Antidepressants: How They Work, Efficacy (?) And Side Effects

Antidepressants were discovered by chance in 1950, and it appears that they suffer from specific deficiencies when it comes to their effectiveness and clinical safety profile . It is something that very few deny in the medical field, although the degree of disagreement can vary.

Depression – a poorly understood disorder

Depression  is a heterogeneous disease, which can be characterized by a group of common symptoms, but the underlying cause can vary from person to person . Despite considerable research into the structural and neurochemical changes caused in the brain of a person suffering from depression, there is no specific brain-based test for the condition. Two of the most widely accepted diagnostic systems, ICD-10 and DSM-IV, have similar but not the same criteria. This means that they have a different threshold for various symptoms of depression.

Some of the universally accepted symptoms of depression are depressed mood, fatigue, loss of interest, feelings of worthlessness, recurring thoughts of suicide, insomnia and changes in appetite.

The rise in antidepressants

Both European and US-based statistics show a sharp increase in antidepressant prescriptions since the 1990s . Although statistics also indicate that not more than 8% of the population suffers from depression, 13% are taking antidepressants. In addition, these drugs are much more commonly used in people over 60 years of age, with almost a quarter of them taking antidepressants and many older adults using them for more than a decade.

Such an increase in the use of antidepressants is also explained by the fact that these drugs are given not only to treat depression. They have become a kind of drug considered useful for treating various mood disorders, painful conditions, inflammatory bowel syndrome, anxiety, panic, and many more.

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How do antidepressants work?

Antidepressants are drugs that belong to different groups. Almost all of them work by changing the level of neurotransmitters in the brain . There are some additional effects as well, just as not all drugs capable of altering the monoaminergic functioning can work as antidepressants.

Antidepressants alter the presynaptic and postsynaptic concentration of dopamine ,  serotonin  and norepinephrine in neurons , with most modern antidepressants targeting serotonin and norepinephrine to some extent. Dopamine, serotonin and norepinephrine are vital neurotransmitters, playing an essential role in the limbic  system and the reward system. The medications help to replace these systems, consequently, contributing to the recovery of mood and emotional balance.

Antidepressants have been shown to increase activation of the prefrontal cortex but decrease activation of the hippocampus , hippocampal region, amygdala, ventral anterior cingulate cortex, and orbitofrontal cortex. These areas of the brain play an important role in the formation of mood and emotions and are part of the limbic and reward system.

In addition to modifying the transmission of monoaminergic neuromediators, antidepressant drugs also have a complex effect on several receptors and on the hypothalamic-pituitary-adrenal (HPA) axis. The impact of some of the new antidepressants on different serotonin receptors (eg, 5-hydroxytryptamine receptors) has been well studied.

Some of the most widely used antidepressants today are tricyclic antidepressants (ADT), serotonin reuptake inhibitors (SSRIs) , serotonin and norepinephrine reuptake inhibitors (SSNRIs).

What are the security issues?

When it comes to drug safety, it’s not just about the adverse effect, but also about the clinical effectiveness. Too many side effects and little clinical efficacy, compared to placebo, could put the usefulness of any drug therapy in doubt.

When it comes to side effects, anticholinergic side effects like dry mouth, blurred vision and dizziness are common with most antidepressants. Most of them can also alter appetite and sexual function, and cause stomach pain, joint and muscle pain, problems with drug interactions, irritability, mood swings, movement disorders, risk of falling in the elderly, and more. In addition, these side effects continue to persist when medicines are used for the long term.

The development of tolerance and withdrawal symptoms is widespread. Discontinuation syndrome can be very bad in many cases.

Perhaps the most worrying of all the side effects of antidepressants is the increased occurrence of suicide and violence in those taking the drugs. Although there are many studies with contradictory conclusions, most seem to show that suicide and violence are much higher in those who take antidepressants . In addition, abnormal behavior is also common with the latest SSRIs and SSNRIs.

There is an abundance of literature mentioning the risk of suicide in depression. However, the effectiveness of antidepressants in preventing depression-related suicide remains inconclusive.

Clinical studies have shown that the most recent non-tricyclic antidepressants are not better in their safety profile in the elderly population.

Finally, a considerable number of studies appear to cast doubt on the effectiveness of antidepressants. Some medical experts believe that antidepressants do not help in any way, and many studies support their view. Thus, in one of the studies published in  JAMA  , it was concluded that the therapeutic benefit with antidepressants may actually be non-existent or minimal for mild to moderate depression, with more substantial benefits in severe cases of depression .


Although the diversity of depression is well recognized, almost all drugs designed to treat depression inhibit the reuptake of one or another monoamine neuromediator, and very little has changed in our approach to treatment since the advent of the first antidepressant medication. In order to overcome the dangers and limitations of antidepressant therapy, there is an urgent need to create antidepressants that have a new mechanism of action and better tolerance. More care should be exercised by medical professionals when prescribing antidepressants, since the ability to promote positive effects in many patients is questionable

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