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 20th 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
