Is there a “best” antidepressant? Is depression more treatable with newer medications? And is there a logical sequence of treatment attempts for people who do not respond to the first treatment?
There are many treatments for depression, not all of them pharmacological. At present, for a number of reasons that are not strictly medical, but also involve practicality, costs, and medico-legal barriers, pharmacological treatment is generally the first choice compared with other treatments that are nevertheless highly effective, such as electroconvulsive therapy (ECT).
The newer antidepressants are not all innovative in terms of their mechanisms of action. Some of them attempt to reproduce the properties of certain older, highly effective medications while avoiding a number of troublesome side effects.
Some authors propose the following approach. The first treatment attempt can be made with any antidepressant, since it is not possible to determine which antidepressant is the “best” for depression—which, rather than being a single disease, is a syndrome corresponding to different disorders.
Above all, it is not possible to say that one antidepressant is simultaneously faster, more effective, and more stable over time, both in maintaining the results obtained and in achieving complete remission.
After a first attempt, the second should involve a drug from a different class. The classes, in order of their historical appearance, are tricyclics, SSRIs, NRIs, SNRIs, dopaminergic drugs, and receptor-acting antidepressants (a mixed group, both in terms of when they appeared and their mechanisms of action).
To simplify matters, some drugs act selectively on the adrenaline system, while others act selectively on the serotonin system (with NRIs at one end and SSRIs at the other, and SNRIs and tricyclics somewhere in between). There are also some drugs that act on the dopamine system.
The third attempt should involve tricyclic drugs if they have not already been used, or MAOIs if they have not already been used. After that, subsequent attempts should include electroconvulsive therapy in combination with pharmacological treatment.
Once these attempts have failed, numerous strategies can be used to augment antidepressant treatment (augmentation), either with other antidepressants, with drugs from different classes, or with non-pharmacological treatments such as vagus nerve stimulation and transcranial magnetic stimulation.
Naturally, a sequence of treatment attempts refers to “monotherapy”—that is, treatment with a single drug at an effective dose, increasing it up to the maximum tolerated dose if there is no response to the minimum effective dose, over a period of at least 12 weeks.
Combinations of antidepressants as a first-line treatment are often reasonable. They are a practical way of producing a good therapeutic effect without producing the side effects associated with higher doses of individual drugs—for example, by using several medications at lower doses. These combinations, usually involving drugs from different classes, cannot, however, be arranged into a precise treatment sequence.
In general, according to these guidelines, someone who has undergone three or more successive treatment attempts including tricyclics and MAOIs would have little likelihood of benefiting from further trials with a single antidepressant.
Failure to respond to ECT combined with antidepressant treatment, after at least one additional trial with an antidepressant from a different class, would likewise be a reason not to continue pursuing single-antidepressant treatments.
Other authors, however, believe that antidepressants and convulsive therapy can both be considered as first-line treatments.
A person who fails to respond to a period of treatment with two different antidepressants (or one antidepressant and ECT) after a period ranging from a minimum of four months to a maximum of twelve months can be considered treatment-resistant.
A further twelve months of treatment trials using augmentation strategies defines a category of “chronic treatment resistance.”
ECT should therefore be considered both as an initial treatment option and as an advanced treatment for pharmacoresistant forms of depression, in which it produces a response in approximately 60–90% of cases.
In fact, ECT should not be regarded solely as a treatment reserved for resistant forms of depression. It is a genuine therapeutic option that can be considered without necessarily waiting until all pharmacological treatment trials have been exhausted.
Among augmentation strategies, lithium is the most extensively studied, particularly in combination with tricyclic antidepressants.
Thyroid hormone, administered as a two- to three-week course, can be combined with any antidepressant class.
Other antidepressant or atypical antipsychotic treatments can also be considered, as can TMS or vagus nerve stimulation, the latter being effective in approximately half of pharmacoresistant cases.
Conclusion
If antidepressants have not been administered at an effective dose for several weeks, it is not possible to conclude that the drug has failed to produce a response.
When there is no response to a particular medication, it is appropriate to consider drugs from different classes.
At most, by the third treatment attempt, tricyclics and MAOIs—that is, the “older drugs”—should be considered. ECT, meanwhile, can be considered among the early treatment options for certain forms of depression and, even more importantly, as a treatment for pharmacoresistant forms.
Treatments for resistant depression are available, and some are still being developed.
The fact that depression has not responded to treatment and has persisted for a long time does not mean that it cannot respond to a new treatment attempt. Certainly, long duration alone is not a reason to assume that the illness has reached a stage in which no treatment can be effective.