Indirectly acting serotoninomimetics The indirectly acting serotoninomimetics act through endogenous serotonin by increasing its synthesis, or by inhibiting its reuptake or its inactivation.
Increased 5-HT biosynthesis
L-tryptophan and L-5-hydroxytryptophan, precursors of serotonin, are used as regulators of sleep and antidepressants. They reduce moreover appetite for carbohydrates. A diet poor or deprived of tryptophan accelerates and worsens the depressive relapses and increases aggressiveness; a diet rich in or supplemented with tryptophan would have the opposite effect. Tryptophan is found in various foods: eggs, meats, cereals, milk where it is present especially in alpha-lactalbumine.
L-tryptophan was used during several years especially as regulator of sleep without inducing notable adverse effects. The appearance of the eosinophilia-myalgia syndrome ascribed to L-tryptophan intake was completely unexpected. Two explanations for this syndrome have been proposed: presence in the pharmaceutical preparation of a toxic contaminant, derived from tryptophan, and an abnormal metabolisation of tryptophan by tryptophan pyrrolase, leading to kynurenine, picolinic acid and quinolinic acid.
But “ the epidemic” of cases of eosinophilia-myalgia syndrome which occurred in the nineties never received clear explanation and its reality has been questioned. The doubt remaining, the use of L-tryptophan and also of 5-OH-tryptophan in the therapeutic indications previously quoted is not advised.
L-5-hydroxytryptophan, called oxitriptan, has been proposed for the treatment of certain types of postanoxic myoclonus.
5-HT reuptake inhibition: SSRI, antidepressants
The compounds which specifically inhibit serotonin reuptake by neurons are named SSRI, Selective Serotonin Reuptake I nhibitors . The SSRI have antidepressant properties in patients, but their mechanism of action is not completely elucidated because their antidepressant effect appears only in two or three weeks, whereas their inhibiting effect on the reuptake is immediate. This delay in onset of antidepressant effect suggests the intervention of complex mechanisms. Some of SSRI have also appetite suppressant properties.
When serotonin reuptake is inhibited, its concentration in the synaptic cleft increases. This increase induces postsynaptic and presynaptic effects, in particular a stimulation of the receptors 5-HT1A, which reduces 5-HT release and, to some extent, offsets the inhibition of its reuptake. The combination SSRI and an antagonist of 5-HT1A presynaptic receptors increases the serotonin release. Pindolol, beta-blocking and non specific antagonist of 5-HT1A receptors, accelerates and improves the effect of SSRI.
The main SSRI are fluoxetin, fluvoxamine, paroxetine, citalopram, escitalopram and sertraline. They do not have atropinic (antimuscarinic) effects.
In addition to their use in the treatment of depressive disorders in which their efficacy is equal or higher than that of other antidepressants, SSRI are used in the treatment of compulsive obsessive disorders, of panic attacks and social phobia. They gave, in particular sertraline, appreciable results in the treatment of post-traumatic stress syndrome (rape, accident, catastrophe…).
Fluoxetine is the leading antidepressant among SSRI and has been the most used. It is a racemic molecule, constituted of two enantiomers R and S, both active, but the S enantiomer is the more active. Fluoxetine metabolite, norfluoxetine, is also active. The plasma half-life of fluoxetine is a few days; that of its metabolite almost ten days, with noticeable differences from one patient to another. These long half-lives explain why its steady state concentration in plasma is reached in certain patients only after several weeks and that its decrease in tissues after its discontinuation is slow. The pharmacokinetic features of fluoxetine explain why it was proposed to give it only once per week.
Fluoxetine is metabolized by P-450cytochrome, CyP-2D6 and CyP-3A4, which also metabolize neuroleptic agents and tricyclic antidepressants. This fact explains why their simultaneous administration to the same patient can induce a reciprocal inhibition of their metabolism.
Fluoxetine has an appetite suppressant effect and can induce a loss of weight. It can also induce nausea, nervousness and insomnia.
The intake of fluoxetine during the first trimester of pregnancy does not seem to increase the risk of malformation in the child but taken during the last trimester, it could increase the risk of perinatal complications.
The efficacy and the tolerance of the other SSRI, fluvoxamine, paroxetine, citalopram, sertraline, seem rather close to those of fluoxetine.
Inhibitors of both noradrenaline and serotonin reuptake are studied elsewhere
The extract of Hypericum perforatum, St. John's wort, has an antidepressant activity. An extract of St. John's wort was shown as effective as fluoxetine in the treatment of moderate depressions. It was thought that the active molecule of St. John's wort was hypericine but it would seem that it is hyperforine, which inhibits the serotonin reuptake. The extract of St. John's wort is an enzymatic inducer of cytochrome CYP3A4 and can lower the concentration of other drugs metabolized by the same cytochrome.
Prescription of an antidepressant to a patient with a recognized depressive disorder is usual but the choice of a particular agent, for example an inhibitor of noradrenaline or serotonin reuptake, is mainly dependant on the psychiatrist habits because there are no validated clinical or biological markers of response to a given compound. Frequency and severity of possible adverse effects or interactions with other drugs of each compound is often the main factor of choice. The current tendency is now to initiate treatment with one of the SSRI and to give it at an appropriate dose for a sufficient time.
If the chosen antidepressant remains ineffective, it can be replaced by another, having for example a different mechanism of action. It is also possible to add another drug: lithium combination can, in resistant cases, improve the therapeutic response.
Note : Appetite suppressant effect
Fenfluramine, a racemic molecule, and dexfenfluramine, its D enantiomer, have on the central nervous system, various and complex serotonergic effects: inhibition of serotonin reuptake, increase of its release and perhaps direct effect on the 5-HT2C receptors. Fenfluramine and especially dexfenfluramine have a recognized appetite suppressant effect, in particular with respect to carbohydrate consumption. Fenfluramine is converted into norfenfluramine which is an active metabolite.
The fact that the majority of inhibitors of 5-HT reuptake have an antidepressant effect and that fenfluramine has an appetite suppressant effect has not received a clear explanation. Perhaps these differences arise from different affinities for serotonergic neurons. But an antidepressant like fluoxetine, parallel to its antidepressant effect, can reduce appetite and induce weight loss.
Fenfluramine was used in the treatment of obesity resistant to dietary measures or etiologic treatment.
The most frequent adverse effects of fenfluramine and dexfenfluramine were digestive disorders (mouth dryness, constipation or diarrhea, nausea) and central disorders (drowsiness or insomnia, headache, nervousness). The most severe adverse effects of fenfluramine and dexfenfluramine, observed especially in sustained use, were pulmonary arterial hypertension, rare but severe affection, and damage to cardiac valves. Because of the severity of these adverse effects, fenfluramine and dexfenfluramine were withdrawn from the market.
5-HTcatabolism inhibition: MAOI
The drugs which inhibit the inactivation of serotonin have antidepressant effects.
The principal route of inactivation of serotonin but also of other monoamines, noradrenaline and dopamine, is oxydative deamination by monoamine oxidase or MAO.
MAO are divided into MAOA and MAO-B according to their preferential activity on various amines. MAO-A inactivates preferentially serotonin. The following table indicates the substrates preferentially metabolized by MAO-A and MAO-B.
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MAO-A |
MAO-B |
substrates |
SEROTONIN
NORADRENALINE
DOPAMINE
TYRAMINE
|
DOPAMINE
PHÉNYLÉTHYLAMIN
TRYPTAMINE
TYRAMINE
|
therapeutic use of MAOI |
antidepressant |
antiparkinsonian |
Tyramine is inactivated by MAO-A and by MAO-B but the maintenance of one of these activities is generally sufficient for its inactivation.
Inhibition can be reversible and disappears with the elimination of the inhibitor from the body, or be irreversible, i.e. to persist after its elimination, until renewal of the enzyme, after approximately two weeks.
First MAO inhibitors (MAOI) which inhibited at the same time MAO-A and MAO-B are called nonspecific inhibitors. It is the case of iproniazid which has, moreover, an irreversible action. Iproniazid, initially intended for the treatment of tuberculosis (its chemical structure is close to that of isoniazid), proved to be a powerful MAOI and to have antidepressant activity. Others non-specific MAOI not used now are phenelzine, nialamide, tranylcypromine.
Many adverse effects (hypertensive emergency, various neurological disorders) were observed in patients treated by the nonspecific MAOI, particularly when they received other drugs such as indirectly acting sympathomimetic drugs or drugs related to morphine, or took cheeses rich in tyramine. Because of these risks, the nonspecific MAOI are little used today.
Recent inhibitors inhibit specifically either MAO-A or MAO-B and have a reversible effect.
- MAO-A inhibitors inhibit serotonin catabolism and are used as antidepressants. Moclobemide is a typical MAO-A inhibitor which has an antidepressant effect considered to be equivalent to that of fluoxetine..
- MAO-B inhibitors inhibit the catabolism of dopamine and are used in the treatment of Parkinson disease. Selegiline, in low or moderate doses, inhibits specifically MAO-B.
The interest of selective inhibition of A or B type is to keep active the other type, sufficient to inactivate tyramine which, in patients treated by the nonselective MAOI, induced many adverse effects such as hypertensive emergency. In practise, however, even with selective inhibitors, caution must be taken to avoid the use of drugs and food able to induce adverse interactions.
Adverse effects
The serotonergic syndrome was described in animals and in human beings after administration of high doses of directly or indirectly acting serotoninomimetics, often in combination with of other drugs like MAOI and lithium.
This syndrome consists of various symptoms:
- psychic: confusional or manic state
- motor: myoclonus, hypertonicity, hyperreflexia, tremors, displacements, incoordination
- vegetative : hypotension, hypertension, diarrhea
- possibly hyperthermia but which is observed particularly in the neuroleptic malignant syndrome.
The serotonergic syndrome results from an overstimulation of the postsynaptic 5-HT1A receptors. The treatment of this syndrome consists of immediate discontinuation of the suspected drugs, and, if necessary, the administration of a nonspecific serotonergic antagonist. Propanolol has also been used in this case.
SSRI can exceptionally give hemorrhagic disorders, petechiae, ecchymosis, hematoma, epistaxis, undoubtedly by inhibition of the serotonin uptake by thrombocytes.
Warnings against the use of SSRI in children and teenagers were made because they could induce behavioral and emotive disorders with an increased risk of suicide. It has been suggested that one of the best tolerated SSRI in children could be fluoxetine.
Whichever the antidepressant chosen, patients should be closely monitored particularly during the first weeks of treatment, until an improvement in depression has been observed.
Note : Electroconvulsive therapy
It should be recalled that electroconvulsive therapy remains the treatment of choice for patients having drug-resistant depressions or presenting a high risk of suicide.
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