The history of antidepressants began in 1957, when two drug types – iproniazide and imipramine – improved the mood of depressive patients; although, these drugs were initially conceived for other therapeutic purposes.
Iproniazide is the first antidepressant drug in the series of monoamine oxidase inhibitors (MAOIs), and imipramine is considered the tricyclic antidepressant pattern. In 1960, amitriptyline was discovered and chlorimipramine was synthesized, and a year later trimipramine, drugs that started the group of sedative tricyclic antidepressants, was created.
In 1964, it was shown that imipramine and other tricyclic antidepressants were able to inhibit the presynaptic reuptake of norepinephrine. A year later, Joseph Schildkraut developed the catecholaminic hypothesis of affective disorders, which highlighted the role of noradrenaline (Nad) in the appearance of depressive disorders.
Second generation antidepressants
In the seventies appeared the so-called second-generation antidepressants (maprotiline, mianserin). To this group would also be added the so-called atypical antidepressants (trazodone, nomifensin, alprazolam). The set of antidepressants: tricyclic, second generation and atypical, are called heterocyclic antidepressants.
In 1972, the Copen group in England developed the indolamine hypothesis of depression, and highlighted the role of serotonin (5HT). In the search for safer antidepressants, the development of selective serotonin reuptake inhibitors (SSRIs, fluoxetine, fluvoxamine, paroxetine, citalopram, sertraline) has represented a significant advancement.
More recently, a series of antidepressants has appeared that has improved the profiles of side effects, with greater specificity on the different neurotransmitter systems.
The available antidepressants have very diverse chemical structures, without any correlation between their chemical structure and their therapeutic specificity.
Although, the mechanism of antidepressant action has not yet been made clear, it is known that effective antidepressants interact, immediately, with one or more receptors or enzymes related to monoaminergic neurotransmitters. These immediate actions provide the pharmacological basis for the current classification of the different antidepressants.
According to this classification scheme, there are at least 8 different pharmacological action mechanisms and more than 2 dozens of antidepressants. Most antidepressants block the reuptake of monoamines, but some of them block alpha-2 receptors, and others, the enzyme monoamine oxidase (MAO). Some antidepressants have direct actions only in one neurotransmitter system and others act on several systems.
Some of the major side effects of antidepressants
This type of psychoactive drug is one of the most used, but it also entails its dangers and risks, despite its benefits in depression.
Since the discovery of the antidepressant effects of monoamine oxidase inhibitors (MAOIs) and the popularization of tricyclics, great progress has been made in this area of pharmacotherapy. At present, there are medications with a high degree of efficacy and that cause few adverse reactions.
In this article, we will analyze the side effects of the main types of antidepressants: MAOIs, tricyclics, serotonin reuptake inhibitors (SSRIs) and fourth-generation antidepressants, including norepinephrine reuptake inhibitors (SNRIs) and those of the reuptake of serotonin and noradrenaline.
Side effects of depressive medicines
All psychotropic drugs that are effective in treating depressive symptoms are agonists (molecules combine with receptors on a cell and caus production of a physiological reaction) of the monoamines, a group of neurotransmitters. Some enhance the action of noradrenaline, while others are related to a greater extent with serotonin. The dual inhibitors, of recent appearance, are associated with both neurotransmitters.
The side effects of antidepressants are due both to their monoaminergic action and to the idiosyncratic mechanisms of some of them. Although, the five classes of drugs we will talk about cause very varied side effects, we will focus on those that appear most frequently and those that have special clinical relevance.
Monoamine oxidase inhibitors (MAOIs)
As the name suggests, MAOIs inhibit the activity of the monoamine oxidase enzyme, which breaks down monoamines to prevent them from concentrating excessively in the synaptic space. The blocking of the enzyme caused by these drugs increases the availability of noradrenaline, serotonin and dopamine, which is effective in the treatment of depression.
Currently, MAOIs are rarely used because they can cause severe hypertensive crises if they interact with foods with tyramine, such as chocolate, coffee or bananas. This phenomenon is known as "cheese effect". They also cause milder side effects such as heart rhythm disturbances, insomnia, headaches, anorgasmia, weight gain, etc.
Tricyclic antidepressants, such as clomipramine and imipramine, inhibit the reuptake of serotonin, norepinephrine and, to a lesser extent, dopamine. Its side effects are important and are due mainly to the agonism of noradrenaline and the collateral antagonism of two other neurotransmitters: acetylcholine and histamine.
Adverse reactions to the tricyclicsinclude neuroleptic malignant syndrome may cause coma and even death. In addition, excessive sedation, memory problems, constipation, urinary retention, weight gain, hypotension and dizziness may appear. Where there is a strong risk of dependence and excessive consumption, it can cause an overdose.
Scientific research has shown that it is not advisable to take tricyclic antidepressants for prolonged periods of time. Not only are they addictive and cause withdrawal symptoms when they are abandoned, but they have also been found to reduce the number of noradrenaline and serotonin receptors in the long term.
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs only interact with serotonin receptors; so, their action is more specific and safe than that of MAOIs and tricyclics. In addition, although bothersome and inevitable, side effects may appear at the beginning of the consumption. However, they tend to be reduced to a certain extent and become more tolerable after one or two weeks of treatment.
Drugs such as fluoxetine, sertraline and citalopram cause anxiety, akathisia, tremors, diarrhea, vomiting and sexual disorders, including decreased desire, difficulty in arousal and delayed orgasm. We speak of "serotonin syndrome" when these reactions are particularly intense.
Selective noradrenaline reuptake inhibitors (ISRN)
Reboxetine is a newly developed drug that is as effective as SSRIs in the treatment of depression symptoms. Its action is related to the selective inhibition of noradrenaline reuptake, and it is often administered in conjunction with an SSRI to enhance the therapeutic effect of both drugs.
The noradrenaline agonism associated with ISRN is especially effective in treating symptoms such as apathy, deficits in social interaction, and problems of memory and concentration. Its side effects are milder than those of SSRIs. The most common are insomnia, nausea, sweating, constipation and dry mouth.
Serotonin and noradrenaline reuptake inhibitors (SNRI)
In recent years, some psychopharmaceuticals have appeared, such as venlafaxine. These combine the specific agonism of serotonin with that of noradrenaline without interacting with other receptors, as with tricyclics, so that associated reactions are scarce. In addition, its therapeutic effects are superior to those of the rest of antidepressants.
Since they act in the same pathways, SNRIs cause side effects similar to those of the other drugs we have mentioned. Other symptoms may include drowsiness or insomnia, headache, dizziness, fatigue, nausea, dry mouth, excessive sweating, memory problems and difficulties to ejaculate and reach orgasm.
Adverse effects of central types
Confusional disorders, mainly related to the central anticholinergic action, especially in people over 50 years of age or with renal or hepatic insufficiency, are common. The alterations of the conscience can be accompanied by anxiety, agitation, and even with hallucinatory or oniric disorders. A number of factors can favor them: strongly atropine products, interaction with other sedative and/or anticholinergic drugs, as well as substances that slow down the metabolism of antidepressants.
Adverse effects are:
- Watchfulness disorders (daytime sleepiness or insomnia).
- Tremor, especially in antidepressants with anticholinergic activity. It consists of a fine tremor of the extremities, emotionally sensitive and variable intensity. It is more common in older people. Occasionally, fasciculations, paresthesias and incoordination appear.
- A decrease in the convulsive threshold. Above all, in very high doses of antidepressants and in subjects with a history of alcoholism, cerebral organic disease, abuse and withdrawal of benzodiazepines may appear.
- Dyskinesias and extrapyramidal syndromes, with high posology in elderly people.
- Decreased intellectual abilities, in elderly subjects, with sedative-type antidepressants and anticholinergic effects, at high doses.
- Others: dysarthria, nystagmus, hyper or hyporeflexia, hallucinations or visual illusions, and a picture of paradoxical psychomotor agitation, with insomnia, anxiety and slight confusion.
Adverse effects of peripheral types
Depressed patients may have fluctuations in heart rate and blood pressure, as a result of autonomic nervous system dysfunctions involving the sympathetic and parasympathetic systems. These cardiovascular dysfunctions can be further aggravated, depending on the pharmacological profile of the drug used, especially by the antidepressants with alphaadrenolytic and anticholinergic action.
These can be seen:
- Orthostatic hypotension, which may be accompanied by vertiginous sensation and rarely loss of consciousness.
- Hypertensive crisis in treatments with non-reversible MAOIs.
- Cardiovascular symptoms, most of which are reversible in the short term or affect patients with previous heart disease (risk of arrhythmias, blockages, tachycardia, sinus cardiomyopathy or exacerbation of heart failure). The alterations in the electrocardiogram (ECG) are: flattening of the T wave, depression of the ST segment, widening of the QRS, prominent U waves and delay in driving speed).
These can be seen:
- Dry mouth (sour or metallic taste) and sometimes mouth infections can be derived, especially with anticholinergic antidepressants.
- Constipation, with decreased intestinal motility (can reach paralytic ileus), with anticholinergic antidepressants.
- Hepatic toxicity, especially with MAOIs, although they have also been described with imipramine, amitriptyline and amineptine.
- Weight gain.
- Dysuria and urinary retention, with or without frequency, and aggravation of prostatic syndrome in the elderly (recurrent urinary tract infections). It is observed, above all, with anticholinergic antidepressants.
- Sexual dysfunctions: delay or inhibition of ejaculation, decreased libido and delayed orgasm and female anorgasmia.
Due to midriatic and cycloplegic action (blurred vision, difficulty reading) may occur. Patients with glaucoma, especially closed-angle patients, should be monitored.
Other adverse effects
- Allergic hypersensitivity (rash, photosensitization, jaundice)
- Hematopoietic alterations (leukocytosis/leukopenia, eosinophilia, agranulocytosis, aplastic anemia, thrombocytopenic purpura).
- Itching, urticaria, erythema.
- Gynecomastia and galactorrhea.
- Alterations of antidiuretic hormone secretion.
Recently, different groups of antidepressants which aim to combine greater efficacy with better tolerance have been synthesized. In this sense, the profile of side effects is a factor that, in the face of comparable efficacy, is a determining factor. However, there are few studies in which these side effects are compared, and those that do exist suffer from inaccuracies and methodological failures.
An example of recent antidepressives is Mirtazapine. It is a specific noradrenergic and serotonergic agent (NaSSA). It facilitates the release of Nad and 5HT. It does not cause virtually any anticholinergic adverse reaction, adrenolytic or serotonergic, by its pharmacological profile characteristic.
Its profile of side effects and interactions is quite small. They have been described as hypotension, tachycardia, drowsiness, sedation, headache, agitation, restlessness, nausea, dyspepsia and constipation.
In comparative studies with SSRIs, a comparable tolerance profile was shown, except for the changes in body weight that were statistically more pronounced in the mirtazapine group.
A general profile of the secondary effects of depressive medicines
The side effects of antidepressants, appear in 15% of patients, but only 5% require the suspension of medication. It is necessary to distinguish between drug toxicity and depressive symptoms (asthenia, anxiety, sleep disturbances). The use of infraterapeutic doses of the drug exposes the adverse effects without adequately treating the depression. These effects depend on several factors:
- The pharmacological properties and their effects; essentially, alphaadrenolytic and anticholinergic.
- The posology and the rhythm of administration.
- The individual sensitivity of each patient.
- The possible associations and drug interactions.
From the classic tricyclic antidepressants and MAOIs, new molecules have appeared that seek to combine a greater antidepressant efficacy with a better tolerance. Although, in the first aspect, the expectations have not been met; a greater tolerance has been achieved.
Tricyclic antidepressants are the standard both for evaluating the antidepressant efficacy and for tolerance. The anticholinergic effects of tricyclic antidepressants in therapeutic doses can cause cardiovascular alterations (orthostatic hypotension, arrhythmias, electrocardiographic alterations), alterations of intestinal motility (constipation, paralytic ileus), urinary retention, pupillary dilation, dry mouth and tremor.
The central anticholinergic effects can cause memory disorders, sedation and confusion (especially in overdose).
Classic MAOIs are practically out of the market. Moclobemide, like RIMA, is the only one of interest, since it has fewer anticholinergic side effects than tricyclic antidepressants and has no excitatory action on the CNS.
The most frequent adverse effects of SSRIs are gastrointestinal (nausea, vomiting, diarrhea), although they can also produce a CNS excitement picture (insomnia, anxiety, intraquility, tremor, dizziness, headaches); the main vegetative effects are dry mouth and sweating. Among the different antidepressants in the group, the profile of side effects seems more unfavorable for fluvoxamine and more favorable for citalopram.
Mirtazapine may cause sedation, weight gain, and, exceptionally, blood dyscrasias have been described. However, in general, there are no serotonergic side effects, and anticholinergics are lower than those of tricyclic antidepressants.
Nefazodone can cause adverse effects, such as drowsiness, dizziness, dry mouth, nausea, constipation, headache, hypotension and amblyopia but at a lower intensity than SSRIs and tricyclic antidepressants.
Venlafaxine can cause nervousness, insomnia, sweating, nausea, dry mouth, sexual dysfunction and hypertension. However, its side effects are lower than tricyclic antidepressants and similar to SSRIs, with a slightly higher percentage of gastrointestinal effects.