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