Are Medication Trials For Depression Too Long In Duration?

Depression is a significant cause of disability in the world.  That is complicated by the fact that there are not enough resources to treat people with depression, access is rationed in many areas including the United States, there is a high rate of attrition during treatment, and depression is often associated with significant medical and neurological disability further restricting access to adequate care. 

Over the past 30 years, strategies for treating depression have increased considerably since antidepressants medications are not uniformly effective and they have side effects that may not be well tolerated.  Antidepressants have evolved over the years from monoamine oxidase inhibitors to tricyclic antidepressants to selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) and norepinephrine dopamine reuptake inhibitors (NDRI).  The suggested pharmacology of more modern antidepressants is even more complex and the initial classifications may mean a lot less than what was initially hypothesized.

Although antidepressant monotherapy is the preferred treatment path – failure of one or two rounds of antidepressants can result in combinations of augmenting agents designed to improve treatment response.  Early augmenting agents included triiodothyronine, thyroxine, and lithium.  More recent augmenting therapies include additional antidepressants (typically bupropion), aripiprazole or brexpiprazole, or buspirone.  There are several additional agents that are used in lower frequencies.  Context is important in considering the origins of the augmenting therapies. When thyroid hormones were added, there was an active research focus on neuroendocrinology including the impact of physical illnesses on thyroid function. Later focus on treatment resistant depression assumed that all depression was treatable - it was just a question of finding the correct treatment. Both hypotheses have had low yields. 

The relative advantage of these approaches is that they are potentially cost effective (most antidepressant medications are generic and prescribed by non-psychiatrists), they are readily available, and they are more culturally accepted than they used to be.  The disadvantages include side effects most commonly nausea, vomiting, diarrhea, sexual side effects, and dry mouth. Patients need close monitoring initially to prevent side effects and assure that the medication is working. The physicians doing that monitoring also have to be aware of rare serious side effects that require emergency treatment – like serotonin syndrome, neuroleptic malignant syndrome, and acute neurological side effects.  A good knowledge of general medicine is also required to avoid treating people with chronic illnesses where there are contraindications. 

Another disadvantage is treatment non-response.  What happens if two different prescriptions are tried for adequate amounts of time and there is no response. Where does the treating physician go from there?  Seeing thousands of patients well into a course of treatment for depression and/or anxiety this is a very common problem – often complicated by additional problems including insomnia and substance use disorder.

Before anyone suggests addition exercise or psychotherapy at that point – practically all patients seeing psychiatrists have already done that.  Most of the people I treated had seen more than one therapist and these days they are branded therapists (CBT, DBT, IPT, etc).  The only non-pharmacological modality that was rarely used was bright light therapy and I typically discussed that as an add on to antidepressants. That therapy requires purchasing a device and using it for set periods of time each day. 

For the people with severe treatment resistant depression, more complicated interventions including electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and ketamine (intranasal, IV, IM) are on the horizon but difficult to find in one place.  As an acute care psychiatrist, I had very easy access to ECT.  As an outpatient psychiatrist there was essentially no access, even when I called the facility where I previously worked. Because of the current systems problems, my patients needing ECT had better access if they presented to emergency departments where they knew ECT was an option and got admitted to that hospital. The same barriers seemed to preclude any contact with me as an outpatient psychiatrist.  No calls for a collegial discussion and in many cases no discharge records from the treating facility.  Siloed care these days is a major impediment to care.

Last weekend, I was exposed to a modern approach that concentrated all the advanced treatment modalities in the same clinic that happened to be staffed by researchers interested in treatment resistant depression. Before I get to their approach – I designed the slide at the top of this post to illustrate the standard approach to moderate to severe depression over the course of my career starting in 1984.  I remind readers that psychiatrists are seeing a highly selected group of patients who have probably already failed several antidepressants and psychotherapies.  As time goes by and the number of non-psychiatric prescribers continues to increase greatly – that selection process will greatly intensify.

Looking at the general scheme of antidepressant approaches to only depressive disorders (DSM major depression and persistent depressive disorder) – there has been a clear progression of newer medications designated by older class names like tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), and monoamine oxidase inhibitors (MAOI). These general class names have significant limitations – not the least of which being reuptake blockade by of specific transporters is probably only part of the mechanism of action and some class designations depend more on chemical structure than physiology. If anyone would like a second explanatory slide with all of the current FDA approved antidepressants and more modern nomenclatures – let me know and I will make the slide.

In treating significant depressions – psychiatry added adequate dosing and duration and therapeutic drug monitoring (TDM) to determine adequate trials of antidepressants therapy.  There were active debates and research suggesting 6 weeks might be adequate on the lower end and 16 weeks as adequate duration on the high end. Pharmacokinetic factors came into play with some antidepressants with longer or shorter half-lives. If an adequate trial of medication was completed there was the question of “What’s next?”  The next issue was either changing the antidepressant or adding an augmenting therapy (adjunctive therapy per the FDA).   As noted in the graphic thyroid hormones (Triiodothyronine or T3 and tetraiodothyronine or T4/thyroxine) were both used early on in doses that were typically much lower than physiological doses (25 – 50 mcg) as well as stimulant medications (amphetamines). As time went by additional adjunctive strategies were added.  The first study of adding lithium to tricyclic antidepressants occurred in 1981 (1).  Adjunctive medications started to take off in the early part of the century with pharmaceutical companies getting that indication for newer antipsychotic medications that also had bipolar disorder indications (see specific dates of approval).   

The upside to these strategies was that antidepressant effects could be improved often to the point that depression remitted. The potential downsides were twofold – the burden of taking a second medication that could introduce new side effects or synergistic side effects with the current therapy and the prospect of endless medication trials.  Now there was the additional time of seeing whether any of several adjunctive therapies worked in addition to the antidepressant monotherapy trials. Although I did not indicate it on the diagram – several antidepressant combinations were also suggested and some patients were taking 3 or 4 antidepressants at once.  That was a significant departure from quality metrics used in the late 20^th century where antidepressant monotherapy was the rule.

The concept of treatment resistant depression – generally defined as a failure of a specified course of pharmacotherapy was often stimulus for these trials. The application in clinical practice was not as clearcut because of the number of choices and how individual patient factors affected those choices. Acuity, disability, and access were the usual limiting factors leading to cessation of pharmacotherapy trials and a trial of neurostimulation like electroconvulsive therapy (ECT).

Last week, I saw a unique solution to this bottleneck problem presented by C. Sophia Albott, MD, MA entitled  “Next Generation Treatments for Resistant Depression: The UMN Interventional Psychiatry Approach.”  She described a well-staffed clinic with a stimulating practice environment that offered ECT, transcranial magnetic stimulation (TMS), ketamine (intranasal, IM, and IV), Vagal Nerve Stimulation (VNS), and Behavioral Activation Therapy provided to all the patients in their clinic.  Their general hierarchy was to start with TMS and if that was not effective to branch out into other specific therapies. The overall description of the clinic and some of their early successes suggests to me that this is potentially a good approach.  The idea of these therapies all being concentrated in one place, taking over treatment of the patient until they are in remission, and additional support is what is lacking in most systems of care.

I am sure that some would wax philosophical about similar clinics being the future of the field – but there still needs to be psychiatrists out in the community providing acute care and consultation to primary care physicians. A subspeciality clinic could function well as back-up those psychiatrists who often lack a referral resource for neuromodulation and other advanced techniques.  The largest potential benefit would be to patients who are being maintained in long term medication trials longer than they should be. This approach may be the best way to shorten the period of disability and suffering from difficult to treat depression as well as the adverse effects of polypharmacy.

George Dawson, MD, DFAPA

 

References:

1:  Dé Montigny C, Grunberg F, Mayer A, Deschenes JP. Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry. 1981 Mar;138:252-6. doi: 10.1192/bjp.138.3.252. PMID: 7272619.

2:  Trivedi MH, Rush AJ, Crismon ML, et al. Clinical Results for Patients With Major Depressive Disorder in the Texas Medication Algorithm Project. Arch Gen Psychiatry. 2004;61(7):669–680. doi:10.1001/archpsyc.61.7.669

3:  Sonmez AI, Wilson S, Olsen S, Sullivan C, Herman A, Widge A, Nahas Z, Albott CS. Outcomes from University of Minnesota Clinical rTMS Clinic for resistant depression: naturalistic data on suicidal ideation. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation. 2021 Nov 1;14(6):1652.

4:  Papakostas, G.I., Trivedi, M.H., Shelton, R.C. et al. Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02468-x

Antidepressants Are Not Miracle Drugs - They Are Also Not Tools Of The Devil

I decided to end the year on a less intense but serious note about antidepressants. I am currently working on some posts on biological psychiatry most notably on the hypothalamus. When you see that posted it will hopefully contain some licensed graphics, numerous worthwhile references, and it will be the first post on this blog where copy-paste function will be blocked.  I have seen the results of not blocking my blog content and many people pointed out that it is just copied to another site and not referenced.  In what had to be a worst case scenario, I was at a conference where an academic used my custom graphics in his PowerPoint presentation without referencing that they were from this blog.  Hopefully those days are over.

But in the meantime a few comments about the war on antidepressants which is really a war on psychiatry. There are numerous posts on this blog refuting some of the published material but I want to speak about what happens at the clinical level without all of the academic references and articles. I decided to post this because antidepressants have been heavily politicized over the years. The initial rhetoric was that psychiatrists were prescribing them because they were being corrupted by pharmaceutical companies. The next step was to suggest that antidepressants were highly toxic medications for one reason or another. When both those criticisms were obviously not valid, the next step was to suggest that antidepressants simply don’t work at all.  In social media this takes on a tone that discourages people from treatment.  Psychiatrists are shamed for prescribing these medications and patients are shamed for taking them. Why would a rational person take a medication that did not work?

There have been slight modifications along the way. A good example would be the “chemical imbalance” theory that has been heavily criticized and attributed to psychiatry despite the fact that no psychopharmacology books contain this reference and the discovery that the term is an advertising meme from the late 20^th century. Some of the critics like the “critical psychiatry” movement came out with an actual position paper that proposed medications basically work because of side effects rather than any primary therapeutic effect. That is an incredible position to maintain and that may be why nobody pays attention to it. The critics of antidepressants and psychiatry are very vocal and if they are not complaining about psychiatric expertise or medications they are complaining about criticism they might receive. But the overall tone of their arguments illustrates that they have nothing positive to offer.  Many of these critics have the luxury of not treating people with severe psychiatric disorders.  In some cases that extends to denying that these disorders exist.

One of the critics complained about being “gaslighted” for some of criticisms. This is more than a little ironic for several reasons.  The standard positions of most antipsychiatrists is the very definition of gaslighting.  That position is to basically create a hostile environment that denies the legitimacy of psychiatry and psychiatric practice and treatments.  I have received hundreds of posts to this blog that never see the light of day. Some say (in many posts) that I am a hack who should not be treating patients. They claim I am an agent of the pharmaceutical industry (search all of the databases and you will see that I have not accepted as much as a nickel). They tell me that my research is poor and I have very little understanding of the literature. Some have suggested that they would like to see me physically assaulted.  One of them went so far as to hide the fact that he was a writer for a major anti-psychiatry blog until the last possible moment. I think he was really expecting that I was going to publish his post and name so that everyone on that website could have a good laugh at my expense. These critics seem to have a very thin skin and can’t take the slightest criticism for what are typically outrageous positions. 

I could quote all the evidence to the contrary hundred times but it would not do any good.  The dynamic is very similar to other antiscience arguments, like the arguments against vaccines.  The average person with a realistic concern about antidepressants should just be aware of the process at this point. There are a group of people who are out to discredit psychiatric care and medications that psychiatrists use strictly based on political agenda that has nothing to do with whether or not medications or psychiatry works.  The lesson of politics is that "the narrative" becomes the truth - particularly if one side "wins." Demonizing a perceived opponent is a common political strategy that may be amplified by social media.  This process focused on demonizing psychiatrists and the medications they prescribe can be observed in social media on a daily basis. 

There’s no better evidence that psychiatry works than the fact that we all go to work and see hundreds of thousands of people every day. Those people come back to see us because they are satisfied both with the relationship they have, the advice they get, and the fact that their treatment is effective. That includes treatment with antidepressants.  People don't take time out of their day, endure the problem of finding a psychiatrist who can see them and hassles with their insurance company, and follow treatment recommendations if the treatment is not effective.  

As I noted in the title - antidepressants are certainly not miracle drugs. About one person out of seven or eight that I see cannot tolerate selective serotonin reuptake inhibitors (SSRIs). About one person out of 15 cannot tolerate any antidepressant from any class. That fact alone points out one of the limitations of antidepressants. Additional patients will get more isolated side effects that create physical effects or affect their lifestyle and they have to make tough decisions especially if the medication is effective. They have to decide whether they want to keep taking it or not. But the clinical truth that you don't hear among the critics is that the majority of people can take an antidepressant and not get any side effects.  I know this because, I ask that specific question to every person I see who is taking a medication - every time I see them.

A more challenging clinical situation occurs when a patient asks me to start an antidepressant that they are certain has worked for them in the past and now they develop a symptom that may be a side effect that they did not have in the past. We need to figure out what is happening and what the best plan will be. The more common scenario is the person for whom the antidepressant does not work completely and we need to figure out how to get rid of their depression or anxiety.

All the negative talk about antidepressants is designed to take psychiatrists out of the equation. Nobody talks about the psychiatrist who is in the room with the patient actively working on and solving all of these problems. The problems that need to be solved from a medical and psychiatric standpoint can often make up a long list. Pre-existing medical conditions, 5-10 medications that are being taken for those conditions, drug interactions with any pre-existing conditions or medications, medication side effects, unstable medications, ECG abnormalities, medical causes of the psychiatric symptoms, neurological problems, significant renal or hepatic disease, and alcohol and substance use problems are all in that room and all need to be acted on by the psychiatrist and the patient in the room.  If somebody suggests that psychiatrists are doing less than that - take a look at the way psychiatrists are actually trained.  The ask yourself why you are not getting the whole story.

And even before we get to that point, there has to be some clarification of a diagnosis indicating that medication might be useful. There has to be a diagnostic formulation looking at how that diagnosis fits into that person’s life and conscious state. The prescription of a medication can’t be a formula based on a checklist. There are many times when a prescription medication is not the right answer. Don’t expect to hear that level of discrimination from somebody who tells you that antidepressants or psychiatrists are either generally bad or all bad.  When you hear that opinion - drill down and figure out what their conflict of interest is.  

In my current capacity, a significant number of people I see have suicidal ideation and many have attempted suicide or are actively contemplating suicide. Some have survived highly lethal suicide attempts. Most of them have depression and substance use disorders. I have to figure out the most likely diagnosis out of about 40 possibilities. In proceeding with treatment, my job is to help the person get well, recover from depression, and recover from suicidal thinking. That is a complex process and it is not just a question of prescribing medication. What is said and done in that process is not the same for any two people. I have to make sure the person is getting well and making necessary changes along the way to recover. There are many people along that path to confirm that the treatment is proceeding in a positive direction. This process is one of many leading to the demand for psychiatrists across the country. Psychiatrists have the clinical expertise to solve these problems and we are often consulted at the last possible moment after all of the other attempts have failed. 

With any luck it will be a better year ahead. I don’t expect the anti-psychiatry gaslighters to go away. I do want to reassure people that psychiatrists are result oriented and we are trained to work intensely with people to help them get better. If you see suggestions contrary to that fact - consider the source. If you see someone suggesting that they are being “gaslighted” by psychiatrists remember what I said about the posts I get here on this blog. And remember, antidepressants are just like any other medication. They don't work for everybody, but most people who can tolerate them notice a difference.  For some people the difference is life changing and it allows them to function the way they used to function. Like practically all medications, the decision to take antidepressants is a highly individual one and a decision that is not made lightly.  Most people making that decision are not making it based on what is on social media.

As professionals we take a safe recovery from mental disorders and substance use problems very seriously. 

Happy New Year!

George Dawson, MD, DFAPA

Graphics Credit:

Color gradient during the sunset in Antarctica. Vernadsky Station. Antarctic Peninsula 2008.

By Maksym Deliyergiyev from Shutterstock per their standard user agreement.

Supplementary:

Academic gaslighting?  Of course, it exists.  I realize that it is a vague and non-specific term A few examples follow from this blog.  Unfortunately, journal editors either don’t seem to get it or they are too desperate for content to care.

The Identity Crisis Card: https://real-psychiatry.blogspot.com/2019/11/there-is-no-identity-crisis-in.html

The Diagnostic Heterogeneity Card: https://real-psychiatry.blogspot.com/2019/09/recent-opinion-about-diagnostic.html

The Epistemic Injustice Card: https://real-psychiatry.blogspot.com/2019/07/some-of-greatest-minds-in-psychiatry.html

The Chemical Imbalance Card: https://real-psychiatry.blogspot.com/2019/05/chemical-imbalance-as-advertising-meme.html

The Critical Psychiatry Card: https://real-psychiatry.blogspot.com/2019/05/chemical-imbalance-as-advertising-meme.html

The Antipsychiatry Card: https://real-psychiatry.blogspot.com/2018/08/why-antipsychiatrists-have-it-all-wrong.html

The Antidepressants Are Toxic Card: https://real-psychiatry.blogspot.com/2018/04/sensational-antidepressant-piece-from.html and this recent review.

The Physicians Are Corrupted by Big Pharma Card:  https://real-psychiatry.blogspot.com/2017/05/wait-minute-is-psychiatry-less-unhinged.html

The Too Much Neuroscience Card: https://real-psychiatry.blogspot.com/2016/10/the-balanced-rhetoric-against.html

The Psychiatrist Shortage Card: https://real-psychiatry.blogspot.com/2016/08/a-better-analysis-of-psychiatrist.html

The Reductionism Card: https://real-psychiatry.blogspot.com/2015/11/reductionism-is-not-dirty-word.html

The Monolithic Psychiatry Card: https://real-psychiatry.blogspot.com/2015/06/the-myth-of-monolithic-psychiatry.html

The Philosophy Card - written by an expert on Foucault: https://real-psychiatry.blogspot.com/2013/02/moralizing-about-psychiatry-and-limits.html

This Supplementary section was added on 1/2/2020 at 0200.  The body of the original post is unchanged.

Sensational Antidepressant Article from the New York Times

Take some quotes taken out of context, the suggestion that doctors know less about the problem than the New York Times does, and the suggestion that you may be "addicted to antidepressants" and what do you have - the latest article on antidepressants by the New York Times.  Although the New York Times has never been an impressive resource of psychiatric advice they continue to play one and the latest article  Many People Taking Antidepressants Discover They Cannot Quit is a great example.

The reader is presented with numbers that seem to make the case "Some 15.5 million Americans have been taking the medications for at least five years. The rate has almost doubled since 2010, and more than tripled since 2000." and "Nearly 25 million adults, like Ms. Toline, have been on antidepressants for at least two years, a 60 percent increase since 2010."  Guaranteed to shock the average reader, especially in a culture that systematically discriminates against the treatment of mental illness.

Adding just a little perspective those figures translates to 15.5M/254M = 6.1% and 25M/254M = 10% of the adult population in the US.  Looking at the most recent epidemiological estimates of depression in the US 1990 - 2003 shows one year prevalences of 3.4 - 10.3% of the adult population.  The lifetime prevalences from some of those studies 9.9-17.1%.  It seems that the claims of antidepressant utilization may be overblown relative to the epidemiology of depression and the number of people disabled by it.  The authors go on to quote a study on the overutilization of antidepressants on data obtained from the National Health and Nutrition Examination Survey (NHANES) study.  These same authors have quoted an increase of antidepressant use of 10.4%.  This same study estimated a lifetime prevalence of depression of 9.5%.

Depression alone is not the sole indication for antidepressants. Anxiety disorders is another FDA approved indication.  Anxiety disorders can add an additional 3% 1 year prevalence and 5-6% lifetime prevalence.  About 16.5% of the population has headaches and antidepressants are used to treat headaches.  Another 6.9-10% of the population have painful neuropathies that are also an indication for antidepressant treatment.  Over a hundred million Americans have chronic back pain another indication for a specific antidepressant.  The main reference points to a study (3) that suggests only about 7.5% of antidepressants are prescribed for nonpsychiatric conditions.  Only 65.3% of the prescriptions were for "mood disorders. A study looking at antidepressant drug prescribing in primary care settings in Quebec Canada (5) provides specific data and concludes that  29.4% of all antidepressant prescriptions were not for depression or anxiety but for insomnia, pain, migraine, menopause, attention-deficit/ hyperactivity disorder, and digestive system disorders. Those same authors go on in a subsequent paper to provide a detailed analysis of the off-label use of those antidepressants.

The number of antidepressant prescriptions is far less drastic when taken in that context.  I am not arguing that every person with an eligible condition should be on antidepressants.  I am definitely saying that given the large numbers of people who will potentially benefit - the number of antidepressant prescriptions is not as outrageous as portrayed in the article.

What follows is a brief descriptions of antidepressant discontinuation symptoms and the fact that the medical profession doesn't know what to do about it.  This is certainly not the case in any setting where I have practiced. Discontinuation symptoms are well know to occur with SSRI and SNRI medications.  I routinely describe them and their varying intensity as part of the informed consent procedure when I prescribe these medications. The reality is that 20% of people will stop taking antidepressants in the first month after getting a prescription. Many will just get the prescription and never start.  An additional 20-30% will stop in the next 3-4 months.  Stopping antidepressants without medical guidance is so common that I routinely ask patients if they have abruptly stopped at any point when I am making any changes in their medications.  The majority have stopped without getting any of the discontinuation symptoms.  I qualify that by the fact that I have not prescribed paroxetine in 30 years because I considered it to be a problematic medication and I have a very low threshold for stopping antidepressants if I don't believe they are tolerated.  Even in their referenced study (2) the authors state: "In one national study, for example, only about one-quarter of adults initiating antidepressants for new episodes of depression continued to take their medications for 90 days...".  Does that sound like it is a medication that is difficult to stop?

They don't stop there.  After making it seem like we are in the midst of an antidepressant epidemic and that people are unable to stop antidepressants they make an even more absurd argument - doctors are unable to help patients get off antidepressants.  Before I go into their details consider this.  I work at a facility where we routinely detox people off high doses of the most addictive drugs in the world.  If we are able to do that, why would a doctor not be able to figure out how to discontinue a non-addictive antidepressant?  This specific statement really had me rolling my eyes:

"Yet the medical profession has no good answer for people struggling to stop taking the drugs — no scientifically backed guidelines, no means to determine who’s at highest risk, no way to tailor appropriate strategies to individuals."

Do I really need a study to do something that I have been doing successfully for 30 years?  Tapering people off of medications is something that every physician has to do.  Successfully using antidepressants means being able to taper and discontinue one and start another or taper and discontinue one while starting another or starting another and eventually tapering and discontinuing the original antidepressant.  That is not innovation - that is standard psychiatric practice.

I can only hope that the quotes from family physicians that follow were totally out of context.  Statements about "parking people on these drugs for convenience sake." and that the "state of the science is absolutely inadequate" are ludicrous.  I would say if you have to park somebody on a psychiatric drug or have questions about how it is used - it is time to send that patient to see a psychiatrist.  Nobody should ever be "parked" on a drug.

These physicians seem to have lost sight of the fact that they do not have similar problems prescribing equal amounts of antihypertensive medications and leaving people on them indefinitely.  There is no rhetoric about "parking" somebody on an antihypertensive medication or a cholesterol lowering drug or a medication for diabetes.  The fact that depression is the leading cause of disability in the world seems to be ignored.  The fact that up to 15% of people with depression die by suicide is not mentioned.  The suggestion is that this disabling and potentially fatal condition should not be addressed as rigorously as other chronic illnesses.

In the midst of all of the confusion created in this article, the authors fail to point out the likely cause of increased antidepressant prescriptions but they quote one psychiatrist who comes close.  He points out that the increase in antidepressants is due to primary care physicians prescribing them after brief appointments and (probably) not being able to follow the patient up as closely as a psychiatrist.  This was one of the main findings in the paper by Mojtabi and Olfson (2).  The specific quote "...the increase in long-term use (of antidepressants) was most evident among patients treated by general medical providers."

What is really going on here?  This blog has repeatedly pointed out that mental health care and treatment by psychiatrists has been rationed for about 30 years.  The result of that rationing is that there are few reasonable resources to treat all kinds of mental illnesses.  With that end result, the argument is now being made that we really don't have to build the infrastructure back up - we just need to shift the burden to primary care clinics.  In order to make it more simple for them we can just screen people with a rating scale for depression (PHQ-9) or anxiety (GAD-7) and treat either symptoms with a medication.  That way we can not only ration psychiatrists, but we can also ration psychologists and social workers who could possibly treat many of these patients with psychotherapy alone and no medication. For that matter, we could treat a lot of these patients with computerized psychotherapy - but managed care organizations will not.  State governments and managed care organizations will screen people, make a diagnosis based on a rating scale, and put that person on an antidepressant medication as fast as possible.

That is a recipe for high volume and very low quality work.  A significant number of those patients will not benefit from a medication because they do not have a compatible diagnosis.  A significant number will not benefit from the medication because it is not correctly prescribed.  In order to compensate for that inadequacy, a model of collaborative care exists that provides a psychiatric consultant to the primary care clinic.  That psychiatrist never has to directly see the patient.  The collaborative care model depends on putting patients on antidepressants as soon as possible and even more classes of psychiatric medication.

That is the real reason for increased antidepressant prescriptions and people taking them.  It is not because nobody knows how to prescribe them or stop them.  It is not because they are "addictive". It is because there is a lack of quality in the approach to diagnosing and treating depression in primary care settings and that is a direct result of federal and state governments and managed care organizations.


To be perfectly clear I will add a series of rules that will not question the current business and political rationing of mental health resources but will address the problem of antidepressant over prescribing and antidepressant discontinuation:

1.  Stop screening everyone in primary care clinics with rating scales - there is no evidence at a public health level that this approach is effective and it clearly exposes too many people to antidepressants and other medications.  I am actually more concerned about the addition of atypical antipsychotics to antidepressants for augmentation purposes when nobody is certain of the diagnosis or reason for an apparent lack of response and nobody knows how to diagnose the side effects of these medications.

2.  Provide any prospective antidepressant candidate with detailed information on antidepressant discontinuation syndrome - including the worse possible symptoms. While you are at it give them another sheet on serotonin syndrome as another complication of antidepressants.  It is called informed consent.  I encourage the New York Times not to write another article about serotonin syndrome.

3.  Triage depressed and anxious patients with therapists rather than rating scales - brief, focused counseling, CBTi for insomnia, and computerized psychotherapy all have demonstrated efficacy in addressing crisis situations and adjustment reactions that do not require medical treatment.

4.  Refer the difficult cases of discontinuation symptoms to psychiatrists who are used to treating it.

5.  Don't prescribe paroxetine or immediate release venlafaxine - both medications are well know to cause discontinuation symptoms and they are no longer necessary.

6.  Every physician who starts an antidepressant needs to have a plan to discontinue it - the idea that a patient needs to be on a medication "for the rest of their life" in a primary care setting is unrealistic.  If that determination is to be made - it should be made by an expert in maintenance antidepressant medications and not in a primary care clinic.

7.  Every patient should be encouraged to ask to see an expert if either their medication prescribing or treatment of depression is not satisfactory.  The standard for treating depression is complete remission of symptoms - not taking an antidepressant.  If you are still depressed - tell the primary care clinic that you want to see an expert.

In an ideal world, people with severe depression would be seen in specialty clinics for mood disorders, by psychiatric experts who could address every aspect of what they need.  That used to happen not so long ago.  It still happens in every other field of medicine.

But quality care like that is no longer an option if you have depression.


George Dawson, MD, DFAPA

References:

1: Carey B, Gebeloff R. Many People Taking Antidepressants Discover They Cannot Quit. New York Times April 7, 2018.

2: Mojtabai R, Olfson M. National trends in long-term use of antidepressant medications: results from the U.S. National Health and Nutrition Examination Survey. J Clin Psychiatry. 2014 Feb;75(2):169-77. doi: 10.4088/JCP.13m08443. PubMed PMID: 24345349.

3: Mark TL. For what diagnoses are psychotropic medications being prescribed?: a nationally representative survey of physicians. CNS Drugs. 2010 Apr;24(4):319-26. doi: 10.2165/11533120-000000000-00000. PubMed PMID: 20297856.

4: van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014 Apr;155(4):654-62. doi: 10.1016/j.pain.2013.11.013. Epub 2013 Nov 26. Review. Erratum in: Pain. 2014 Sep;155(9):1907. PubMed PMID: 24291734.

5: Wong J, Motulsky A, Eguale T, Buckeridge DL, Abrahamowicz M, Tamblyn R.Treatment Indications for Antidepressants Prescribed in Primary Care in Quebec, Canada, 2006-2015. JAMA. 2016 May 24-31;315(20):2230-2. doi: 10.1001/jama.2016.3445. PubMed PMID: 27218634.

6: Wong J, Motulsky A, Abrahamowicz M, Eguale T, Buckeridge DL, Tamblyn R.Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system. BMJ. 2017 Feb 21;356:j603. doi: 10.1136/bmj.j603. PubMed PMID: 28228380.

More on Benzodiazepines (Like Xanax).

The topic of benzodiazepines will just not go away.  At the top and bottom of this post - I include a number of book covers from my library on the topic from the last 30 years.  The publication dates are 1983, 1985, and 1990.  I wrote a brief review for the Psychiatric Times and included my unedited version  on this blog from earlier this year.  My overall message was that benzodiazepines as a group are great for very specific indications.  In fact for some indication like detoxification from alcohol or sedative hypnotic drugs and catatonia they are life saving.  The majority of benzodiazepines are not prescribed for those indications.  They are prescribed primarily as add on medications for anxiety and insomnia.  Their use is limited by tolerance and addictive properties that are expected from a medication that reinforces its own use.  It is also problematic to prescribe them to any population of patients where alcohol use is prevalent and not expect significant drug interactions or abuse.

I really wanted to include a graphic from the paper listed below (1) from JAMA Psychiatry on the prescribing rates of benzodiazepines in patients being treated for depression.  I will post it if I get permission.  That graph illustrates the growth in benzodiazepine prescribing from 2001 to 2104.  During that time the fraction of patients taking a benzodiazepine in addition  to an antidepressant rose from 6% to 12.5% of the depression treated patients.  Subgroups were analyzed and psychiatry came across as a the top prescriber of benzodiazepines across all years.  Other practitioners and specialists came in under the curve prescribed by psychiatrists. 

 A recent anxiety disorder diagnosis was a strong predictor of concurrent use of benzodiazepine use with 24.1% of patients with a recent unspecified anxiety disorder diagnosis and 39.1% or patients with a panic disorder diagnosis taking both the benzodiazepine and antidepressant.  At 6 months 45.6% of the antidepressant + benzodiazepine and 48.1% of the antidepressant monotherapy were still taking an antidepressant.  After initial adjustments 12.3% of the simultaneous benzodiazepine and antidepressant users received long term benzodiazepines with 5.7% taking them for one year.  The prescribed benzodiazepines were almost all high potency including alprazolam (43.9%), lorazepam (26.3%), and clonazepam (21.8%).  About a tenth (13.5%) of the patients got a limited supply of for only 1-7 days).

The authors generally conclude that benzodiazepine prescribing seems to be consistent with current guidelines.  These suggest that a Cochrane report that concomitant benzodiazepine use with antidepressants increased the short term antidepressant response and decreased the drop out rate attributable to antidepressant side effects.  I would think that would be offset at least as much by guidelines suggesting limited use.

The overall strength of this report is that it is a study of a very large insurance database population of 684,100 new antidepressant users and 81,020 simultaneous antidepressant and benzodiazepine users. They give a breakdown of antidepressant classes (overwhelmingly SSRIs).  Only 12.7% and 16.5% (respectively) of the patients in each class were treated by psychiatrists.  Interestingly 77.4% and 80% of each class had not received any form of psychotherapy, although it is conceivable that at least some patients were being seen by therapists outside of the database.  As noted psychiatrists were more likely to prescribe combination therapy.  The authors speculate that may be due to referral patterns and psychiatrists seeing patients with more severe anxiety and depression, training patterns in psychiatry, or more familiarity with benzodiazepine pharmacology.  I think a more likely factor is chronicity and the fact that psychiatrists tend to see more patients with chronic anxiety and temperamental forms of anxiety that are not taken into account in DSM-5 nosology.

Despite the large N, there are many drawbacks to database studies like this one.  I think it is useful in terms of the basic pharmacoepidemiology of prescriptions but it doesn't say anything about symptoms severity and many of the practical issues involved with benzodiazepine prescribing (like substance used disorders) are eliminated by the study protocol.  The authors do a good job of describing the downsides (use disorders, falls/fractures, motor vehicle accidents) of benzodiazepines in their discussion.  I would have included cognitive problems and tolerance. It also does not address the optimal way to address combined anxiety and depressive disorders. My biggest concern is the current "evidence based" fad of diagnosing anxiety and depressive disorders using symptom rating scales like the PHQ-9 (Patient Health Questionnaire-9) and the GAD-7 (Generalized Anxiety Disorder 7-item).  In a primary care setting they pass for a diagnosis.  In a psychiatric setting they short circuit any analysis of the etiological factors of anxiety or depression.  Instead these disorders are conceptualized as disorders that that require a basic medical treatment and they resolve.  That is a gross oversimplification.     

But the main limitation should be evident - we do not have a specific enough diagnostic system with reliable objective markers.  In that context a large N doesn't mean as much unless we know how many subtypes there are and the associated treatment parameters.

George Dawson, MD, DFAPA

References:

1:  Bushnell GA, Stürmer T, Gaynes BN, Pate V, Miller M. Simultaneous Antidepressant and Benzodiazepine New Use and Subsequent Long-term Benzodiazepine Use in Adults With Depression, United States, 2001-2014. JAMA Psychiatry. 2017;74(7):747–755. doi:10.1001/jamapsychiatry.2017.1273

Not Taking Antidepressants

I came across this open access article on my Twitter feed that highlights some of the reality of antidepressants that I was trying to get at in my previous post.  I encourage a full reading of the article in order to understand it - specifically how patients were selected from a large commercial database.  In this retrospective study the authors selected patient with a diagnosis of major depressive disorder (MDD) who were taking and antidepressant but only in a specific time interval.  They did this for the purpose of constructing the above survival curve.  They started with a group of 6,562,955 people on antidepressants between 7/1/2003 and 1/1/2014 and ended up excluding all but 527,907.  Exclusions were based on no diagnosis of MDD in the previous 6 months, no prescription of an AD in the previous 6 months, lack of continuous enrollment in the previous 6-12 months, and pharmacological  therapies that included initiating treatment with more than one AD or 3+ ADs or augmenting agents (AA).  The final study population was 527,907 patients.

Two major endpoints were defined as measures of medication adherence - medication possession ratio (MPR) and proportion of days covered (PDC).  PDC was considered the primary measure of adherence due to previous convention.  Calculations were made at 3, 6, 9, and 12 months.  Persistence and adherence were calculated for each major antidepressant class (SSRI, SNRI, TCA, MAOI, and Other).  Adherence and persistence were calculated across all of these dimensions.  Bar graphs are available in the full text.

Adherence and persistence at 6 months was 31-36%.  SNRIs had the highest persistence and adherence rates at 6 months at 37% and TCAs the lowest at 16-17%.  Looking at the Kaplan-Meier survival above the curves were significantly different with the lowest adherence to initial TCA and MAOI therapy.  The curves also show natural break points at 30 and 90 day intervals that correspond to the typical length of prescriptions although most primary care physicians provide a significant number of refills beyond that.

A study like this has obvious limitations and the authors do a good job of explaining them. Most of them had to do with the limitations of using a database like this one with limited granularity.  For example - no data about the status of the prescriber or practice context.  I would have the question of whether adherence was any different among those given and antidepressant based on a screening questionnaire versus more detailed assessment and follow up.  It would also be interesting to see if subjects seeing psychiatrists were any more adherent than than what I am guessing are the majority of patients being see in primary care.  Surrogate markers for psychiatric care could have been devised based on AD and AA combinations but that would be an imperfect marker since most primary care depression guidelines incorporate these strategies.   There was a very minor erratum (2) essentially a typographic error that does not change the main paper.                      

When I look at a study like this, I always ask myself if the study group resembles the people I am currently seeing or have seen.  In this case 64% of the population was female and 81% were covered by commercial insurance.  Twenty-four percent had comorbid anxiety, 24% had comorbid chronic noncancer pain, and 6% had both.  Sertraline has the largest percentage of prescriptions at 18.7% with only about 5.4% of people on bupropion extended release.  I currently see a large number of people on sertraline or citalopram +/- bupropion augmentation.  Despite the FDA warning about maximum doses of citalopram - I still see people on 60 mg/day or > 40 mg/day who are 62 years of age or older.  Both of those situations were flagged in the FDA warning.

I do find that SNRI medication are better tolerated than SSRI and do not hesitate to make that change sooner than later.

Give the limitations this is an interesting study.  At several levels it matches my experience.  At least 20-40% of people do not tolerate SSRIs very well.  I have also found that  SNRIs are effective and more well tolerated than SNRIs.  The major limitation from my perspective is that without the data that the authors refer to - it is really not possible to design a clinical program that optimized adherence or that provides much of a foundation for the differences.  Many psychiatrists have the experience that they see the same people with severe depression for years.  In many cases plasma levels of antidepressants are measure to optimize dosing but they also confirm adherence.  In other cases, the patients are in settings where medications are administered.  A critical dimension in psychiatric practice is the ongoing relationship with the patient.

Looking at how the relationship with the patient and how that effects adherence is needed, but it is obviously a more difficult study to capture in a retrospective database.              


George Dawson, MD, DFAPA



References:

1:  Keyloun KR, Hansen RN, Hepp Z, Gillard P, Thase ME, Devine EB. Adherence and Persistence Across Antidepressant Therapeutic Classes: A Retrospective Claims Analysis Among Insured US Patients with Major Depressive Disorder (MDD). CNS Drugs. 2017 May;31(5):421-432. doi: 10.1007/s40263-017-0417-0. PubMed PMID: 28378157.


2: Keyloun KR, Hansen RN, Hepp Z, Gillard P, Thase ME, Devine EB. Erratum to:Adherence and Persistence Across Antidepressant Therapeutic Classes: A Retrospective Claims Analysis Among Insured US Patients with Major Depressive Disorder (MDD). CNS Drugs. 2017 Apr 27. doi: 10.1007/s40263-017-0435-y. [Epub ahead of print] PubMed PMID: 28451963.

Attribution 1:

The above graphic is directly from reference 1 reposted per terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license.  No changes were made to the graphic.  Click on the graphic to enlarge.


Thanks:

To Barney Carroll for putting this reference on his Twitter feed.

When To Not Prescribe An Antidepressant?

I encountered that interesting question just last week.  Antidepressant medications have been around for a long time at this point and they have an increasing number of indications.  Everywhere around the Internet there are algorithms that make prescribing these drugs seem easy and automatic.  Qualify for the vague diagnosis and follow the line to the correct antidepressant. At the same time there is plenty of evidence that their use is becoming less discriminate than in the past, largely due to the use of checklists rather than more thoughtful diagnostic processes.  It is common for me to encounter people who have been put on an antidepressant based on a "test".  When I ask them what that test was it is almost always the PHQ-9 or GAD-7, checklist adaptations of DSM criteria for depression and anxiety that can be completed in a couple of minutes.  There is a significant difference between the checklists and the diagnostic process as I pointed out in a previous post about the sleep question on the checklist compared with more detailed questions about sleep.  The list that follows contains a number of scenarios that will not be accessible by a checklist.  In those cases a more thorough diagnostic assessment may be indicated.

1.  Intolerance of antidepressants - Every FDA package insert for medications includes this warning, usually referring to an allergy or a medical complication from previous use.  In addition to allergic reactions (which are generally rare with antidepressants), there a number of significant problems that preclude their use.  Serotonin syndrome can occur with low doses and initial doses in sensitive individuals.  In the case of the more potent classes of serotonergic medications - the SSRIs as many as 20% of patients will experience agitation, nausea, headaches, and other GI symptoms.  By the time that I see them, they will tell me the list of antidepressants that made them ill and that they cannot take.  It is an easy decision to avoid medications that are known to make the patient ill.

2.  Behavioral intolerance of antidepressants - SSRIs in particular can have the effect of restricting a person's emotional range to a narrow margin.  They will typically say: ""I don't get low anymore but I also don't get as happy as I used to get."  A person who is affected in that way finds that to be a very uncomfortable existence.  Many have been told that they will "get used to it" - a frequently used statement about these medication related side effects.  I have never seen anyone get used to a restricted range of emotion and I tell them to stop it an not resume it.  I avoid prescribing antidepressants form that class and that class is typically SSRIs.

While I am on the topic, I frequently use the following vignette when discussing the concept of "getting used to" side effects:

"Many years ago I treated a man who came to me who had been taking a standard antidepressant for about 7 years.  He was not sure that he was depressed anymore.  He was sure that he had frequent headaches and very low energy.  I recommended that we taper him off the antidepressant and see how he felt.  He came back two weeks later and said: 'Doc - I feel great.  For about the last 6 years I felt like I had the flu every day and that feeling is gone.'  That is my concern about 'getting used to a medication'.  It may mean that what you really get used to is feeling sick.  That is why I encourage everyone that I treat to self monitor for side effects, and if they happen we stop the medicine and try something else."

That advice sounds straightforward but it is not.  I still get people who think that they need to "get used to" a medication and will only tell me in a face-to-face interview.

3.  Lack of a clear diagnosis - many of the people I see were started on an antidepressant during an acute crisis situation like the sudden loss of a significant person in their life or a job or their financial status.  There is no real evidence that antidepressants work for acute crisis situations, but some doctors feel compelled to prescribe a medication because it makes it seem like they are trying to help the patient.  I have also heard the placebo response rationalized for these prescriptions.  A similar cluster of symptoms can be observed along with the associated anxiety, but in the short term the main benefits to be gained will be from medication side effects like sedation rather then any specific therapeutic effect.   The real problem is that the medications don't get stopped when the crisis has passed.  I may be seeing a person who has been taking an antidepressants for ten years because they had an employment crisis or divorce at that time and have been taking the medication ever since.  They have been tolerating the medication well for that time, but it now takes a lot of effort to convince them that they don't need the medication and taper them off of it.

I try to prevent those problems on the front end by not prescribing antidepressants for vague, poorly defined emotional problems or crisis situations where they are not indicated.  In my experience, psychotherapy is a more effective approach and it helps the affected person make sense of what has been happening to them.

4.   An unstable physical illness is present - that can mean a number of things.  The commonest unstable physical illness that I routinely deal with is hypertension with or without tachycardia.  Patients and their doctors will often go to extraordinary lengths to avoid treating hypertension even hypertension that is outside of the most current and most liberal guidelines.  I am told that the person has "white coat hypertension".  How do they know that is all that they have?  Have they ever had a normal blood pressure reading outside of a physician's office?  Would they be willing to purchase their own blood pressure device, monitor their blood pressures at home and bring me the readings?  I have had people become angry at me because of these suggestions, even after a thorough explanation of the rationale.  It is almost like patients expect a psychiatrist to hand them a magical pill that takes care of all of their problems.  As an example the following warning if from the FDA package insert for milnacipran but most antidepressants don't include this warning - even when they might affect blood pressure:

"Elevated Blood Pressure and Heart Rate: Measure heart rate and blood pressure prior to initiating treatment and periodically throughout treatment. Control pre-existing hypertension before initiating therapy with FETZIMA"

There are a number of conditions ranging from glaucoma to angina that need treatment before antidepressants can be safely prescribed.  In some cases I am not happy with the pharmacotherapy for associated medical conditions.  Desiccated thyroid rather than levothyroxine for hypothyroidism is a good example.  Why is desiccated animal thyroid gland being used in the 21st century instead of the specific molecule?  In many cases, I will refer the patient to see a specialist and they will never come back because their real problem has been solved.  I posted about cervical spine disease some time ago after I had a number of patients come in for treatment of depression.  What they really had was insomnia from cervical spine disease and when that chronic pain was addressed their depression resolved completely.

I will run into some situations where I insist the patient see a specialist (generally a Cardiologist) to get an opinion on safety of treatment.  This used to be called "clearance" by the Cardiologist but for some reason that term has fallen out of favor.  I think the "clearing" specialists don't want the designation, but from my perspective the patient is not going to get the antidepressant that we discussed unless the Cardiologist agrees.

5.  The patient prefers not to take the medication - I think that patients are often surprised at how easily they can convince me to not prescribe a medication.  Many expect an argument.  I will supply them with the information they want and direct them to reputable sites on the Internet where they can read as much as they want about the medication.  I am very willing to discuss their realistic and unrealistic concerns.  I will attempt to correct their misconceptions  and also provide them with my real life estimate of how many people tolerate the medication and the common reasons why people stop it.  I fully acknowledge that I cannot predict if a medication will work for them or give them side effects.  At the end of that discussion, if they don't want to try the medicine that is fine with me.  I have absolutely no investment in prescribing medication for a person who does not want it.  If the person has clear reservations, I let them know they don't have to come to a decision right in the office - they can go home and think about it and call me with their decision.  I am never more invested in the medication than the person who is taking it.  I will also provide them with feedback on whether or not their decision seems reasonable or not.

6.   Additional patient preferences -  Many people will talk with me about antidepressants and say that they want to solve their problems with psychotherapy, exercise,  or some other non-medical option.  Many people will also talk about drugs, alcohol, cannabis,  hallucinogens, psychedelics, and other drug based treatments for depression.  I can offer people what is known about the scientific basis of treatments for depression and encourage effective non-medical treatment where it is indicated.  I do not endorse the use of the use of alcohol or street drugs for treatment and let people know that I cannot prescribe antidepressant medication if those other substances are being used.  That includes "medical marijuana".  There is a risk for serotonin syndrome with various combinations of stimulants, hallucinogens, and/or psychedelics in combination with antidepressants.  Some web sites that profess to provide neutral advice to people who want to experiment will often have some posts on how to mix these medications to get enhanced effects.  None of that advice should be considered safe or reliable.  It is an indication to me that the person cannot be expected to take the prescription reliably.

7.  Context - very important consideration.  Seeing a person who has just survived a suicide attempt in the intensive care unit is a much different context than seeing a long  line of people who are dissatisfied with life for one reason or another.  Twenty three years of acute care work taught me that medical interventions are much more likely to work for clear cut severe problems than vaguely defined problems.  There are many people who are looking for a fast solution to difficult problems.  When I suggest to them that environmental factors need to be addressed or that they may benefit from psychotherapy or even more explicitly that psychotherapy will work better for your problem than medications - I am often met with resistance.  Common replies are that they cannot commit that kind of time or energy to psychotherapy.  Since most managed care companies discriminate against psychotherapy - many will tell me that their copays are too expensive.  If I point out that their work schedule or job is the problem - they will give me many reasons why they can't change it.  Treatment becomes conditional - as in - I am hoping that this antidepressant will work because I cannot change my life in any reasonable way and I can't do psychotherapy.

8.  Commitment to treatment - too many people come in and expect the prescription of an antidepressant to not only solve the problems but that nothing else is required of them except to show up for an occasional appointment.  If I want to see medical records like exams, labs, imaging studies, ECGs. EEGs, pharmacy records or other information it is generally not an option.  I need that information before any prescription occurs.  The same is true if I need to order these tests and see the results.  I am quite capable of having a discussion of the costs of these orders and that is why I have a preference for not repeating tests and looking at existing results.  That does not prevent the occasional complaints about how I am interested in making money off the person by ordering basic tests, even though I do not get anything at all for ordering tests.

The other part of treatment does involve agreeing to take the medication reliably and following the other recommendations that can be very basic.  If someone tells me that they are drinking two pots of coffee per day and they are anxious and can't sleep but are unwilling to stop the coffee because: "I know that I can drink two cups of coffee and still fall asleep" - I am probably not going to be able to do much with an antidepressant.  The same is true for somebody binge drinking a 12-pack of beer every night after work.  The effects of common substances like caffeine and alcohol are contrary to the goals of treating anxiety and depression with or without medication.

9.  Mania - it is possible for people who have taken antidepressants for years to become manic either while taking the antidepressant regularly or when the antidepressant has been disrupted.  Even though the incidence of mania from antidepressants is low and the treatment of bipolar disorder depressed includes an antidepressant-atypical antipsychotic combination (olanzapine-fluoxetine combination or OFC) stopping the antidepressant acutely is the best idea.  Many people discover at that point that mood stabilizers seem to work much better for their periods of depression than antidepressants.                              
10.  Misunderstanding the treatment alliance - fortunately treating depression and anxiety is not like treating standard medical problems.  Most office visits for new general medical and surgical problems are one or two visits in duration.  A medication is prescribed and it either works or it doesn't.  When it doesn't the problem either resolves on its own or becomes a chronic problem.  One of the best examples anywhere is acute bronchitis.  Over the past decades - tons of antibiotics have been prescribed for no good reason.  Acute bronchitis generally resolves on its own in young healthy people.  I try to be very clear with people that their response (good or bad) to the medication is in no way guaranteed.  I let them know that these medications are moderately effective at best and then only in the hands of somebody who knows how to rapidly switch them up and in some cases augment them.  Even then there will be some people who do not respond.  The key to all of that treatment is communication and it may require significant patience on the part of the patient.  It may also require more frequent appointments then they anticipated especially is associated problems like suicidal thinking and psychosis are also being addressed.

Those are my thoughts about the question of who I would not prescribe an antidepressant to.  I hope to transform those thoughts into dimensions in a useful graphic.  Feel free to let me know if I missed anything.



George Dawson, MD, DFAPA

The Recurring Question Of Antidepressants During Pregnancy

Over the course of my career, the question of whether  or not women should take antidepressants while pregnant has been a recurring question.  The point-counterpoint seems to depend on whether you are a psychiatrist treating women with severe forms of depression or not.  A lot of these studies seem to be driven by the fact that there is a registry somewhere for pregnant women who have had exposure to various medications.  Studies like this make headlines and are simplistically interpreted.  That is a much different perspective than a psychiatrist who is talking with a woman who has had severe postpartum depression and does not want to experience that again.  There is also the case of acute care psychiatrists who have assessed many women who had a significant change in their mood and mental state during or after a pregnancy and never recovered from that.  They became chronically mentally ill at that point and sustained all of the expected comorbidity.  The first few times I encountered that situation it was difficult to accept.  Nobody teaches that in medical school or residency training.  It seemed like a well kept secret.  Since then I have seen many women who developed a chronic mental illness that started as a severe mood change in or immediately after pregnancy.

The most recent question arose as a result of the study in reference 1, an analysis of the Quebec Pregnancy Cohort.  These same authors have an additional 9 references in Medline.  Full text is available for the current study.  The conclusion of these authors is that SSRI, SNRI, and TCA type antidepressants are associated with a significant increase in congential malformations - specifically as cardiac, musculoskeletal, craniofacial, digestive and respiratory defects.  The authors have a detailed flow diagram that details patient selection from the original cohort of 289,688 pregnancies between 1998-2009.  The flow diagram is a good illustration of how the original cohort was narrowed down to 18,487 pregnancies with either first trimester exposure to antidepressants (3,640) or no exposure (14, 847).  Subgroups for the antidepressant exposure include SSRIs (2,327), SNRIs (738), TCAs (382), and other (193).  The numbers and percentages of major malformations for each group were no exposure 1650/14,847 (11.1%), SSRI 279/2327 (12%), SNRI 91/738 (12.3%), and TCA 51/382 (13.4%).    Over the ten year course of the study the prevalence of antidepressant use doubled from 21 to 43 women per 1,000 pregnancies.  Doing some quick arithmetic on those numbers we find that 11.6% (421/3,640) of the antidepressant exposed pregnancies resulted in major congenital malformations.  Using the baseline rate of the unexposed pregnancies to calculate the expected number of major malformations results in 404/3,640 or a difference or 17 major malformations in the exposed group of 3,640 pregnancies.

What did the authors consider to be major malformations?  They used definitions of major congenital malformations according to conventions in two databases and they provided ICD-9 and ICD-10 diagnostic codes.  There were very few named diagnoses as far as I could tell.  There is some concern here because the literature on congenital malformations varies a bit in terms of the rate of birth defects and whether they are considered to be major or not.  Some of this was expressed in a NEJM editorial by Greene in 2007(2).  In commenting on two papers (3,4) on the subject of major congenital malformations associated with SSRIs in that edition he notes that  "A survey of the aggregate data now available — positive, negative, and equivocal — makes it clear that neither SSRIs as a group nor individual SSRIs are major teratogens on the order of thalidomide or isotretinoin."  He goes on to elaborate that there is a low risk with SSRIs but it is not zero and it is not clear cut.  That opinion is in contrast to some written since suggesting that the risk is high enough that no women should be exposed to SSRIs. 

One of the strengths of this study is that they used depressed and anxious mothers as the reference group to attempt to remove any confounders due to those conditions.  A variety of diagnostic codes were determined including 33 ICD9/10 codes for episodic mood disorders, 17 ICD9/10 codes for neurotic disorders, 19 ICD9/10 codes for depressed, anxious, and other cognitive disorders, 3 ICD9/10 codes for adjustment disorders, and 2 ICD9/10 codes for depression not otherwise specified.  Data on indications for antidepressant use were not available but the authors sought to limit indication bias by comparing only women selected for diagnoses of depression.  Women were selected with diagnoses of anxiety or depression who were treated with antidepressants one year before their pregnancy and several exclusion criteria such as exposure to more than one antidepressant or multiple births were applied.  Total psychiatric visits were viewed as a proxy measure for severity rather than confirmation of the diagnosis.        

The primary statistic used in this paper was the Odds Ratio (OR) or Adjusted Odds Ratio (aOR).  I have been skeptical of some applications of OR in the past.  There are also theoretical concerns as discussed in reference 2 below.  The authors present an excellent argument that the OR is widely used in epidemiological studies because it characterizes population variations in risk.  The weakness is that it has low accuracy as a classifying marker and it tends to overestimate relative risk when sample size is low.  A number of papers also point out that when large numbers of comparisons are done like calculating the OR and aOR for a large number of antidepressants it is likely that some of the findings will be explained by chance.  In this case they do the calculations by antidepressant, overall major congenital malformations and by individual body systems.  They conclude that only exposure to citalopram  [(aOR) 1.36, 95% CI 1.08 to 1.73]  in the first trimester increases the risk of major malformations but that there was a trend with other antidepressants (ADs) and that some ADs seemed to result in more system specific malformations.  Another methodological problem that can occur and affect comparisons is when the control group has an unexpectedly large number of malformations and this has happened in some of the research studies.

A much larger study of the problem was provided by the NICE consortium in the UK and their 923 page document on the subject (17).  The supplement of Forest plots alone for this document is an additional 313 pages long.  The authors of this document carefully selected studies of prenatal exposure to psychiatric medications and compiled fairly large studies.  They also showed the actual numbers of lesions in the exposed and unexposed groups by rates and the absolute differences in addition to the OR.  The NICE methodology was exhaustive and included very large number of patients across 6 major drug classes - antidepressants, antipsychotics, anticonvulsants, lithium, benzodiazepines, and stimulants.  The antidepressants studies listed sample sizes ranging from 50,257 to 2,548,463.  According to the authors there was no statistically increased risk in major congenital malformations with SSRIs even though the absolute risk difference was 12 more per 1,000.  There were some possible system specific risks with paroxetine and fluoxetine with a range of absolute risk difference of 3-9 more per 1,000.  In their guideline they translated this to a series of prescribing principles that could be applied to prescribing antidepressants in pregnancy (p 813).  These principles amount to a detailed informed consent discussion about potential risk during pregnancy and breastfeeding.  The document also contains the observation that up to 90% of women stop taking medication when they find out they are pregnant.  That often happens without consultation.

Attending meetings where psychiatrists are the presenters and focused on maternal health provides a much different perspective than pregnancy databases focused on congenital malformations.  In the past couple of years I was to attend three conferences, two of which occurred at the University of Wisconsin Annual Updates.  In all three of those conferences the maternal burden of anxiety and depression is the context and is generally presented first.  Katherine Wisner (11) presented in Madison last year.  Here arguments were based on the fact that psychiatric disorders are the most common chronic conditions of women of childbearing age and that the rate of treatment is very low: 25.5% of non-pregnant women and 14.3% of women who were pregnant in the past year.  She pointed out that medication free and disease free pregnancies are a myth.  Pregnant women get sick and sick women get pregnant.  About 14.5% of pregnant women have a new episode of depression and about 14.5% of women have an episode of postpartum depression.  Dr. Wisner is one of several authors who referenced Cohen's work (6) on the recurrence risk of depression in women who discontinued antidepressants  around the time of conception versus those who did not (68% versus 26%).  Click to enlarge this graphic.

JAMA. 2006 Feb 1;295(5):499-507 with permission

The presentation by Zachary Stowe (10) used the Cohen survival curve to illustrate recurrent depression with antidepressant discontinuation in pregnancy.  He also showed survival curves of treated versus untreated bipolar disorder by Viguera (16) showing that 90% of untreated pregnant bipolar patient relapse during the pregnancy out ot 12 weeks post partum compared to 40% of treated bipolar patients.  He also had two excellent slides on the acute maternal and neonatal consequences of a relapse to a mood disorder documenting numerous neonatal complications maternal complications including suicide.

Michelle Wiersgalla (12) expanded the postpartum disorders to include anxiety and psychosis.  She pointed out that suicide accounts for 20% of the post partum deaths and that suicide was the second leading cause of death in post partum women.   Some sources have classified it as the leading cause of maternal death (13, 14).  Infanticide occurs at the rate of about  8/100,000 and is associated with post partum psychosis.

All of those presenters would seem to have made a strong case for treating mood and anxiety disorders in pregnancy.  And of course the sterile research statistics are nothing like stress of clinical practice when a patient suddenly is destabilized and becomes unpredictable to both their family and the treating physician.  There is also the stress of an unplanned pregnancy in a woman who is being treated for a psychiatric disorder and that speaks to one of Dr. Stowe's main point and that is to treat all women of childbearing age in your practice as being potentially pregnant and documenting method of contraception and advice adn planning on pregnancy given the medication that they are taking.

It seems to me that the recurring problem of antidepressant safety during pregnancy is driven by a large body of research with widely discrepant low frequency findings.  We are generally talking about rates that are in the single to low double digits out of a thousand.  I think the conclusions of that research are probably affected by who is doing it.  You can find people who are interested in "proving" that antidepressants are harmful on the one hand.  They are likely to write from that perspective and minimize or completely ignore the severity of the associated women's mental health problems and the fact that they can be clearly treated with antidepressants.  They also never mention the potentially severe outcomes associated with untreated postpartum depression that can be observed in acute care settings.  On the other hand, there is research written from the perspective of treating women's mental health problems that (unexpectedly) will show less harm.  Clinicians - especially psychiatrists on the front lines who are often left advising women with unexpected pregnancies on what to do about their antidepressant treatment are stuck in the middle.  

A reasonable informed consent discussion with women of childbearing age begins by treating all women in this category as though they are potentially pregnancy or will be at some time. That includes a history of pregnancy and any associated changes in mood or anxiety.  It also includes a discussion of going from a no risk state for the fetus of not being pregnant while taking medications  to pregnancy while taking medication.  That includes plans for pregnancy and documenting the method of birth control.  With some high risk drugs - screening for pregnancy can be done.  If there is any concern about absolute minimization of risk pregnancy screening can be done and repeated if necessary.  In the case of planned pregnancies a window of 6-12 months prior to conception allows for a scheduled taper and discontinuation of the antidepressant medication.  The psychiatric evaluation can be valuable to determine the risk of relapse in these situations.  There are many patients who started taking antidepressants in acute situations where the stressor no longer applies.  There are many patients taking antidepressants for anxiety disorders who have never received psychotherapies for anxiety.  After these practical measures have been exhausted the decision comes down to whether or not there is an unplanned pregnancy and exposure or a situation where the discontinuation of the antidepressants would potentially be problematic.  In the cases I have been involved in, the women were also seeing high risk obstetric specialists and their pregnancies were closely monitored.    

As far as the actual drugs go, I do not think that paroxetine should be prescribed.  I am not basing that on anything in the pregnancy or congenital malformation literature.  I am basing it on my experience in psychiatry and the fact that in the first few years of its release - I determined it was a problematic drug in terms of drug interactions and discontinuation symptoms.  Why prescribe a problematic drug when there are plenty of other equivalent drugs?  I do not understand why anyone prescribes paroxetine these days.  That said, you can look at all of the data from the analyses of pregnancy registries and the difference in complication rates between drugs is so narrow and so small that the difference in changing to another drug with a lower odds ratio for congenital malformations probably makes little sense.  That does not mean that nobody will want to change and patient preference in this case requires a thorough and neutral discussion.



George Dawson, MD, DFAPA


References:

 1: Bérard A, Zhao JP, Sheehy O. Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: an updated analysis of the Quebec Pregnancy Cohort. BMJ Open. 2017 Jan 12;7(1):e013372. doi: 10.1136/bmjopen-2016-013372. PubMed PMID: 28082367

2: Greene MF. Teratogenicity of SSRIs--serious concern or much ado about little? N Engl J Med. 2007 Jun 28;356(26):2732-3. PubMed PMID: 17596609.

3: Alwan S, Reefhuis J, Rasmussen SA, et al. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007;356:2684-2692

4: Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007;356:2675-2683

5: Andrade C. Understanding relative risk, odds ratio, and related terms: as simple as it can get. J Clin Psychiatry. 2015 Jul;76(7):e857-61. doi: 10.4088/JCP.15f10150. PubMed PMID: 26231012.

6:  Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P.  Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker.  Am J Epidemiol (2004) 159 (9): 882-890 https://doi.org/10.1093/aje/kwh101

7: Davies HT, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ. 1998 Mar 28;316(7136):989-91. Review. PubMed PMID: 9550961.

8: Deeks J. When can odds ratios mislead? Odds ratios should be used only in case-control studies and logistic regression analyses. BMJ. 1998 Oct 24;317(7166):1155-6; author reply 1156-7. PubMed PMID: 9784470.

9: Bracken MB, Sinclair JC. When can odds ratios mislead? Avoidable systematic error in estimating treatment effects must not be tolerated. BMJ. 1998 Oct 24;317(7166):1156; author reply 1156-7. PubMed PMID: 9841055.

10: Zachary N. Stowe, MD  Treatment of Mood Disorders in Pregnancy and Lactation: Where Are We Now?  Presented at 2nd Annual Update And Advances In Psychiatry.  October 10-11, 2014; Madison, Wisconsin

11: Katherine Wisner, MD, MS.  Treating Depression During Pregnancy: Are We Asking the Right Questions?  Presented at 4th Annual Update And Advances In Psychiatry.  October 14-15, 2016; Madison, Wisconsin

12: Michelle Wiersgalla, MD.  Postpartum Mood and Anxiety Disorders.  Presented at the Minnesota Psychiatric Society.  October 1, 2016.

13: Oates M. Suicide: the leading cause of maternal death. Br J Psychiatry. 2003 Oct;183:279-81. PubMed PMID: 14519602.

14: Knight M, Nair M, Tuffnell D, Kenyon S, Shakespeare J, Brocklehurst P, Kurinczuk JJ (Eds.) on behalf of MBRRACE-UK. Saving Lives, Improving Mothers’ Care - Surveillance of maternal deaths in the UK 2012-14 and lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2009-14. Oxford: National Perinatal Epidemiology Unit, University of Oxford 2016.

"Maternal suicides have now been reclassified by the World Health Organisation as a direct cause of maternal death. The rate of maternal death by suicide remains unchanged since 2003 and maternal suicides are now the leading cause of direct maternal deaths occurring within a year after the end of pregnancy" p. 11.

15:  Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R,Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006 Feb 1;295(5):499-507. Erratum in: JAMA. 2006 Jul 12;296(2):170. PubMed PMID: 16449615.

16:  Viguera AC, Whitfield T, Baldessarini RJ, Newport DJ, Stowe Z, Reminick A,Zurick A, Cohen LS. Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry. 2007 Dec;164(12):1817-24; quiz 1923. PubMed PMID: 18056236.

17.  National Collaborating Centre for Mental Health.  Antenatal and Postnatal Mental Health Clinical Management and Service Guidance (Updated  Edition 2014). National Clinical Guideline Number 192.

Specific guidelines on treating depression in pregnancy for psychiatrists starts on about page 848 and continues.  A full gamut of treatment interventions in the context of clinical history and evaluation, patient preferences, and informed consent is presented.


antidepressants "congenital malformation"

antidepressants congenital malformation 

antidepressants pregnancy



Attribution:

The figure in the above post if from reference 15 - the figure is entitled:  "Figure. Kaplan-Meier Curves Illustrating the Time to Relapse by the 4 Medication Categories and Medication Reintroduction Categories" with permission from the American Medical Association, order number 4043410033700.  Thank you AMA.


Supplementary 1:

I tried to get permission to post survival curves from references 16.  The APA (of which I am a 32 year member) wanted to charge me $150 to repost a single 10 year old graphic that I have seen used in presentations.

Supplementary 2:

The graphics at the top are the actual fliers for the two conferences mentioned.  Other than two years of residency training, I have no affiliation with the University or Wisconsin Department of Psychiatry.