A fortunate knock of luck is always welcomed by scientists and researchers, yet any treatment modalities should be novel by design rather than by serendipity. Antidepressants were discovered by chance in the 1950s, and it seems that they suffer from specific deficiencies when it comes to their clinical effectiveness and safety profile. It is something that very few in the medical field negate, although the degree of disagreement may vary.

Depression—a poorly understood disorder

Depression is a heterogeneous disorder that may be characterized by a group of common symptoms, but the underlying cause may vary from person to person. Despite considerable research about 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 identical criteria. This means that they have a different threshold for various depression symptoms.

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

The rise of antidepressants

Both the US- and European-based statistics show a sharp increase in the prescription of antidepressants since the 1990s. Although statistics also indicate that no more than 8% of the population suffers from depression, 13% are taking antidepressants. Moreover, these drugs are much more commonly used in people above 60 years of age, with almost one-fourth of them taking antidepressants and many older adults using them for more than a decade.

Such a rise 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 all-purpose drugs that are considered useful to treat various mood disorders, painful conditions, inflammatory bowel syndrome, anxiety, panic disorders, and many more.

How antidepressants work?

Antidepressants are drugs belonging to various groups. Almost all of them work by changing the level of monoamine neurotransmitters in the brain. There are some additional effects too, as not all drugs capable of altering monoaminergic functioning may work as antidepressants.

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

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

Apart from modifying the transmission of monoaminergic neuromediators, antidepressant drugs also have a complex effect on various receptors and the hypothalamic–pituitary–adrenal (HPA) axis. The impact of some of the novel antidepressants on different serotonin receptors (e.g., 5-hydroxytryptamine receptors) has been well-studied.

Some of the most commonly used antidepressants these days are tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and selective serotonin noradrenaline reuptake inhibitors (SSNRIs).

What are the safety issues?

When we talk about drug safety, it is not just about the adverse effect but also about the clinical efficacy. Too many side effects and little clinical effectiveness as compared to placebo could put the utility of any drug therapy under doubt.

When it comes to side effects, anticholinergic side effects like dryness of mouth, blurring of vision, and dizziness are common with most antidepressants. Most of them may also alter appetite and sexual function, and cause an upset stomach, joint and muscular pains, problems with drug interactions, irritability, mood changes, movement disorders and the risk of falling in the elderly, and much more. Moreover, these side effects continue to persist when the drugs are used long term.

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

Perhaps the most worrisome of all the adverse effects is the higher occurrence of suicide and violence in those on antidepressants. Although there are many studies with contradicting conclusions, the majority seem to show that suicide and violence are much higher in those taking antidepressants. Moreover, abnormal behavior is equally common with the newer SSRIs and SSNRIs.

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

Clinical studies have demonstrated that the newer non-tricyclic antidepressants are not any better in their safety profile in the elderly population.

Finally, a considerable number of studies seems to put doubt on the effectiveness of antidepressants. Some medical specialists believe that antidepressants do not help at all, and many studies support their view. Thus in one of the studies published in the 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.

Conclusion

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

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