The first antidepressant, used clinically, was iproniazid, in 1957. In its discovery, as in so many others in the history of medicine, chance played an important role. Since then the pharmaceutical industry has not stopped researching and discovering new drugs to fight depression.
Antidepressants are classified into several groups:
- MAOI : Mono amine oxidase inhibitors.
- ADT : Tricyclic antidepressants.
- Second-generation or atypical antidepressants .
- SSRI : Selective serotonin reuptake inhibitors.
- SSRIs : Selective serotonin and norepinephrine reuptake inhibitors.
- Other groups.
MAOI: Mono amine oxidase inhibitors.
In 1952 some researchers observed that some tuberculosis patients treated with isoniazid were particularly “happy.” This improvement in the mood of consumptive patients led them to modify the original molecule, obtaining iproniazid , which can be considered the first commercialized antidepressant.
In 1957, Kline et al. Published the first study, which demonstrated the efficacy of iproniazid in nontuberculous depressive patients. The first group of antidepressant drugs had just been born: mono amine oxidase inhibitors, known as MAOIs .
Iproniazid was withdrawn from the market in 1961, due to frequent cases of liver and kidney toxicity.
After the withdrawal of iproniazid, new drugs from the same group appeared: mono amine oxidase inhibitors (MAOIs). The main ones were phenelzine (NARDELZINE) and tranylcypromine (PARNATE). These MAOI antidepressants were very effective and have been prescribed for decades around the world. However, they had a very serious adverse effect.
When MAOIs are taken together with foods rich in tyramine , they cause severe attacks of high blood pressure. For this reason, patients taking MAOIs had to follow strict dietary guidelines, eliminating from their intake any food rich in tyramine, such as cheese . In addition, cases of acute liver failure have been described after taking MAOIs in patients with an alcoholic history.
For this reason, MAOIs were second-line drugs. Its main indication was depressions refractory to treatment with tricyclic antidepressants.
Imipramine: First Tricyclic Antidepressant (TDA)
Around the same time, the Swiss laboratory Geigy was conducting a clinical trial with schizophrenic patients. They were looking for an antipsychotic that would improve the results of chlorpromazine.
Again, fortune intervened decisively. Kuhn, the Swiss psychiatrist in charge of the trial, found that the new drug, imipramine , barely improved the symptoms of schizophrenia. However, he found that it considerably improved the mood of the patients treated.
The new drug began to be used in antidepressant patients. It soon demonstrated an efficacy far superior to all drugs used to date. In 1958, imipramine was marketed under the name Tofranil. To date, it has been a reference drug in the treatment of depression. Imipramine was the first drug in the group of so-called tricyclic antidepressants (TCAs) .
The mechanism of action of imipramine is based on the inhibition of the reuptake of two neurotransmitters: serotonin and norepinephrine. From this fact, the monoamine hypothesis was formulated:
Depression could be caused by a deficit of neurotransmitters (the monoamines: serotonin, norepinephrine and dopamine).
Tricyclic antidepressants (TCAs) have been the drugs of choice for the treatment of depression for many years.
After imipramine (TOFRANIL), new TDA drugs appeared with an effect on the metabolism of serotonin and norepinephrine: Amitriptyline (TRYPTIZOL), Clomipramine (ANAFRANIL) and Amoxapine (DEMOLOX).
Others only have an effect on norepinephrine: Desipramine (Norpramin), Nortriptyline (PAXTIBI) or trimipramine (SURMONTIL).
The main drawback of ADTs is that high doses (very close to toxicity) are needed to achieve the antidepressant effect. Doses must be adjusted gradually and from time to time. They also have some frequent side effects : hypotension , cardiac arrhythmias , which can be serious in older people.
SSRI: Selective serotonin reuptake inhibitors.
In the 1980s, a new group of antidepressant drugs appeared, which was a real revolution in the treatment of depression. The SSRIs have similar efficacy to ADT , but many fewer side effects . These drugs work by preventing the reuptake of serotonin in the neuronal synapse, which results in an increase in the levels of this neurotransmitter.
They belong to this group: fluoxetine (PROZAC), fluvoxamine (DUMIROX), paroxetine (SEROXAT), sertraline (BESITRAN), citalopram (PRISDAL) and escitalopram (CIPRALEX).
This group of drugs has skyrocketed sales of antidepressants around the world, and some of the trade names are in the public domain, even giving the title to a book (“More Plato and Less Prozac”).
These days they put on television the movie “Love and other drugs” played by Jake Gylenhaal, who plays a medical visitor for Pfizer, which markets Prozac and is in a tough fight against the representative of Zoloft, the trade name of sertraline in the USA. Finally, the protagonist is assigned the commercialization of Viagra and their struggles for the SSRI market end.
Indications for SSRIs.
Currently, the indications for SSRIs are major depression (moderate and severe), dysthymia, obsessive compulsive disorder (OCD), generalized anxiety disorder (GAD), eating disorders such as bulimia and binge eating disorder (especially fluoxetine for its anorectic effect).
Interestingly, one of its most frequent side effects (the delay in reaching orgasm), has been used for its indication in the treatment of premature ejaculation, although in this indication the SSRIs with a short half-life such as dapoxetine (PRILIGY) are used.
Side effects can be numerous: nausea, vomiting, diarrhea, sleep disturbance, headaches, tremors, etc. In general, they tend to be of little importance and disappear after a short time. If treatment is started with low doses and gradually increased, they do not usually appear.
Sexual side effects are quite common: decreased libido, impotence, anorgasmia, or difficulty reaching orgasm. Other effects, much rarer, such as cardiac arrhythmias, have been minimized after reducing the maximum recommended doses of drugs such as citalopram and escitalopram, especially in older people.
Abrupt withdrawal of SSRIs can lead to withdrawal symptoms (much less than benzodiazepines). For this reason, withdrawal of treatment should always be done gradually.
SSRI and Suicide.
The increased risk of suicide and suicidal ideas in young people and adolescents is an issue that has generated not a few controversies, since the different studies that have been carried out in this regard give contradictory results.
The debate began in 2004, when a review of clinical studies observed a statistically significant increase in suicide attempts and suicidal ideation in young people and adolescents treated with SSRIs.
As a result of these publications, the FDA (American Federation of Drugs and Foods) forced the laboratories to include a “Black Box Warning”. This is a warning, included in the product information. It noted the increased risk of suicide. In 2004 this indication was put for children and in 2007 it was extended to those under 25 years of age. This “Black Label” was a warning and not a ban on use. This does not mean that SSRIs should not be used in people under 25 years of age, but rather that they should be used with caution, when strictly necessary and adopting special medical controls.
When it is necessary to prescribe an SSRI to an adolescent, fluoxetine (PROZAC) is the drug with the best risk / benefit ratio, thus being the drug of first choice.
After the introduction of the “Black Label”, the consumption of SSRIs in people under 25 years of age decreased sharply. Since then, a statistically significant correlation has been observed, in those under 25 years of age, between the increase in suicides and the decrease in the medical prescription of SSRIs. In other words, by prescribing fewer SSRIs to young people, suicides have increased.
One possible explanation.
Suicidal thoughts are one of the symptoms of depression. Another depressive symptom is psychomotor inhibition. This means that, although the patient has suicidal ideas, he does not see himself with physical or mental energy to carry them out.
On the one hand, antidepressants, by improving depressive symptoms, decrease self-destructive ideation and suicide attempts. Likewise, it has been shown that they produce a significant improvement on psychomotor inhibition.
However, in some patients they can decrease psychomotor inhibition, before making suicidal ideas disappear. In these cases, patients may be able to carry out their suicidal ideas or at least they are able to verbalize those ideas.
It seems prudent, in depressed patients with suicidal ideas, to monitor the response to treatment more closely. It would be possible to associate an anxiolytic with the antidepressant, at least in the first weeks of treatment, to avoid suicide attempts, by increasing their psychomotor activity.
SSRIs as anxiolytics in children and adolescents.
The indication of SSRIs in anxiety disorders , in those under 25 years of age, does not seem to have the disadvantage of the risk of suicide. This is because suicidal ideas are typical of depression. This risk does not exist in anxiety disorders (obsessive compulsive disorder, generalized anxiety, social phobia , post-traumatic stress disorder , etc.).
However, given the frequent association of anxiety disorders and depression, one must be cautious. In these cases, SSRI treatments cannot be prescribed to those under 25 years of age, lightly. The presence or absence of an associated depression should always be assessed. Lower-risk SSRIs should be used in adolescents. Specifically, fluoxetine is the only SSRI indicated in children.
After the incredible revolution, which led to the emergence of SSRIs, the pharmaceutical industry did not stop and continued its research. Antidepressants had proven to be a veritable gold mine and were being prescribed to millions around the world.
The next step was to find a group of drugs that act on serotonin and other neurotransmitters at the same time, as “the old ADTs” did, but trying to minimize side effects.
Thus were born the SSRIs or selective serotonin and norepinephrine reuptake inhibitors. These new drugs have been shown to have the efficacy of tricyclic antidepressants (TCAs) but not their side effects such as hypotension and cardiac arrhythmias.
Most used SSRIs.
In Spain, the best known marketed SSRIs are venlafaxine (VANDRAL), duloxetine (CYMBALTA). The mirtazapine (REXER) may be included in this group, although it is a derivative of mianserin. The Sibutramine (Reductil), belongs to this group of drugs, but marketing has been directed towards the treatment of obesity due to its anorectic action (suppress appetite).
Like the SSRIs, they are indicated in major depression and some anxiety disorders. They have been used successfully in the treatment of neuropathic pain (due to nerve involvement) and rheumatic fibromyalgia.
The most common side effects are: nausea, tremor, altered appetite, nightmares, constipation, dry mouth, headache, and blurred vision.
Other antidepressant drugs
Other antidepressant drugs.
ISRDs are selective dopamine reuptake inhibitors. Among them are amineptin and phenmetrazine.
ISRDNs are selective norepinephrine and dopamine reuptake inhibitors. Among them are bupropion and reboxetine.
Agomelatine (VALDOXAN) is a modern antidepressant for which there is no evidence to show greater efficacy than other antidepressants.
Looking for the triple inhibition.
It seems that research efforts are directed towards the search for molecules with a triple inhibition of neurotransmitter reuptake. The good results of SSRI treatments plus bupropion, which acts on dopamine, support this option. Thus, it would seek to increase the levels of serotonin, norepinephrine and dopamine.
Recommendations on antidepressants.
Why treat depression?
If not treated properly, depression can last from 6 months to 1 year or more. Without treatment, the risk of chronicity or subsequent relapses is greater.
After having suffered two relapses, the possibility of suffering a third depressive episode is 90%. Hence the importance of treating the first depressive episode correctly.
Antidepressants lower the risk of suicide.
What treatment to choose?
There are no studies that show a greater superiority of one antidepressant over another.
In mild depressions, it is recommended to start treatment with psychotherapy, and only if it does not improve, to associate antidepressants. In moderate depressions SSRIs are indicated.
In the case of patients with major depression, the treatment of choice is antidepressants. In adaptive depression (produced by stressful situations) the first choice treatment is psychotherapy.
In dysthymia, psychotherapy and anxiolytics should be combined. Although antidepressants are the main indication in major depression, studies have shown that the combination of antidepressants and psychotherapy gives better results.
In patients with severe depression, treatment with Venlafaxine or with tricyclic antidepressants (if tolerated well) should be started.
You should wait a period of between one and two months to assess the effect of the medication. If after this period there is no satisfactory clinical response, it is convenient to reconsider the diagnosis and if we are certain that we are facing major depression, the dose should be increased or a new drug added.
Once all the symptoms of the depressive picture have disappeared, it is advisable to continue the treatment without lowering the dose for at least six months. If there has been a previous relapse, the term will be 1 year.
After this period, a gradual and progressive withdrawal of the antidepressant will be carried out.
Electroconvulsive therapy (ECT).
In the case of severe depression or those that do not respond to medication, electroconvulsive therapy (ECT) can be used, which today no longer has anything to do with the one that began at the beginning of the 20th century.
Today ECT is performed with the patient anesthetized, with muscle relaxants to avoid the risk of fractures and with oxygen therapy. There are many prejudices about this technique, especially because of the images that we all keep about it, released by the cinema, where it was used more as an element of torture than of healing.
Lovers of good cinema will still have the memory of Jack Nicholson, receiving shocks from electroshock, in the film “Somebody flew the cuckoo’s nest,” directed in 1975 by Milos Forman and winner of five Hollywood Oscars.
Transcranial Magnetic Stimulation or TMSC, which consists of applying a magnetic field to the brain, is also beginning to be used. The same effect is sought as with ECT, but in this case without producing seizures. It is usually applied in those cases in which a rapid response to antidepressant treatment is sought.
Alexa Clark specializes in Cognitive Behavioral Therapy. She has experience in listening and welcoming in Individual Therapy and Couples Therapy. It meets demands such as generalized anxiety, professional, love and family conflicts, stress, depression, sexual dysfunction, grief, and adolescents from 15 years of age. Over the years, She felt the need to conduct the psychotherapy sessions with subtlety since She understands that the psychologist acts as a facilitator of self-understanding and self-acceptance, valuing each person's respect, uniqueness, and acceptance.