An antidepressant or thymoleptic is a drug from the class of psychotropic drugs that is primarily used in the treatment of depression . Antidepressants can also be used for a variety of other mental disorders . Other areas of application are e.g. B.
- Obsessive-compulsive disorder and panic attacks ,
- some anxiety disorders or phobias , the post-traumatic stress disorder ,
- Eating disorders , chronic pain, and withdrawal syndromes ,
- Sleep disorders and premenstrual dysphoric syndrome .
With over 1.4 billion DDD ( defined daily dose ), antidepressants were by far the most frequently prescribed group of psychotropic drugs in Germany in 2016. The first classic antidepressants were introduced in the 1950s.
The effectiveness of antidepressants depends heavily on the severity of the disease. While the effectiveness is lacking or low in mild and moderate severity, it is clear in severe depression. In the most severe forms, up to 30% of treated patients benefit from antidepressants over and above the placeborate. Meta-analyzes indicate that antidepressant drugs vary widely in effectiveness from patient to patient and, in some cases, a combination of different drugs can have advantages. The current S3 guideline indicates that in the perception of the (professional) public, the effectiveness of antidepressants is more likely to be overestimated, since studies in which the antidepressant performed better than placebo are published much more frequently in specialist journals than those in which the antidepressant was not superior to placebo.
The various antidepressants differ in terms of their profile of action. They can in addition to a mood-enhancing effect even drive-increasing (thymeretische), drive-neutral or drive-absorbing and soothing ( sedative ) and anti-anxiety ( anxiolytic unfold) effects. The most common side effects of antidepressants affect the cardiovascular system , nervous system and sexuality . Here, too, there can be considerable differences between individual antidepressants.
With a large number of antidepressant types, the full effect only develops after a few days to weeks of continuous use. The reason for this is probably the neurophysiological adaptation of the brain tissue, which takes a certain amount of time. These include changes in the sensitivity and frequency of receptors and similar structures. The permanent improvement probably occurs indirectly due to cellular adaptation processes under constant active ingredient levels.
In practice, antidepressants are regarded as equivalent to psychotherapy for moderate to severe depressive periods; this is based on various psychometric studies and is reflected in a national guideline . For severe depression, a combination of psychotherapy and antidepressant medication is recommended. They can only enable psychotherapy in the case of severe depression , as in these cases the responsiveness required for successful therapy is often not given. On the other hand, psychotherapy apparently also makes pharmacotherapy more possible because patients treated with psychotherapy take their medication more regularly.
Basic research on mice has recently found indications that antidepressants develop their effectiveness not only through their influence on the interconnection of nerves (via neurotransmitters), but possibly also in part by increasing the growth factor BDNF in the brain.
Classification of antidepressants
Tricyclic antidepressants , or tricyclics for short , derive their name ( tricyclic - from Greek : three rings ) from the triple ring structure of these active ingredients . Structural and thus also neurophysiological differences can be seen in the substitution and in the side chains of these aromatics . The first tricyclic antidepressant imipramine was developed by Ciba-Geigy in 1956 . Clomipramine and amitriptyline , for example, followed as further substances . They intervene in several neurotransmitter systems at the same time by inhibiting the uptake of serotonin , noradrenaline and dopamine and acting on acetylcholine , histamine and adrenoceptors . Therefore, with tricyclic antidepressants, the side effects are also diverse.
Traditionally, tricyclics are divided into three basic types according to the (simplified) Kielholz scheme :
- Substances of the amitriptyline type tend to have a calming (dampening) effect and are particularly suitable for the treatment of agitated-anxious depression;
- Substances of the imipramine type are drive-neutral and primarily have a mood-enhancing effect; they can be used to treat both the agitated-anxious and the inhibited-depressive depression type;
- Substances of the desipramine type have a more awakening or drive-increasing effect, they are particularly suitable for the treatment of inhibited-depressive depression.
This classification comes from a time when the knowledge about neuro-receptors, neurotransmitters and their mechanisms of action was still relatively low and antidepressants were classified according to target symptoms. Today, the tricyclic antidepressants are also divided into the following four groups based on their effect on the monoamine neurotransmitter systems, whereby it should be noted that the system that is mainly influenced is decisive for classification in one of the groups, but the other neurotransmitter systems always to a different extent ( from barely to significantly, depending on the substance):
- Serotonin Reuptake Inhibitors (SRI, also SSRI)
- Norepinephrine reuptake inhibitors (NRI)
- Serotonin norepinephrine reuptake inhibitors (SNRI)
- Tricyclic antidepressants with a different or unsecured mechanism of action (TCA)
Because of this non-selective effect, the tricyclic antidepressants are assigned to the non-selective monoamine reuptake inhibitors ( NSMRI , German non-selective monoamine reuptake inhibitors ).
Some tricyclic antidepressants (for example, clomipramine) are effective for anxiety and panic disorders , and are also used in the treatment of obsessive-compulsive disorder . Some tricyclics, especially amitriptyline and clomipramine, are used in pain management for neuropathic or other chronic pain. The analgesic effect is probably due to noradrenergic activation of the descending pain- relieving system in the central nervous system and is not related to the antidepressant effect.
The tricyclic antidepressants are structurally and chemically related to the tricyclic neuroleptics . Depending on the three-dimensional conformation of the tricyclic ring system, the substances have either an antidepressant or a dampening effect: if the rings are almost level with each other, the neuroleptic effect is more likely, if they are strongly angled against each other, the antidepressant effect is more likely.
With the tetracyclic antidepressants (TetraCA) the spatial structure of the other three rings is positively stabilized by the fourth ring in favor of the antidepressant conformation. The tetracyclic antidepressants are very similar to the tricyclic in both their effect and structure; some substances (for example maprotiline ) have a stronger effect on norepinephrine in particular. Despite their close relationship to the tricyclics, they are not simply subsumed under these and in practice are not combined in a separate group of the tetracyclics . Rather, they are classified into the group noradrenergic and specifically serotonergic antidepressant or - as in the case of maprotiline - left as a single substance. Maprotiline can, however, be assigned to the tricyclic norepinephrine reuptake inhibitors in terms of effectiveness.
Because of their side effects (dry mouth, visual disturbances, circulatory disorders, cardiac arrhythmias, delirious conditions and poisoning), tricyclics are rarely the first choice these days. However, they are used in severe and / or chronic cases, for example if the patient does not respond to newer, more vegetatively tolerated substances (especially SSRIs ). Then tricyclics represent an alternative in drug therapy . Older people and men seem to respond particularly well to TCAs.
Serotonin Reuptake Inhibitors (SRI)
Tricyclic SRIs act primarily as serotonin reuptake inhibitors. Active ingredients are: clomipramine .
Norepinephrine reuptake inhibitors (NRI)
Serotonin norepinephrine reuptake inhibitors (SNRI)
TCA with an uncertain mechanism of action
Trimipramine is a tricyclic active ingredient in which the main monoaminergic active component has not yet been clarified with certainty.
Genotoxic potential of TCA
Some tricyclic antidepressants caused genetic damage in the fruit fly and, according to new studies, may increase the risk of breast cancer. These include: clomipramine , desipramine , doxepin , imipramine , trimipramine and other tricyclic antidepressants that are not approved in Germany.
No mutagenic or carcinogenic potential could be demonstrated with other tricyclic antidepressants. These include amitriptyline and other active ingredients that are not approved in Germany.
Selective reuptake inhibitors
Selective Serotonin Reuptake Inhibitors (SSRI)
The SSRI specifically block the receptors that are responsible for the resumption of the messenger substance serotonin . The side effects of tricyclic antidepressants caused by intervention in other transmitter systems play a correspondingly smaller role in SSRI treatment.
Active ingredients of this group are, for example, fluvoxamine , fluoxetine , citalopram , escitalopram , sertraline , paroxetine and vortioxetine , the latter having a so-called "multimodal mechanism of action" and thus simultaneously effective on five different serotonin subunits. Several drugs in this group are also used to treat anxiety disorders , panic attacks , obsessive-compulsive disorder, and bulimia .
SSRIs are the most commonly used antidepressants. The effect of SSRIs on the depressive syndrome depends on the severity of the illness. In mild depression, there is often no statistically demonstrable superiority over the administration of dummy drugs (placebo). In more severe depression, however, around 50–75% of patients respond to an SSRI, while around 25–33% of patients respond to placebo.
Shortly after the introduction of the first active substances in this group, reports of violent behavior and suicides under SSRI medication; a possible suicidality-increasing effect of these substances has so far neither been confirmed nor refuted. Withdrawal syndrome may develop when stopping SSRIs after prolonged use. However , there is no known dependence on SSRIs according to the DSM-IV definition.
Selective norepinephrine reuptake inhibitors (SNARI, SNRI)
The NARI inhibit the transporter that naturally returns noradrenaline to its storage locations after the signal has been transmitted. Norepinephrine remains at the site of action longer and its effectiveness as a signal transmitter increases. Active ingredients in this group are, for example, reboxetine and viloxazine . Areas of application are acute depressive illnesses, including depression associated with drive disorders. Viloxazin was withdrawn from the market in July 2006. Reboxetine, on the other hand, is still on the market in Germany. However, since April 1, 2011, the statutory health insurances no longer have to bear the costs for drugs with the active ingredient reboxetine. The patient has to pay the costs himself, unless the patient's health insurance makes an exception.
Dopamine reuptake inhibitors (DRI, DARI)
According to BtMG (D), amineptine has not been a prescription since 2005 . It was the only prescription drug used as an antidepressant that could induce addiction . More DRI are nomifensine and medifoxamine , which now are no longer in use but because of severe side effects.
Selective serotonin / norepinephrine reuptake inhibitors (SSNRIs)
Selective norepinephrine / dopamine reuptake inhibitors (SNDRI)
The NDRI inhibit the reuptake of norepinephrine and dopamine. Areas of application are depression, especially with lack of drive, and attention deficit / hyperactivity disorder (ADHD).
Monoamine Oxidase Inhibitors (MAOIs / MAOI / RIMA)
MAOIs work by blocking the monoamine oxidase enzymes . These enzymes normally break down monoamines such as serotonin, norepinephrine and dopamine, thereby reducing their availability for signal transmission in the brain.
MAOIs are divided into selective or non-selective and reversible or irreversible. Selective inhibitors of MAO-A (e.g. moclobemide , reversible) only inhibit type A of monoamine oxidase. They show an antidepressant effect and are usually well tolerated. Selectively MAO-B-inhibiting agents (e.g. selegiline , rasagiline , both irreversible) are primarily used in Parkinson's treatment. Nonselective MAOIs (e.g. tranylcypromine , irreversible) inhibit MAO-A and MAO-B and are effective in depression and anxiety disorders. Irreversible MAO inhibitors bind the MAO-A or MAO-B permanently. In order to reverse this effect, the affected enzyme must first be regenerated by the body, which can take weeks. Reversibility means that the drug binds only weakly to the MAO, and MAO-A or MAO-B is released again intact at the latest when the drug breaks down.
Patients taking non-selective, irreversible MAOIs must be on a strict, low-tyramine diet. Because in connection with the consumption of certain foods (e.g. cheese and nuts ) the intake of non-selective irreversible MAOIs can lead to a dangerous increase in blood pressure . In addition, there must be a waiting period between taking an irreversible MAO-A inhibitor and another antidepressant in order to avoid serious interactions (for example serotonin syndrome ). For this reason, reversible MAO-A inhibitors ( Reversible Inhibitor of Monoamine Oxidase A , RIMA ), such as moclobemide, are used as antidepressants today . This is considered to be effective and free from these side effects. Non-selective MAOIs also have a stronger noradrenergic effect than selective MAO-A inhibitors, which could explain that they are considered more effective compared to RIMA and SSRI . Moclobemide and tranylcypromine are prescribed roughly the same number of times.
Other types of antidepressants
Noradrenergic and specifically serotonergic antidepressant ( NaSSA )
This tetracyclic in English noradrenergic and Specific Serotonergic Antidepressants ( NaSSA ) hot forming agents are antagonists at the presynaptic auto-receptors of the alpha-2 Adrenozeptortyps and thus cause an increased release of noradrenaline. They are also antagonists of specific serotonin receptors, mostly 5-HT 2A and 5-HT 2C . Usually they act as H1 antihistamines as sedating. They are used for depression (especially for inhibitions, weight loss, sleep disorders and fears), and sometimes NaSSA is also used as a sleep aid. Active ingredients: for example mirtazapine and mianserine .
Serotonin Antagonist and Reuptake Inhibitors ( SARI )
These active ingredients, called Serotonin Antagonist and Reuptake Inhibitor (SARI), are antagonists at serotonin receptors, mostly ( 5-HT 2A ). In addition, they are mostly antagonists of the alpha-1 adrenoceptor type . One active ingredient from this group is trazodone . It is used for the treatment of depression of various etiologies with or without anxiety components, persistent sleep disorders in depression, and for the treatment of erectile dysfunctions occurring in the context of depression without serious organic causes.
Serotonin (5-HT2) antagonist and melatonin (MT1 and MT2) agonist
Agomelatine has an agonistic effect on the melatonergic MT 1 and MT 2 receptors and antagonistic on the serotonergic 5HT 2C receptors . The chemical compound from the group of antidepressants, which is structurally related to melatonin , is used in the treatment of major depressive episodes in adults.
In depressive emergencies ( suicide risk ), several studies have confirmed a rapid antidepressant effect of ketamine , an antagonist of the glutamate - NMDA receptor complex . In a study from 2014 with 21 patients with bipolar disorder , effects of ketamine in brain regions that are of particular importance in depression were registered by means of imaging procedures . Among other things, the improvement in symptoms with ketamine was correlated with changes in the right ventral striatum . Further study results showed a significant improvement over a period of up to seven days after a single dose. There is no EU drug approval for ketamine for the treatment of depression. Despite possible side effects, there are recommendations for off-label prescriptions. On 12 February 2019, a independent committee of experts recommended that the US Food and Drug Administration approval of the enantiomeric pure eutomer ( S ) -ketamine ( generic name : Esketamin) as a nasal spray for the treatment of treatment-resistant depression, in March 2019 was followed by the approval under strict conditions as Spravato .
A phytopharmaceutical [Greek φυτόν phyton (plant) and φάρμακον pharmakon (medicine)] is a finished medicinal product used in phytotherapy , the active components of which are exclusively of herbal origin. A phytopharmaceutical consists of one or more herbal active ingredients , whereby the herbal active ingredients are mostly themselves multicomponent mixtures of different plant ingredients.
Among the antidepressants, this includes, in particular, St. John's wort ( Hypericum perforatum ). St. John's wort is available in various dosage forms (for example as tea, tablets, etc.) and some are freely available. Higher-dose preparations that could be helpful against depression are only available in pharmacies.
Standardized St. John's wort extracts are used for mild to moderate depression. The Institute for Quality and Efficiency in Health Care assumes that St. John's Wort has an effect on mild depression. In general, however, there was a clear dependence of the effect size on the study quality: the poorer the quality of the studies, the greater the extent of the effects shown and vice versa. If only those studies with the best methodological quality are considered, St. John's wort shows only a very small effect. The institute also assumes that St. John's wort does not help with severe depression. It was not found to be superior to placebo in any study in major depression.
In the context of depression treatment, amine precursors refer to the metabolic precursors of the monoamine neurotransmitters serotonin, norepinephrine and dopamine. These include L - tryptophan , 5-hydroxytryptophan for serotonin and L - phenylalanine , L - tyrosine and L - DOPA for both norepinephrine and dopamine.
Phase prophylactic agents (mood stabilizers) with antidepressant effects
Different drugs are used for the prophylaxis of depression than for acute therapy. A distinction is made between a monopolar course and a bipolar course (switching between manic and depressive).
- Lithium (usually with a complex mechanism of action) → lithium therapy
- Valproate : In several studies no significant antidepressant effect of valproate could be found, but a good anti-manic effect.
- Carbamazepine : A clear antidepressant effect is confirmed by several studies; best available data regarding an antidepressant effect among all anticonvulsants.
- Lamotrigine : The available data support an antidepressant effect (in monopolar depression) with this anticonvulsant, although there are not many studies on the antidepressant effect of lamotrigine in monopolar depression. However, there is no doubt about its antidepressant effectiveness in the context of bipolar disorder - in Germany it is approved as a preventive agent against depressive episodes in bipolar disorders.
Omega-3 fatty acid eicosapentaenoic acid (EPA)
Vitamin D 3
Strictly speaking, cholecalciferol (vitamin D 3 ) is not a vitamin, but a prohormone (unlike real vitamins, the body can produce it itself). The hormone calcitriol is formed from cholecalciferol . Calcitriol (also called vitamin D hormone ) has a much broader effect in interaction with vitamin D receptors in the body than only in connection with the known bone formation, etc. a. also in areas that have a direct impact on the mood. According to a study by the University of Amsterdam, the vitamin D content in the blood of patients with depression is on average 14% lower than in the control group . The effect of treatment with vitamin D 3 is, however, small.
Various undesirable effects can occur during treatment . Due to the large differences between antidepressants, these depend on the substance in question.
When stopping some antidepressants, both rebound and withdrawal phenomena may occur. The withdrawal symptoms when weaning are very often underestimated, as it turned out in various reviews between 2011 and 2018. If the use of antidepressants is necessary after a detailed analysis of the causes, they should therefore only be used temporarily and ideally in combination with psychotherapy. In the opinion of some affected groups, the dose reduction necessary in very small steps can take several years to discontinue.
With regard to the use of SSRIs and SSNRIs in children and adolescents with depressive disorders, there are indications from studies for an increased suicidality under this therapy . In particular, the risk of suicidal thoughts and hostile actions directed against oneself or others seems to be increased, while no committed suicides were reported. An increased suicidal tendency under SSRIs could not be demonstrated in adults. The findings are controversial in psychiatry. Depressive illness itself is the most important risk factor for suicidality. The ATT (average treatment effect on the treated) is often used in meta-research to remove this main risk factor with regard to causality .
According to several studies, taking it during pregnancy can increase the risk of a disorder from the spectrum of autism in children. This applies to the often prescribed SSRIs as well as to older tricyclic antidepressants. In addition, according to a new study with antidepressants, postpartum bleeding is more common in late pregnancy.
With some antidepressants (such as doxepin, amitriptyline and maprotiline), QT syndrome prolongation of the QTc time can lead to cardiac arrhythmias.
In 2002, around 4 billion euros were spent in Germany on treating depressive disorders (direct medical costs). The share of costs for drugs in the total direct costs is internationally comparable and amounts to around 4–11%.
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