Pathogenesis and clinical picture of depression
Depression (from Latin depressio — suppression) is a severe mental disorder that has a significant negative impact on social adaptation and reduces the patient's quality of life. The leading clinical symptom is hypothymia, i.e., a persistent depressed mood.
The patient's psychological status is characterized by a pessimistic evaluation of their own personality and surrounding reality, a sharp decrease in drive, and a high likelihood of suicide attempts. At the psychomotor and physiological levels, marked inhibition of motor activity and intellectual performance, as well as various somatovegetative disorders, are observed.
Modern concepts of etiology rely on several factors. The possibility of hereditary transmission of the pathology (genetic factor) has been proven, and negative social and emotional influences play a significant role in the development of reactive depressions. However, the biochemical (monoamine) theory is considered fundamental. According to it, the primary cause lies in decreased monoaminergic activity — a deficiency of norepinephrine and serotonin in the central nervous system. In response to this deficiency, a compensatory receptor response is triggered: up-regulation occurs (an increase in the number and a change in the sensitivity of receptors, especially postsynaptic adrenergic receptors). In addition, intracellular disturbances are recorded at the level of the postsynaptic membrane, closely related to G-protein function.
Classification by clinical effect
The choice of drug largely depends on whether excitation or inhibition predominates in the clinical picture. According to the clinical effect, two main groups are distinguished:
- Thymeretics. These are medicinal products with a stimulating component. Their main purpose is the therapy of depressions proceeding with persistent inhibition.
- Thymoleptics. Drugs with a pronounced sedative (calming) effect. They are indicated for the treatment of depressions accompanied by signs of agitation.
Monoamine reuptake inhibitors
The pharmacological action of antidepressants is directed at specific synaptic targets. Noradrenergic synapses (mediator — norepinephrine) and serotonergic synapses (mediator — serotonin) are involved in the pathogenesis. Normally, the inactivation of these mediators occurs through neuronal reuptake by transport proteins or enzymatic destruction within the nerve ending.
The first major group of drugs is monoamine reuptake inhibitors:
- Non-selective agents. Predominantly inhibit the reuptake of two mediators simultaneously: serotonin and norepinephrine. The main group here is tricyclic antidepressants (TCAs). Prominent representatives: amitriptyline, imipramine, clomipramine, and pipofezine.
- Selective agents. They act selectively on the reuptake of specific neurotransmitters. These include selective serotonin reuptake inhibitors (SSRIs — fluoxetine, paroxetine, fluvoxamine, sertraline), norepinephrine reuptake inhibitors (maprotiline), and serotonin-norepinephrine reuptake inhibitors (venlafaxine).
MAO inhibitors and drug profiles
The second important group is monoamine oxidase inhibitors (MAOIs). They prevent the enzymatic destruction of mediators by the mitochondrial enzyme MAO, thereby increasing their concentration.
- Selective MAO-A inhibitors. A representative is moclobemide. The mechanism consists in the preferential inhibition of MAO type A enzyme, which selectively increases the concentration of serotonin and norepinephrine.
- Non-selective MAO inhibitors. A representative is nialamide. It is characterized by the non-selective blockade of both enzyme types (MAO-A and MAO-B). This fundamentally distinguishes it from selective drugs and causes a broader spectrum of side effects.
Each drug has its own unique pharmacodynamic profile. For example, fluoxetine (an SSRI) has a pronounced psychostimulating effect, but is capable of causing akathisia — agonizing motor restlessness and inability to sit still. Amitriptyline (a TCA) has an M-cholinolytic effect, leading to xerostomia (dry mouth). In addition, it affects the cardiovascular system: it lowers blood pressure (hypotension) and has a dangerous arrhythmogenic potential. Also, tetracyclic antidepressants (NaSSAs), represented by mirtazapine, are distinguished in modern classification.
Briefly: answers to topical questions
Which drugs belong to tricyclic antidepressants (TCAs)?
Tricyclic antidepressants (TCAs) include non-selective monoamine reuptake inhibitors. This group includes the following drugs:
- Amitriptyline — a classic drug with a pronounced sedative and M-cholinolytic effect.
- Imipramine — a drug with a stimulating action component.
- Clomipramine — a non-selective inhibitor.
- Doxepin — a non-selective inhibitor.
- Pipofezine — a non-selective inhibitor.
Which drugs are included in the group of selective serotonin reuptake inhibitors (SSRIs)?
The group of selective serotonin reuptake inhibitors (SSRIs) includes drugs that selectively disrupt neuronal serotonin reuptake. These include:
- Fluoxetine — has a moderate psychostimulating effect.
- Sertraline — used, among others, in patients with chronic heart failure.
- Paroxetine — a highly selective serotonin transporter blocker.
- Fluvoxamine — a selective inhibitor.
- Citalopram — a selective inhibitor.
- Escitalopram — a selective inhibitor.
- Trazodone — a selective inhibitor.
What side effects are characteristic of amitriptyline?
Amitriptyline is characterized by adverse reactions caused by the non-selectivity of its action and its effect on various receptor systems. The main side effects include:
- Atropine-like effects — xerostomia (dry mouth), mydriasis, accommodation disorders, and urinary retention.
- Cardiovascular disorders — orthostatic hypotension, cardiac rhythm disturbances, and arrhythmogenic potential.
- Central effects — drowsiness and dizziness.
- Allergic reactions — non-specific manifestations.
Which drugs belong to monoamine oxidase inhibitors (MAOIs)?
Monoamine oxidase inhibitors (MAOIs) include drugs that block the enzyme destroying monoamines. They are subdivided into the following groups:
- Moclobemide — a selective reversible MAO-A inhibitor.
- Pirlindole (pyrazidol) — a reversible MAO inhibitor.
- Nialamide — a non-selective irreversible MAO-A and MAO-B inhibitor.
- Iprazid — a non-selective irreversible inhibitor.
- Phenelzine — a non-selective irreversible inhibitor.
What side effects does fluoxetine cause?
Fluoxetine causes a number of specific side effects, predominantly associated with its psychotropic profile. These include:
- Psychoneurological disorders — akathisia (motor restlessness and inability to sit still), nervousness, insomnia, and headaches.
- Gastrointestinal disorders — anorexigenic effect manifested by appetite disturbance.
The drug has low toxicity compared to tricyclic antidepressants and has insignificant M-cholinolytic activity.
Which drugs belong to the group of serotonin and norepinephrine reuptake inhibitors (SNRIs)?
The group of serotonin and norepinephrine reuptake inhibitors (SNRIs) includes dual-action drugs. This group includes:
- Venlafaxine — a modern agent that blocks the reuptake of norepinephrine and serotonin.
- Duloxetine is a drug that additionally possesses a weak inhibitory effect on dopamine reuptake.
- Milnacipran is a combined norepinephrine and serotonin reuptake inhibitor.
What are the absolute contraindications to prescribing tricyclic antidepressants?
An absolute contraindication to prescribing tricyclic antidepressants (TCAs) is their co-administration with non-selective monoamine oxidase (MAO) inhibitors.
- Combination with MAOIs is strictly prohibited due to the risk of severe complications.
For a safe transition between these drug classes, the washout period rule must be observed: the interval between taking TCAs and MAO inhibitors must be at least two weeks.
Which drugs belong to tetracyclic antidepressants (NaSSAs)?
The tetracyclic antidepressant group (NaSSA — noradrenergic and specific serotonergic antidepressant) includes the drug mirtazapine. Its mechanism of action includes:
- Blockade of presynaptic α2-adrenergic receptors, which removes the "brake" on neurotransmitter release.
- Blockade of postsynaptic serotonin 5-HT2 and 5-HT3 receptors.
Thymoretics stimulate (in case of depression). Thymoleptics treat through quiescence (sedative effect in agitation).
Class and exam questions
What is hypothymia and what do antidepressants have to do with it?
Hypothymia is a persistent depressed mood, which is the leading clinical symptom of depression. Antidepressants are prescribed precisely to relieve this condition and restore social adaptation.
What is the essence of the biochemical theory of depression?
The primary cause of the disease is a decrease in monoaminergic activity, i.e., a deficiency of norepinephrine and serotonin in the central nervous system. In response to this, the number of receptors and their sensitivity compensatorily increase (up-regulation).
How do selective and non-selective MAO inhibitors differ?
Selective (e.g., moclobemide) inhibit only the MAO-A enzyme. Non-selective (nialamide) block both types — MAO-A and MAO-B, which significantly broadens their spectrum of side effects.
What else to study on this topic
- The role of G-proteins in postsynaptic membrane signaling impairments in depression.
- Presynaptic autoreceptors and heteroreceptors: negative feedback mechanisms in synapses.
- Akathisia as a specific side effect of selective serotonin reuptake inhibitors.
- M-cholinolytic action and arrhythmogenic potential of tricyclic antidepressants.
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