Products
Most antidepressants are commercially available in the form of film-coated tablets. In addition, oral solutions (drops), meltable tablets, dispersible tablets, and injectables are also available, among others. The first representatives were developed in the 1950s. It was discovered that the antituberculosis drugs isoniazid and iproniazid (Marsilid, Roche) had antidepressant properties. Both agents are MAO inhibitors. The effects of the tricyclic antidepressant imipramine (Tofranil, Geigy) were discovered – also in the 1950s – by Roland Kuhn at the psychiatric clinic in Münsterlingen in the canton of Thurgau. The selective serotonin reuptake inhibitors (SSRIs) were developed beginning in the 1970s.
Structure and properties
The majority of the first antidepressants were derived from antihistamines. This is also true of the older SSRIs. Fluoxetine, for example, is a derivative of diphenhydramine. The first MAO inhibitors are derivatives of hydrazine.
Effects
The active ingredients (ATC N06A) have antidepressant and mood-lifting properties. In addition, they may have concomitant effects such as sedative, depressant, sleep-inducing, activating, and antianxiety effects. The effects are usually based on interaction with neurotransmitter systems in the central nervous system. Most antidepressants inhibit the reuptake of neurotransmitters such as serotonin, norepinephrine, or dopamine into presynaptic neurons by inhibiting the neurotransmitter transporters SERT, NET, or DAT (Figure). As a result, their concentration in the synaptic cleft is increased and they interact more with their receptors on the postsynaptic neuron. Various antidepressants additionally also exhibit affinity for these receptors, particularly serotonin receptors. However, the so-called “monoamine hypothesis” is also critically questioned and further conjectures exist regarding the mechanism of action. Antidepressants are classified according to their selectivity (see below). On the one hand, they are selective with respect to the neurotransmitters they affect. On the other hand, with respect to other drug targets with which they interact. The tri- and tetracyclic antidepressants also have an affinity for other receptors such as the muscarinic acetylcholine receptor, histamine receptors and alpha-adrenoceptors. The maximum effects of classical antidepressants usually occur after two to four weeks of regular use. In recent years, substances have also been discovered that are effective within hours. These include, for example, the NMDA receptor antagonist ketamine, see under esketamine nasal spray. Rapid-acting antidepressants are in clinical development, such as the new group of glyxins with representatives such as rapastinel.
Indications
On the one hand, antidepressants are administered for the treatment of depression. On the other hand, numerous other indications exist. These include (selection):
- Panic disorders
- Obsessive-compulsive disorder
- Social phobia
- Bulimia (Bulimia nervosa)
- Generalized anxiety disorders
- Post-traumatic stress disorder
- Chronic pain, neuropathic pain
- Sleep disorders
- Migraine prophylaxis
- Attention-deficit/hyperactivity disorder (ADHD)
Many countries do not have approval for all of these indications.
Dosage
According to the professional information. Several drugs are available today that need to be taken only once daily because of their long half-life. Because of the delayed onset of action of most antidepressants, continuous therapy is required. Discontinuation should be gradual to avoid possible withdrawal symptoms.
Abuse
Antidepressants have no direct effect on mood and therefore do not euphoric. However, reports of abuse do exist in the literature, but these appear to be rare. Antidepressants are not addictive, unlike other psychotropic drugs such as benzodiazepines.
Active Substances
The major drug groups include: Tricyclic antidepressants (TCAs):
- E.g., trimipramine, amitriptyline.
Tetracyclic antidepressants (TeCA):
- E.g., maprotiline, mirtazapine
Selective serotonin reuptake inhibitors (SSRIs):
- E.g., citalopram, escitalopram, fluoxetine
Serotonin antagonists and reuptake inhibitors (SARI):
- E.g., trazodone
Selective norepinephrine reuptake inhibitors (SNRIs):
- E.g., reboxetine
Selective serotonin and norepinephrine reuptake inhibitors (SSNRIs):
- E.g. duloxetine, venlafaxine
Selective norepinephrine and dopamine reuptake inhibitors (SNDRIs):
- E.g., bupropion
Monoamine oxidase inhibitors (MAOIs):
- E.g., moclobemide
Trace elements:
- Lithium
Anesthetics:
- Esketamine nasal spray
Serotonin Precursor:
- Oxitriptan (5-hydroxytryptophan).
Melatonin receptor agonists:
- Agomelatine
Phytopharmaceuticals:
- St. John’s wort
- Saffron
Contraindications
Full precautions can be found in the drug label.
Interactions
Antidepressants generally have a high potential for drug-drug interactions. Many agents interact with CYP450 isoenzymes and prolong the QT interval. MAO inhibitors prevent the breakdown of other agents, increasing their plasma concentrations. When combined with other serotonergic drugs, serotonin syndrome may occur.
Adverse effects
Adverse effects depend on the agents used. Typical side effects of antidepressants include dry mouth, constipation, weight gain or loss, fatigue, tremor, headache, dizziness, sweating, and cardiovascular disorders. Furthermore, sexual function may also be disrupted. Antidepressants can prolong the QT interval, cause serotonin syndrome, and promote suicidal ideation, especially in adolescents and young adults.