Serotonin reuptake inhibitors
Serotonin reuptake inhibitors ( English Serotonin Reuptake Inhibitors , SRI) are a class of antidepressants . What these substances have in common is that they block serotonin transporters and thereby increase the concentration of serotonin in the tissue fluid of the brain.
They are also selective serotonin reuptake inhibitors ( selective serotonin reuptake inhibitor, SSRI called) as it to other monoamine transporter or only very weakly bind. This selectivity distinguishes the SSRI from the older tricyclic antidepressants .
Prominent SSRIs are fluoxetine , fluvoxamine , paroxetine , sertraline, and citalopram . In Escitalopram is the more active enantiomer of the hitherto as a racemate (enantiomer mixture ) citalopram used. It was brought onto the market after patent protection was discontinued and is said to be more effective than the racemate (see overview ).
|Active ingredient||First registration in Germany||Approved areas of application in Germany (as of November 2010)|
|Fluvoxamine||1984||depressive illness , obsessive-compulsive disorder|
|Fluoxetine||1990||Major depressive episodes, obsessive-compulsive disorder, bulimia|
|Paroxetine||1992||Major depressive episodes, panic disorder with or without agoraphobia , social phobia , generalized anxiety disorder , obsessive-compulsive disorder, post-traumatic stress disorder|
|Citalopram||1996||depressive illnesses, panic disorder with or without agoraphobia|
|Sertraline||1997||Depressive illnesses and relapse prevention, panic disorder with or without agoraphobia, social phobia, post-traumatic stress disorder, obsessive-compulsive disorder|
|Vortioxetine||2013||Major depressive episodes|
Furthermore, the tricyclic antidepressant clomipramine developed in the 1960s is also referred to as a serotonin reuptake inhibitor (SRI), as it predominantly inhibits serotonin reuptake, but this is not the only essential component of action (therefore not selective ). Clomipramine is approved in Germany for the treatment of depressive syndromes, obsessive-compulsive disorder and panic disorders, phobias, for the long-term treatment of pain as part of an overall therapeutic concept, for the treatment of sleep paralysis, cataplexy and hypnagogic hallucinations in narcolepsy and nocturnal enuresis . In general, newer SSRIs are considered more tolerable compared to clomipramine.
With dapoxetine , another SSRI has been on the market since 2009 , which is marketed and approved for the treatment of premature ejaculation alone . Vilazodon, approved in the USA in 2011, also acts as a selective partial agonist on the 5-HT 1A receptor .
- With regard to interactions with other drugs, citalopram, escitalopram and sertraline are considered beneficial over other SSRIs.
- Citalopram, escitalopram and sertraline are sometimes referred to as second or new generation SSRIs in Germany.
- In Germany, citalopram is prescribed by far the most frequently, followed by sertraline and escitalopram, then fluoxetine and paroxetine; Fluvoxamine is significantly less common.
- Of the main substances, only escitalopram was not available generically in Germany until 2014 . A defined daily dose of escitalopram cost about three to four times as much as citalopram in 2011. The manufacturer's statement that the enantiomer has a stronger and faster effect than the racemate could not be proven in studies.
- In contrast to citalopram, escitalopram received broad approval for indications early on after its market launch. In the summer of 2009, sertraline was also expanded to a similar extent in Germany. The latter is often not taken into account in the most recent literature on psychopharmacotherapy.
SSRIs inhibit the reuptake of the neurotransmitter serotonin (5-HT) into the presynapse and thus increase its concentration in the synaptic cleft . Some of the SSRI drugs also bind weakly to postsynaptic receptors (to an extent that is hardly clinically relevant).
Paradoxically, at the beginning of therapy with SSRIs, the desired increase in 5-HT concentration is reduced by another effect. The initially high serotonin level in the synaptic cleft at the same time floods the autoreceptors of the presynapse , which serve as feedback sensors for the cell. The activation of the autoreceptors (by agonists such as serotonin) triggers the signal in the cell to reduce serotonin production. The resulting deficiency in serotonin remains in total because the transporter inhibition is only downstream and cannot eliminate the deficiency. On the continued receptor stimulation of the body reacts with a lowering of the sensitivity ( sensitivity ) of the autoreceptors ( somatodendritic 5-HT 1A and terminal 5-HT 1D ). This process can take a few weeks. The number / density of 5-HT 1 receptors also decreases.
A similar adaptation process that is more important for the antidepressant effect is the desired reduction in the number of serotonin (5-HT) 2A receptors in the central nervous system . The sensitivity of postsynaptic 5-HT 1A and 2 receptors may increase. These phenomena are likely to be important for an antidepressant effect, and they could explain why a sustained antidepressant effect only develops fully after weeks of pharmacotherapy.
SSRI versus TZA
Compared with tricyclic antidepressants or tricyclics, SSRIs have a significantly lower affinity for α-adrenoceptors , histamine receptors and muscarinic receptors . The activity at these receptors is responsible for a large part of the side effects of tricyclics.
Many different (pharmaco) therapeutic approaches to treating depression are possible. The SSRIs use one of these approaches. A main area of application for all SSRIs except dapoxetine is depression of clinically significant severity (depressive episode, major depression) . In recent years, SSRIs have expanded their indications considerably, particularly in the area of anxiety and obsessive-compulsive disorders . In addition to the areas of application mentioned above, there is evidence of the effectiveness of SSRIs in various syndromes, e.g. B. the premenstrual dysphoric syndrome and menopausal symptoms, various eating disorders and the fibromyalgia syndrome .
One advantage of using SSRIs is that most preparations only have to be given once a day, which increases patient compliance . However, the antidepressant effect of SSRIs occurs only with a delay, which requires discipline on the part of the patient at the beginning of treatment and makes appropriate advice necessary. This time delay in effect applies similarly to most other indications and is one of the reasons why SSRIs are not suitable for rapid treatment for direct reasons, e.g. B. for an acute panic attack, but require regular use over a longer period of time.
When used correctly, SSRIs have relatively few side effects and are safe. In contrast to the desired effect, the described side effects mainly only occur in the first few days.
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 the case of more severe depression, however, around 50–75 percent of patients respond to an SSRI, while around 25–33 percent of patients respond to placebo.
The most common adverse effects affect the gastrointestinal tract : loss of appetite, nausea, vomiting and diarrhea . The risk of bleeding in the upper gastrointestinal tract increases by up to 2.5-fold and by the combination with a nonselective non - steroidal drug through selective serotonin reuptake inhibitors (through reduced absorption of the blood platelet aggregation-enhancing serotonin from the blood into the platelets ) Anti-inflammatory drug up to 9.1 times if no stomach protection agent is used. When selective serotonin reuptake inhibitors are combined with antiplatelet drugs such as clopidogrel or low-dose acetylsalicylic acid , the risk of bleeding in the upper gastrointestinal tract increases up to 4.7 times. Other common side effects that often lead to discontinuation of therapy (lack of compliance ) are sexual dysfunction (decline in erectile function , ejaculation disorders , orgasm difficulties , temporary decrease in sperm quality , see SSRI-related sexual dysfunction ). However, with long-term therapy, sexual functions can return to normal. The possible occurrence of a certain emotional numbness (such as the reduced ability to feel feelings such as anger or sadness, to cry or a decline in sexual interest) as an undesirable effect has possibly been underestimated so far. Like classic anti-epileptic drugs , SSRIs can trigger or intensify the syndrome of inadequate ADH secretion. This can lead to a dangerous sodium deficiency .
Most SSRIs cause an increase in drive . This can lead to nervousness, excitement and sleep disorders , especially at the beginning of therapy . Unlike the older tricyclic antidepressants , SSRIs have no anticholinergic side effects. SSRI withdrawal syndrome and SSRI-related sexual dysfunction can occur when SSRI therapy is stopped . During therapy with SSRIs, changes in the QT time in the ECG must be observed.
In children and adolescents
The incidence of suicidal behavior is increased in children and adolescents receiving SSRI or SSNRI treatment, especially at the start of treatment, as confirmed by meta-analyzes . In 2005, the Federal Institute for Drugs and Medical Devices warned that the following should be observed in children and adolescents treated with antidepressants:
- In clinical trials, increased levels of suicidal (attempted and suicidal thoughts) and hostile behavior (predominantly aggressiveness, oppositional behavior and anger) were observed in children and adolescents treated with SSRI / SNRI treatment compared to placebo treatment.
- SSRIs and SNRIs should therefore not be used in children and adolescents unless they are explicitly approved for use in this age group.
- Most SSRI / SNRI are not approved in Europe for the treatment of depression and anxiety disorders in children or adolescents.
- Should it be necessary due to clinical circumstances to treat children and adolescents with these disorders with medication, the patient should be closely monitored with regard to the occurrence of suicidal behavior as well as self-harming or hostile behavior. This is very important, especially at the beginning of treatment.
As early as 2004, the use of paroxetine as an antidepressant in under 18-year-olds was classified as contraindicated. Taking into account the risk of suicide in the event of non-treatment and the available data on its effectiveness, fluoxetine is considered the drug of choice if drug therapy is nevertheless being considered. In 2013, a retrospective study of over 36,000 children and adolescents receiving SSRI or SNRI treatment in the USA showed that sertraline, paroxetine, citalopram, escitalopram and venlafaxine have a suicide risk in this age group comparable to that of fluoxetine.
An association with the risk of suicide in adults receiving SSRI treatment is unclear. A review from 2005 came to the conclusion that the risk of suicide increases , especially at the beginning of treatment . A placebo-controlled US meta-analysis from 2012 with 9185 patients, on the other hand, could not find any connection between the administration of SSRIs, here fluoxetine and venlafaxine (which is an SSNRI), and an increased risk of suicide. The study comes to the conclusion that the assumptions of the American health authority FDA, which led to the warning labels, are incorrect.
At the same time, the instruction leaflets for SSRI drugs indicate the initially increased risk of suicide, which is also based on their typical effect curve. On February 21, 2014, ARD broadcast a documentary entitled “Dangerous Lucky Pills” on the subject for the first time. The discussion is whether there is a connection between the income from SSRIs and aggressive acts, such as shooting sprees. A website collects cases of suicide and violence in which SSRIs played a role. Some researchers recommend further studies to investigate a possible causal link.
Long-term use of SSRI antidepressants increases the risk of developing tooth decay . The dry mouth caused by SSRIs and a number of other antidepressants and the associated adverse effects on the oral flora are believed to be the main causes. Dry mouth is a typical anticholinergic symptom, which occurs more frequently and more strongly with the more strongly anticholinergic tricyclic antidepressants than with SSRIs.
If you overdose on SSRIs, there is a risk of developing serotonin syndrome , especially when combined with other MAOI- type antidepressants . SSRIs are usually only fatal after a 50–100 times overdose. An overdose often leads to psychosis-like conditions.
SSRIs in the elderly
It has long been discussed that therapy with SSRIs can lead to an increased apathy syndrome in older patients. Current study results seem to confirm this. The risk of bleeding also seems to be increased, especially in older people undergoing SSRI therapy (see under interactions)
In a study of 248 nursing home residents with dementia, SSRIs increased the risk of a serious fall by up to two-fold. A dose dependency could be shown. An even higher risk resulted from comedication with sedatives. Substances with a lower risk of interaction such as citalopram, escitalopram and sertraline are preferred.
SSRI and pregnancy
The use of SSRIs is associated with greater risks for the child than the mother's depression alone. Low birth weight and breathing problems were significantly more common. Even considering the severity of maternal depression, that doesn't change that result.
A withdrawal syndrome (see above) can occur in up to every third child after maternal SSRI intake during late pregnancy . The SSRIs fluoxetine , paroxetine , sertraline and citalopram / escitalopram as well as the SNRI venlafaxine were named as triggers . Symptoms are rigidity or increased muscle tone, increased crying, various gastrointestinal problems and others.
Pulmonary hypertension (high blood pressure in the pulmonary circulation) is a rarer, but far more dangerous, damage caused by maternal use of SSRIs . The connection was revealed by a case-control study , which was intended to test the suspicion from a cohort study with fluoxetine. The pathophysiology is probably based on an increase in the serotonin level in the child's organism - a striking parallel to other known trigger mechanisms of pulmonary hypertension.
The risk is dose-dependent (dose reduction reduces the risk) and exists above all from the 20th week of pregnancy. Newborns with this form of permanent pulmonary hypertension have a reduced life expectancy. In almost ten percent of the cases, the damage is fatal. The risk is estimated at around one percent, i.e. H. one in 100 newborns is born damaged after their mother has taken SSRIs.
At the end of 2005, the American health authority FDA warned of increased malformation rates after taking paroxetine . According to epidemiological data from October 2006, taking all SSRIs is associated with increased rates of malformations.
A publication in the American Journal of Obstetrics and Gynecology in April 2006 warned of an increased risk of premature and stillbirth, low birth weight, and seizures in newborns after the mother had taken SSRIs. The increased risk for newborns was again confirmed for all SSRIs in a study published in August 2006.
All SSRIs are strong inhibitors of the cytochrome P450 isoenzymes (especially paroxetine and fluoxetine) and thus inhibit e.g. B. the activation of codeine and the breakdown of benzodiazepines . The combination with the cough suppressant dextromethorphan, which is often contained in over-the-counter flu medicines, can lead to psychotic behavior.
The interactions between SSRIs can also be used for the benefit of therapy. So z. For example, the lack of effect of citalopram in citalopram non-responders can sometimes be remedied by simultaneous administration of a low dose of paroxetine or fluoxetine. Since both paroxetine and fluoxetine inhibit an enzyme that breaks down citalopram, simultaneous administration can increase the plasma concentration and thus the potency of citalopram.
|Substances that, in combination with an SSRI , can cause serotonin syndrome|
|Real St. John's wort||Venlafaxine|
|Amphetamine (speed)||MDMA (ecstasy)|
|5-HT 1 agonists|
|Adapted from Rossi, 2005. See also Gillman 2010.|
The combination of SSRIs with substances that influence the synthesis or breakdown of serotonin is dangerous, since the potentially life-threatening serotonin syndrome can be triggered by increasing the serotonin concentration in the CNS . The risk is particularly high when taking SSRIs and MAO inhibitors at the same time . Therefore, there must be a minimum interval between the two medications, the length of which differs depending on the active ingredient (usually two weeks). Taking these drugs at the same time can also lead to very unpleasant symptoms of paralysis, in which the person affected is fully conscious but cannot communicate with one another verbally or through body movements ( locked-in syndrome ).
Simultaneous use of SSRIs and triptans can also lead to serotonin syndrome , according to a warning from the FDA . The FDA points out that this possible interaction may not be considered immediately, as SSRIs and triptans are often prescribed by different doctors or the migraine drugs are only taken irregularly.
Additional intake of L - tryptophan or 5-hydroxytryptophan (5-HTP) can also lead to serotonin syndrome by increasing serotonin synthesis. The table provides an overview of substances that, in combination with an SSRI, can trigger a serotonin syndrome.
Affecting blood clotting
The use of SSRIs can impair platelet function and thus blood clotting. The release of serotonin from the platelets plays an important role in regulating the hemostatic response to the vascular injury. Serotonin is not formed in the platelets, but absorbed from the bloodstream by serotonin transporters into the platelets. At therapeutic doses, fluoxetine and other SSRIs block the uptake of serotonin by platelets. This leads to a depletion of serotonin after a few weeks. This increases the risk of bleeding. Clinical symptoms are e.g. B. the spontaneous appearance of bruises (bruises), nosebleeds or increased menstrual bleeding in women. Even if this bleeding is classified as "harmless" from a medical point of view, it can be a cause for concern for those affected, especially if they do not know the cause. The combination of an SSRI with drugs that directly or indirectly increase the risk of bleeding increases the probability of gastrointestinal bleeding by 43% ( odds ratio : 1.43; 95% confidence interval : 1.09–1.89). Simultaneous therapy with proton pump inhibitors significantly reduced the risk.
In the case of high-risk patients, the careless combination of an SSRI with z. B. Aspirin (acetylsalicylic acid) or other non-steroidal anti-inflammatory drugs such as indomethacin, phenylbutazone , naproxen, ibuprofen or fenoprofen warned. Patients over 65 years of age who have had a history of gastric ulcer or gastrointestinal bleeding are particularly at risk. It should be borne in mind here that, especially for older people, doctors from different specialties often prescribe medication from their respective point of view without having an overview of the medication that has already been prescribed, so that they do not always properly assess the risk of possible interactions.
SSRI and pharmacogenetics
There is an ever-growing wealth of scientific publications on the influence of certain gene variants or markers on the effectiveness or tolerability of SSRIs. These results have so far not led to an improvement in therapy, as they either could not be confirmed in further studies, genetic tests have proven to be impractical or have not yet been developed sufficiently:
The gene most frequently examined in connection with the SSRI effect is that of the serotonin transporter ( SERTPR or 5-HTTLPR ), which has a direct influence on the (re) absorption of serotonin. The study situation is inconsistent and a practical applicability of these findings is currently unlikely.
Another gene specifically linked to the ineffectiveness of SSRIs in some patients is that of tryptophan hydroxylase ( TPH-1 and TPH-2 ). According to a study, this gene is said to be ten times more likely to mutate in depressed patients than in healthy controls. Patients with this mutation may respond worse to SSRIs. This gene is still being investigated intensively, including in patients with bipolar disorder , but so far without clinical consequences.
The metabolism of SSRIs via the CYP-450 isoenzymes has been a genetic research approach that has previously proven impractical. Genetic tests to identify “poor metabolizers” have not improved the tolerability of SSRIs, and “rapid metabolizers” do not benefit from a dose increase.
- Selective norepinephrine reuptake inhibitor (NARI)
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