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)

Preference for Psychotherapy or General Dislike of Medication?

I haven't see the study mentioned in many places yet, but there was a meta-analysis of patient preference for psychological versus pharmacological treatment of psychiatric disorders in the Journal of Clinical Psychiatry.  It contained all of the usual buzzwords about evidence based medicine and why this is a hot topic to study because of the possible cost savings and potential for better outcomes if preferences were matched to actual treatments.  Interestingly, in the same month a more high tech approach to matching depressed patients with pharmacotherapy versus psychotherapy came out in JAMA Psychiatry where the independent variable was a brain imaging result rather than patient preference.

The authors here looked at a final sample of 34 studies out of 644 studies that were screened.  They end up with a chart of effect sizes with confidence intervals for each of the 34 studies.  There were a total of 90,483 participants but 78,753 were included in one study.  All of the studies are of depression and anxiety.  They had tried to include studies on schizophrenia and bipolar disorder and found that they were not published.  The authors conclude that their meta-analysis was valid and that there was a consistent preference for psychological treatment in the treatment seeking and non-treatment seeking or recruited patients.  From this the authors suggest that patient prefernce should trump other considerations if the efficacy of both treatments are equivalent.  They question why medication related treatments have increased and psychological therapies have dimished over the past decade.  They suggest that the patients who prefer medication related therapies are non adherent.

In their discussion of the limitations of the study they find there was not enough data to compare combination therapy as a choice, they excluded non-published studies and therefore included potential publication bias, and they were not able to address the question about why psychological treatments were preferred over medication based therapies by a factor of 3:1.

These and other important questions have already been answered on this blog, but don't expect to see any publications on this anytime soon.  Managed care has taken the very evidence based treatments that these authors emphasize and stood them on their head.  I have written many times about the diagnosis of depression using rating scales and the preferred treatment of antidepressants.  If you are using a primary care physician follow up code and a PHQ-9 score result to diagnose depression in ten minutes and treat all of these patients with a generic antidepressant ($4/month) - there is no psychotherapy that compares to that low cost.

All psychiatrists who are actively looking for psychotherapists to treat anxiety and depression encounter the problems of a lack of qualified therapists and more specifically a lack of therapist time in managed care systems.  Managed care systems especially those that are actively managed to reduce outpatient mental health treatment has reduced available therapy in many systems to 2 or 3 sessions of crisis management and essentially limited or eliminated additional services like psychological testing that some therapists require to do their work.  It is no accident that patients seeking psychological therapy can't get it.  It is a conscious business decision.

The second problem is the lack of availability to research proven psychotherapies.  Any psychiatrist doing patient evaluations will hear the story that therapy sessions are often very non-specific, lack goals, and often result in the patient losing faith in the process and stopping the therapy.  Being seen in a psychological therapy is no assurance of a good outcome.  Many patients who are provided with excellent research proven therapy are frustrated with the time commitment and stop because of the cost or number of sessions.  Psychotherapy may look a lot better on paper than the reality of the relationship with the therapist and the logistics of getting to and paying for the sessions.

What can be done to improve the situation right now?  The decision to take a medication for any reason is never a casual one.  Taking that medication reliably is even more significant.  Non medication alternatives and combination therapies to reduce exposure to medications should be available in every clinic.  Instead of screening everyone for a medication on day one, non-medication alternatives should be presented at that time.  There are innovative non-medication therapies such as computer delivered psychotherapy for depression, anxiety and obsessive compulsive disorder.  No clinic appointments.  The therapy is delivered online or by phone any time of the day or night.  With the appropriate implementation, these therapies could be offered as first line treatment to massive numbers of patients.  The human cost is so low they could essentially be made available across an entire health plan for free.  There is no reason why networks of therapy clinics cannot be linked to primary care clinics who see the majority of patients with depression and anxiety.  Any medication alternative can be discussed if the psychotherapy or non-medication intervention works.

From a research perspective if only 34 of 644 studies were suitable for inclusion in a meta-analysis, the problem is clearly not being studied very well.  I think it is important to ascertain patient preference for psychological, combination, pharmacological and other (eg. lifestyle change) therapies in all registered clinical trials.  In clinical practice, it is all part of informed consent for treatment.  I think it is the universal experience of physicians that most people prefer to not take medications.  The negative treatment of psychiatry and  psychiatric medications in the press create an understandable bias against psychiatric medications relative to others as a potential source  of the described phenomenon.   There is some evidence that the advertising of these medications is different and potentially stigmatizing.  We also need better design of clinical trials.  If therapies are in fact equivalent, they need to be tested in actual clinical populations where psychiatrists work.  That includes severely ill patients with comorbidity, patients who are acutely agitated and suicidal, women and children and adolescents.  Much of the discussion of equivalent therapies is based on extrapolation from populations of people who are mildly depressed and in some cases who have enrolled in a number of studies.

This study highlights the current weaknesses in studying how people actually receive psychiatric treatment and how to best approach that from a research perspective.  It points out that we need much better research designs and better patient selection in order to answer even basic questions about the treatment process.  It should be apparent that a research design that is not adequate to describe clinical practice is not a commentary on clinical practice.

George Dawson, MD, DFAPA

McHugh RK, Whitton SW, Peckham AD, Welge JA, Otto MW.  Patient preference of psychological vs pharmacological treatment of psychiatric disorders: a meta-analytic review.  J Clin Psychiatry 2013; 74:6: 595-602.

Critical Article on the Efficacy of Psychiatric Medication

There is a seminal article in this month’s British Journal of Psychiatry by Leucht, Hierl, Kissling, Dold, and Davis.  The authors did some heavy lifting in the analysis of 6175 Medline abstracts and 1830 Cochrane reviews to eventually compare 94 meta-analyses of 48 drugs in 20 medical diseases and 33 meta-analyses of 16 drugs in 8 psychiatric disorders.  The authors have produced a graphic comparing the Standard mean difference of effect sizes between the general medicine drugs and the psychiatric drugs.  It is apparent from that graphic that the psychiatric drugs are well within the range of efficacies of the general medical drugs.

This is an outstanding study that merits reading on several levels.  The authors have used state of the art approaches to meta-analysis following suggested conventions.  They provide the summary of the studies reviewed and actual details of their calculations in the accompanying tables. (the document including references and PRISMA diagrams is 59 pages long.)  They have a comparison of standard criticisms of psychiatric drugs and illustrate how the criticisms are not fair and the toxicity considerations are often greater in the general medicine drugs than the psychiatric drugs. 

This paper should be read by all psychiatrists since it is an excellent illustration of an approach to large scale data analysis using modern statistical techniques.  It is a good example of the application of the discussion by Ghaemi of hypothesis testing statistics versus effect estimation.  The authors also have an awareness of the limitations of statistics that the detractors of psychiatric care seem to lack.  Their statements are qualified but they provide the appropriate context for decision making about these medications and the implication is that decision matrix is clearly squarely in the realm of other medical treatments in medicine.

From the standpoint of the media and the associated politics it will also be interesting to see if this article gets coverage relative to the articles that have been extremely critical of psychiatric drugs.  I can say that I have provided the link to the article by Davis, et al on the issue of antidepressant effectiveness to several journalists including the New York Times and it was ignored.  The press clearly only wants to tell the story against antidepressants and psychiatric medications.

Never let it be said that any aspect of psychiatric treatment gets objective coverage in the press.  That problem and the lack of investigation of that problem is so glaring at this point that the press lacks credibility in any discussion of psychiatric treatment.

George Dawson, MD

Leucht S, Hierl S, Kissling W, Dold M, Davis JM. Putting the efficacy of psychiatric and general medicine medication into perspective:review of meta-analyses. Br J Psychiatry. 2012 Feb;200:97-106. PubMed PMID: 22297588

S. Nassir Ghaemi (2009) A Clinician’s Guide to Statistics and Epidemiology in Mental Health: Measuring Truth and Uncertainty.  Cambridge University Press, New York.

Davis JM, Giakas WJ, Qu J, Prasad P, Leucht S. Should we treat depression with drugs or psychological interventions? A reply to Ioannidis. Philos Ethics Humanit Med. 2011 May 10;6:8.

Seemuller F, Moller HJ, Dittmann S, Musil R. Is the efficacy of psychopharmacological drugs comparable to the efficacy of general medicine medication? BMC Med. 2012 Feb 15;10(1):17. Free full text commentary on the main article from another journal    -      download the pdf.

Antidepressants - the limited analysis of a polarized argument

The current President John Oldham and President-elect Jeffrey Lieberman of the American Psychiatric Association came out with this press release today on a 60 Minutes episode characterizing antidepressants as no better than placebo.  They describe this characterization as “irresponsible and dangerous reporting” and “a message that could potentially cause suffering and harm to patients with mood disorders.”

It is good to see the APA finally taking a stand on this issue.  Antidepressants and the psychiatrists who prescribe them have been taking a pounding in the popular press for years.  The main proponent here was also featured in a Newsweek headline story two years ago.  This is a prototypical example of how the media and special interest groups can distort science and facts and politicize the discussion that must be nuanced.  The problem is that you have to know something and be fairly free of bias to participate in a nuanced discussion.  Like most issues pertaining to psychiatry, the issue is always polarized and poorly discussed in the media.

I got involved in this issue as a managing editor of an Internet journal and I solicited a paper from a world renowned epidemiologist to get his current view on antidepressant meta-analyses. In order to present the entire argument I also solicited response from a world renowned psychopharmacologist with broad expertise in this field. Both articles are available online for free and I think if they are both read in total they represent the most accurate picture of antidepressant response.  Both references are listed at the bottom of this page.

Rather than get into the specific details at this point I will say that it was extremely difficult to find a anyone willing to provide a rebuttal to the to the original article by Ioannidis, but anyone who reads that paper by Davis, et al and who follows the antidepressant literature will have a greater appreciation of the effectiveness of these medications.  I hope to post some information on the statistical analysis as well.  At some level people tend to view statistics as a hard mathematical science and there is plenty of room for interpretation.  The use of meta-analysis is a common approach to these problems and a detailed look at the shortcomings of meta-analysis are seldom discussed.  That might explain why one meta-analysis shows minimal effects and another shows that there might be some antidepressants with unique effectiveness (see Cipriani, et al)

A final dimension that is critical in the analysis of any source is potential conflicts of interest.  The only conflict of interest that is typically discussed is the financial interests of authors and pharmaceutical companies in producing positive trials.  That ignores the fact that many of these trials have been very public failures and that post trial surveillance limits the use of some of these compounds.  There are other conflicts of interest to consider when an author is selling a viewpoint and can potentially profit from it – either financially or politically.

The APA could provide a valuable service here in making the documents from the FDA and the EMA widely available for public discussion and analysis.

George Dawson, MD

 “60 Minutes” Segment on Antidepressants "Irresponsible and Dangerous" – APA New release Febrary 22, 2012.

Ioannidis JP. Effectiveness of antidepressants: an evidence myth constructed

from a thousand randomized trials? Philos Ethics Humanit Med. 2008 May 27;3:14.

Davis JM, Giakas WJ, Qu J, Prasad P, Leucht S. Should we treat depression with drugs or psychological interventions? A reply to Ioannidis. Philos Ethics Humanit Med. 2011 May 10;6:8.

Cipriani A, Furukawa TA, Salanti G, Geddes JR, et al.  Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis.  The Lancet - 28 February 2009 ( Vol. 373, Issue 9665, Pages 746-758 )