Many people are concerned about the long-term effects of medications used to treat neuropsychiatric disorders, commonly referred to as psychotropic drugs. The prevailing idea is probably that it is better to avoid taking them whenever possible; that, if they are taken, it is better to use them for short periods; and that, whenever possible, other forms of treatment should be preferred, also with the aim of discontinuing medications that have been taken for a long time.
Since speaking of “psychotropic drugs” as a whole does not make much sense, given that they comprise a highly heterogeneous group of medications used for different disorders, it is useful to focus our attention on antidepressant treatments, which are used for depression, anxiety disorders, and “somatization.”
When considering whether treatment is necessary and how long antidepressant treatment should last, people often focus first on the possible risks of treatment. However, they rarely begin with the first logical question: what is the course of untreated depression?
Some depressive disorders are recurrent but short-lived, lasting one month or less, while others are persistent and vary in severity. In between these extremes lies the majority of cases: depressions that, if left untreated, last for many months or several years before eventually resolving, often followed by further episodes in subsequent years or by residual symptoms that persist continuously.
It has been demonstrated that antidepressant treatment lasting at least two years reduces the probability of relapse after treatment is discontinued. In other words, short treatments lasting only a few months tend to be followed by relapses that occur earlier and are more numerous.
This argument is simple and clear, but relapses do not merely represent a repetition of symptoms; they represent a progression of the disease.
If depression corresponds to an instruction that the brain executes, treatment removes that instruction and prevents depression, over time, from constructing “its own” brain—that is, a brain that preferentially “produces” depression.
The depressed brain becomes structured in such a way as to maintain and reproduce depressive symptoms, as though it had effectively been trained in depression and could therefore produce it without any particular external reason, automatically, continuously, and rigidly in response to external factors that might otherwise correct it.
If, during treatment, the brain has not sufficiently recovered from the initial depressive “instruction,” and treatment is discontinued prematurely, the biological process that “fixes” this instruction in the brain and makes it increasingly structured and rigid resumes and progresses.
Relapse therefore means adding another brick to the wall of depression—a wall that has not been completely dismantled if treatment has not continued for long enough.
This line of reasoning clearly suggests that the disease drives the brain toward rigidity and deterioration, whereas treatment, particularly when maintained over a longer period, helps the brain recover, improves its “plasticity,” and reverses the disease process.
In broad terms, the depressed brain becomes simplified: interconnections are reduced, as is the volume of certain brain regions. The underlying idea is that it becomes a brain capable of doing fewer things, reacting less, changing states less easily, and becoming increasingly organized to reproduce itself regardless of external factors.
Consequently, spontaneous recovery from subsequent episodes is reduced when relapses occur repeatedly. This explains why, after yet another relapse, a medication that was previously effective may no longer work, or may work only at a higher dose.
This process of “restructuring” of the brain, beyond its effects on symptoms, is mediated by antidepressant medications—and by other drug classes as well—through hormonal and neurobiological mechanisms that would probably be useful indicators of relapse risk if it were practical and easy to measure them directly within specific brain regions.
If the neurotransmitters that are commonly cited to characterize antidepressants—serotonin, adrenaline, dopamine, and others—are involved in the initial level of antidepressant action, this mechanism explains the correction of symptoms.
However, the maintenance of a particular configuration of neurotransmitters and receptors may subsequently lead to changes in the “hormonal” signaling systems through which neurons communicate with one another, thereby establishing and maintaining both normal and pathological structures and patterns of functioning.
Relapses, as well as chronicity resulting from the absence of treatment, therefore act upon the neurobiological systems that construct a brain organized to sustain depression, whereas treatment acts in the opposite direction.
It is likely that this is precisely why, in more persistent forms of depression, treatment may produce increasingly better results over time after initially modest or disappointing responses.
It may therefore be worthwhile to persist with and intensify treatment in order to stimulate a change that may not occur easily or immediately at the symptomatic level but may gradually occur at a deeper neurobiological level, involving the progressive “dismantling” of the depressive structure that has been built over time.
One way of enhancing this “trophic” effect—that is, the stimulation of neuronal growth, generally associated with more flexible and richer brain functioning, with less rigidity and greater vitality—is regularity in taking treatment.
Medications taken irregularly may still provide relatively stable remission of symptoms, but their therapeutic effect is less effective.
In other words, taking treatment intermittently, or taking it on some days but not others, is not equivalent to taking a lower dose: irregular treatment produces a weaker therapeutic effect.
Even more “precise” in promoting a therapeutic effect are extended-release formulations, which allow the medication to maintain relatively stable levels in the brain over the 24-hour period between doses.
In essence, depression is a disease that should be treated early and for a sufficiently long period, with the understanding that medications—apart from the issue of possible adverse effects while they are being taken—can improve brain functioning both during treatment and, potentially, after a sustained course of treatment has ended.
Conversely, relapses are not merely possible new episodes that can subsequently be treated in the same way as the first episode. They deepen an already established pathway and therefore advance the disease process.
The number of previous episodes consequently increases the risk of future episodes, chronicity, and persistent residual symptoms.
In patients with a long history of depression and repeated relapses, it may be useful to consider combination treatments and augmentation strategies, and probably to allow more time for treatment to work, because the effects of antidepressants—which may not be immediately visible at the symptomatic level—may nevertheless be taking place at a deeper neurobiological level.
It is somewhat like an old, rusted machine: before it can be put back into operation, the rust must first be “removed”; only afterward can the machine be properly lubricated and restored to effective functioning.