Antidepressants
In this chapter, we will review pharmacological concepts underlying the use of antidepressant
drugs. There are many different classes of antidepressants and dozens of individual
drugs. The goal of this chapter is to acquaint the reader with current ideas about
how the various antidepressants work. We will explain the mechanisms of action of
these drugs by building upon general pharmacological concepts introduced in earlier
chapters. We will also discuss concepts about how to use these drugs in clinical practice,
including strategies for what to do if initial treatments fail and how to rationally
combine one antidepressant with another, or with a modulating agent. Finally, we will
introduce the reader to several new antidepressants in clinical development.
Our discussion of antidepressants in this chapter is at the conceptual level, and
not at the pragmatic level. The reader should consult standard drug handbooks (such
as the companion Stahl’s Essential Psychopharmacology: the Prescriber’s Guide) for details of doses, side effects, drug interactions, and other issues relevant
to the prescribing of these drugs in clinical practice. Here we will discuss putting
together an antidepressant “portfolio” of two or more mechanisms of action, often
requiring more than one drug, as a strategy for patients who have not responded to
a single pharmacological mechanism. This treatment strategy for depression is very
different than that for schizophrenia, where single antipsychotic drugs as treatments
are the rule and the expected improvement in symptomatology may be only a 20–30% reduction of symptoms
with few if any patients with schizophrenia becoming truly asymptomatic and in remission.
Thus, the chance to reach a genuine state of sustained and asymptomatic remission
in major depression is the challenge for those who treat this disorder; this is the
reason for learning the mechanisms of action of so many drugs, the complex biological
rationale for combining specific sets of drugs, and the practical tactics for tailoring
a unique drug treatment portfolio to fit the needs of an individual patient.
General principles of antidepressant action
Patients who have a major depressive episode and who receive treatment with any antidepressant
often experience improvement in their symptoms, and when this improvement reaches
the level of 50% reduction of symptoms or more, it is called a response (Figure 7-1). This used to be the goal of treatment with antidepressants: namely, reduce symptoms
substantially, and at least by 50%. However, the paradigm for antidepressant treatment
has shifted dramatically in recent years so that now the goal of treatment is complete
remission of symptoms (Figure 7-2), while maintaining that level of improvement so that the patient’s major depressive
episode does not relapse shortly after remission, nor does the patient have a recurrent
episode in the future (Figure 7-3). Given the known limits to the efficacy of available antidepressants, especially
when multiple antidepressant treatment options are not deployed aggressively and early
in the course of this illness, the goal of sustained remission can be difficult to
reach. In fact, remission is usually not even reached with the first antidepressant
treatment choice.
Do antidepressants work anymore in clinical trials?
Although remission (Figure 7-2) without relapse or recurrence (Figure 7-3) is the widely accepted goal of antidepressant treatment, it is becoming more and
more difficult to prove that antidepressants – even well-established antidepressants
– work any better than placebo in clinical trials. This is generally due to the fact
that in modern clinical trials, the placebo effect has inflated so much over recent
decades that placebo now seems to work as well as antidepressants in some trials and
nearly as well as antidepressants in other trials. Why this is occurring is the subject
of vigorous debate. Some experts propose that it is due to problems conducting clinical
ratings in a clinical trial setting that is now unlike a clinical practice setting
since patients are seen weekly, often for hours, whether they receive an antidepressant
or not; other experts point out that subjects in trials may really be “symptomatic
volunteers” who are less ill and less complicated than “real” patients. Critics of
psychiatry and psychopharmacology proclaim from clinical trial evidence that antidepressants
don’t even work and that their side effects and costs do not justify their use at
all. This phenomenon of shrinking and erratic efficacy of long-established antidepressants
as well as new antidepressants in clinical trials has also caused
the pharmaceutical industry
to increasingly abandon the development of new antidepressants. Even patients seem
to be affected by this debate, perhaps losing their confidence in the efficacy of
antidepressants, since up to a third of patients in a real clinical practice setting
never fill their first antidepressant prescription, and for those who do, perhaps
less than half get a second month of treatment and maybe less than a quarter get an
adequate trial of 3 months or longer. One thing is for sure about antidepressants,
and that is that they don’t work if you don’t take them. Thus, the clinical effectiveness
of antidepressants in clinical practice settings is reduced by this failure of “persistency”
of treatment for a long enough period of time to give the drug a chance to work.
Whatever the cause of this controversy over the efficacy of antidepressants in clinical
trials, one only needs to spend a short time in a clinical practice setting to be
convinced that antidepressants are powerful therapeutic agents in many patients. Nevertheless,
there have been some useful consequences of the debate on the efficacy of antidepressants,
such as re-energizing the integration of psychotherapies with antidepressants, searching
for new non-medication
neurostimulation therapeutics, and studying the combination of currently available
antidepressants in order to gain better outcomes, all of which will be discussed in
this
chapter.
How well do antidepressants work in the real world?
“Real world” trials of antidepressants tested in clinical practice settings that include
patients normally excluded from marketing trials, such as the STAR*D trial of antidepressants
(Sequenced Treatment Alternatives to Relieve Depression), have recently provided sobering
results. Only a third of such patients remit on their first antidepressant treatment,
and even after a year of treatment with a sequence of four different antidepressants
given for 12 weeks each, only about two-thirds of depressed patients achieve remission
of their symptoms (Figure 7-4).
What are the most common symptoms that persist after antidepressant treatment, causing
this disorder not to go into remission? The answer is shown in Figure 7-5, and the symptoms include insomnia, fatigue, multiple painful physical complaints
(even though these are not part of the formal diagnostic criteria for depression),
as well as problems concentrating, and lack of interest or motivation. Antidepressants
appear to work fairly well in improving depressed mood, suicidal ideation, and psychomotor
retardation (Figure 7-5).
Why should we care whether a patient is in remission from major depression or has
just a few persistent symptoms? The answer can be found in Figure 7-6, which shows both good news and bad news about antidepressant treatment over the
long run. The good news is that if an antidepressant gets your patient into remission,
that patient has a significantly lower relapse rate. The bad news is that there are
still very frequent relapses in the remitters, and these relapse rates get worse the
more treatments the patient needs to take in order to get into remission (Figure 7-6).
Data like these have galvanized researchers and clinicians alike to treat patients
to the point of remission of all symptoms whenever possible, and to try to intervene
as early as possible in this illness of major depression, not only to be merciful
in trying to relieve current suffering from depressive symptoms, but also because
of the possibility that aggressive treatment may prevent disease progression. The
concept of disease progression in major depression is controversial, unproven, and
provocative, but makes a good deal of sense intuitively for many clinicians and investigators
(Figure 6-23). The idea is that chronicity of major depression, development of treatment resistance,
and likelihood of relapse could all be reduced, with a better overall outcome, with
aggressive treatment of major depressive episodes that leads to remission of all symptoms,
thus potentially modifiying the course of this illness. This may pose an especially
difficult challenge for treatment of younger patients, where risks versus benefits
of antidepressants are currently debated (Figure 7-7).
Antidepressants over the life cycle
Adults between the ages of 25 and 64 might have the best chance of getting a good
response and with the best tolerability to an antidepressant (Figure 7-7). Adults aged 65 or older may not respond as quickly or as robustly to antidepressants,
especially if their first episode starts at this age, and especially when their presenting
symptoms are lack of interest and cognitive dysfunction rather than depressed mood,
but do not have increased suicidality from taking an antidepressant. At the other
end of the adult age range, those younger than 25 may benefit from antidepressant
efficacy but with a slightly but statistically greater risk of suicidality (but not
completed suicide) (Figure 7-7). Age is thus an important consideration for whether, when, and how to treat a patient
with antidepressants throughout the life cycle, and with what potential risk versus
benefit.