconcile this with serotonin transporter (SERT) studies that show that 80% SERT occupancy occurs at the minimum doses of SSRIs or venlafaxine with further dose increases showing small increase in SERT occupancy.

In the case of venlafaxine they suggest that noradrenalin reuptake transporter (NET) may require higher doses of venlafaxine in the 225 mg to 375 mg per day range. Given the lack of efficacy of atomoxetine, a logical question might be whether NET blockade adds much to the antidepressant effect.

The authors review other dose-efficacy studies of antidepressants and point out that they are variable. The variability ranges from optimal doses of fluoxetine in the 21-40 mg per day range to doses at the recommended lower end of the range being superior. Response to doses in the higher range were variable in some studies. One study found a significant greater response for high-dose antidepressants but the dose of 40-50 mg fluoxetine equivalents showed the greatest efficacy.

The authors considered strengths and limitations their study. They thought that their state-of-the-art meta-analysis was a strength as well as the size of the data set. They also examined dose dependency for both efficacy and tolerability and acceptability. The limitations they discussed included patient selection and dosing not reflecting clinical practice. They also discussed the calculation of dose equivalency among antidepressants and how that might be problematic.

Another obvious strength of this study is the calculation of relative risks for response across SSRIs, venlafaxine, and mirtazapine. The figures are modest but favor antidepressants across all dosage ranges with the exception of mirtazapine at the 60 mg dose.  The authors don’t seem to mention it but it would seem that the optimal dosage ranges could be predicted from the regulatory information since that is based on dose ranging studies and tolerability studies. In that regard, the conclusion about dose ranges don’t seem to be that surprising but they may be needed given what is happening clinically.

Getting back to the issue with venlafaxine I see people respond to dosing within the lower and of the range from 37.5 to 75 mg in many cases. That same response rate continues up to the 150 mg dose and then starts to diminish between two or 25 and 375 mg. Over that same range there is a significant increase in dropout rates due to adverse effects.

How clinicians approach this new information will be interesting. There will still be people like me and the conservative camp looking for the first signs of side effects and toxicity and deciding at that point whether to stop dose escalation. I explicitly tell people that the goal is not to experience any side effects and that I doubt that people “get used to” side effects. There are clearly clinicians out there who are doing exactly the opposite and that is increasing the dose of venlafaxine and advising people to either tolerate the side effects or expect that they will go away.

The balance between therapeutic effect and side effects is a central issue in all branches of medicine. In many cases, the severity of adverse effects like an allergic reaction determines the decision. In the case of the medication like venlafaxine making that decision can be complex. Some of the side effects like sedation and lethargy at high doses can mimic symptoms of depression. At this point in time neither pharmacogenomics or most plasma level determinations guarantees either tolerability or efficacy.  

Detailed analysis of the situation by an expert with a bias toward preventing side effects is required as the first step in any dose increase.

George Dawson, MD, DFAPA

References:

1:  Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G.  Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis.  Published:June 06, 2019DOI:  https://doi.org/10.1016/S2215-0366(19)30217-2.

Attribution:

Above figure of the venlafaxine dose response and drop outs are directly from the paper in reference 1 and used per the Creative Commons Attribution 4.0 International Public License.

Attribution 4.0 International (CC BY 4.0)

Attribution 4.0 International (CC BY 4.0)