The New Antidepressants and Sexual Dysfunction

By: | Tags: | Comments: 0 | June 25th, 2018

-MECHANISMS OF ANTIDEPRESSIVE ACTION

The several dozen antidepressant drugs can be classified according to 10 mechanisms of action, two classic types: tricyclic and inhibitors of monoamine oxidase (MAOI) with the old irreversible subtype, and 8 new ones, of which the best known are the selective inhibitors of the serotonin reuptake (SSRI), another new serotonin receptor agonist and a recent one that is a stimulator (agonist) of the melatonin system.
Classical antidepressants dominated the psychopharmacological treatment of depression from the late 1950s to the late 1980s, when SSRIs appeared.
Traditional drugs have not been clearly overcome in therapeutic potency, however new antidepressants are safer in overdoses and are generally better tolerated and have a different profile of adverse effects.
MAOIs inhibit the enzyme monoamine oxidase (MAO) and thus produce an increase in neurotransmission at the synapse. The older ones were not selective for the MAO types and irreversible in their enzymatic binding (phenelzine, tranilcipramin, etc.).
The known tricyclics are considered non-selective drugs because they act on at least 5 levels, two of which have to do with their therapeutic action: they inhibit the reuptake of serotonin and noradrenaline.
Some tricyclics have greater serotonergic action, such as clomipramine and others are more noradrenergic, such as maprotiline and desipramine. The other three levels of action of tricyclics have to do with side effects:
They block histaminergic receptors, causing weight gain and drowsiness.
Blockade of acetylcholine receptors producing constipation, dry mouth, blurred vision and drowsiness.
Blockade of alpha 1 adrenergic receptors, causing hypotension, dizziness and drowsiness.
Next, we will review the remaining mechanisms of action exhibited by the new antidepressants.
1. Reversible monoamine oxidase inhibitors (IRMA). The best known drug is moclobemide. This antidepressant establishes a relatively unstable union with the MAO, that is when there is an elevation of monoamines, for example, tyramine appears a competition for the enzyme, together with a greater release of enzymatic molecules, preventing the accumulation of vasoconstrictive neurotransmitters. and cardiac, without producing hypertensive episodes that caused the first generation MAOIs.
Moclobemide also selectively inhibits type MAOIs that has to do with the neurotransmitters that are altered in depressive illness. Therefore, this drug is reversible and selective, it is widely used in social phobia.
2. Selective serotonin reuptake inhibitors (SSRIs). The serotonin reuptake pump to the presynaptic neuron is readily inhibited when administering an SSRI. This causes an immediate increase of serotonin available in the somatodendritic area and not in the terminal area of ​​the axon, where the therapeutic action on the postsynaptic neuron would be exerted.
If the SSRI is administered in prolonged form, the increase of serotonin in the somatodendritic area of ​​the presynaptic neuron causes the desensitization of the 5-HT1A autoreceptors, leading to a greater conduction of impulses, releasing a greater amount of serotonin in the axon, stimulating the postsynaptic receptors.
The disinhibition of the different serotonergic pathways and the consequent stimulation of 5-HT2 receptors can explain the broad spectrum of therapeutic actions of SSRIs. The disinhibition of serotonergic neurotransmission in the path that goes from the raphe of the midbrain to the prefrontal cortex would have to do with its antidepressant action.
The disinhibition of the pathway from the raphe to the basal ganglia could correspond to the therapeutic activity in obsessive-compulsive disorder. The pathways to the limbic cortex and hippocampus would explain the therapeutic action in the panic disorder, while the disinhibition of the pathways to the hypothalamus would have therapeutic action in eating disorders.
The stimulation of other 5-HT2 receptors could also explain several of the adverse effects of SSRIs: anxiety, insomnia and sexual dysfunction. Libido and pleasure appear to be mediated by mesolimbic dopaminergic pathways, which can be inhibited by serotonergic pathways that respond to 5-HT2 receptors; thus, the former tend to increase sexual activity and the latter tend to inhibit it.
SSRIs that inhibit serotonergic function can cause sexual dysfunction, whereas drugs that increase dopaminergic activity, such as bupropion, can reverse the alteration of the libido induced by SSRIs.
The alterations of sexuality that these antidepressants provoke also seem to originate in the serotonergic descending pathways of the brain stem that control spinal reflexes such as ejaculation and orgasm.
This would explain that antagonists of 5-HT2 receptors can sometimes reverse the sexual dysfunction of SSRIs. On the other hand antidepressants (mirtazapine, bupropion) with different mechanism of action can improve the sexual dysfunction of SSRIs.
The serotonergic impulses that start from the stimulation of 5-HT2 receptors towards the basal ganglia can inhibit dopaminergic pathways that cause agitation and akathisia (tendency to be in motion) and in rare cases extrapyramidal effects (rigidity, tremors).
At the beginning of administration, SSRIs can induce anxiety and rarely panic attacks, perhaps due to the stimulation of 5-HT2 receptors in the pathways that project to the hippocampus and limbic cortex. Insomnia can appear due to the stimulation of 5-HT2 receptors in the pathways that reach the cholinergic neurons of the brainstem sleep centers.
The stimulation of the 5-HT3 receptors whose pathways go to the center of vomiting in the brainstem and the hypothalamus that controls the appetite seem to be responsible for the nausea, anorexia and weight reduction that this family of antidepressants sometimes causes. Also these same receptors located in the wall of the intestine, can be associated with abdominal discomfort.
3. Inhibitors of the reuptake of dopamine and / or noradrenaline. The only antidepressants that do not act through the serotonergic system would be reboxetine and bupropion.
Bupropion acts selectively on noradrenergic and dopaminergic neurons. The symptoms that seem to depend on a deficit of dopamine would respond quite well to bupropion: psychomotor retardation, anhedonia, hypersomnia, psychomotor and craving lentificación (that can be translated by crave for, or crave after, also imperious desire).
When some patients do not tolerate or do not respond to SSRIs, they can be replaced or enhanced by bupropion, perhaps due to the different neurochemical action profile.
It may be useful to eliminate side effects of SSRIs, especially sexual dysfunction. Also the improvement of the dopaminergic activity would contribute to its effect in the decrease of the nicotine appetite and eating appetite.
Recently in combination with naltrexone, is useful as a medication for obese people, it was launched with the brand Mysimba 8/90 mg. While its noradrenergic action can cause hyperactivity, restlessness and insomnia. Several studies show its usefulness in the depressive episode of bipolar disease.
Reboxetine is a drug that works by selectively inhibiting the reuptake of noradrenaline and would be more potent than desipramine.
4. Blocking of 5-HT2 receptors with serotonin reuptake block. The drug that currently captures the attention of this family is nefadozone. This antidepressant is similar to SSRIs with a particular difference, since it blocks or antagonizes the 5-HT2 receptors, which are stimulated by the former.
This causes a reduction in anxiety and insomnia, which tends to rise transiently with SSRIs. By this same mechanism nefadozone does not increase the restlessness or sexual dysfunction in depressive patients. Another drug in this family is trazodone, that produces sleep induction and is known with the name Deprax.
5. Inhibitors of the reuptake of serotonin, noradrenaline and dopamine. The only representative is venlafaxine. Its action is dependent on the dose; at low doses it functions as an SSRI, at medium and high doses it has norepinephrine reuptake inhibitory action and would act as a tricyclic, while at higher doses it could show a weak ability to inhibit dopamine reuptake and perhaps could function as bupropion.
6. Blocking alpha adrenergic receptors and blocking 5-HT2 and 5-HT3 receptors. The only representative of this group is mirtazapine, which has noradrenergic and serotonergic action. The first is due to blockade of alpha 2 autoreceptors of the presynaptic neuron leading to an increase in the release of noradrenaline, with a marked central and non-peripheral effect.
It also blocks 5-HT2 receptors, making it similar to nefazodone, relieving insomnia, anxiety and without interfering with sexual function. On the other hand the blockade of 5-HT3 receptors would lead to no gastrointestinal discomfort.
The stimulation of other 5-HT2 receptors could also explain several of the adverse effects of SSRIs: anxiety, insomnia and sexual dysfunction. Libido and pleasure appear to be mediated by mesolimbic dopaminergic pathways, which can be inhibited by serotonergic pathways that respond to 5-HT2 receptors; thus, the former tend to increase sexual activity and the latter tend to inhibit it.
SSRIs that inhibit serotonergic function can cause sexual dysfunction, whereas drugs that increase dopaminergic activity, such as bupropion, can reverse the alteration of the libido induced by SSRIs.
The alterations of sexuality that these antidepressants provoke also seem to originate in the serotonergic descending pathways of the brain stem that control spinal reflexes such as ejaculation and orgasm.
This would explain that antagonists of 5-HT2 receptors can sometimes reverse the sexual dysfunction of SSRIs. On the other hand antidepressants (mirtazapine, bupropion) with different mechanism of action can improve the sexual dysfunction of SSRIs.
The serotonergic impulses that start from the stimulation of 5-HT2 receptors towards the basal ganglia can inhibit dopaminergic pathways that cause agitation and akathisia (tendency to be in motion) and in rare cases extrapyramidal effects (rigidity, tremors).
3. Inhibitors of the reuptake of dopamine and / or noradrenaline. The only antidepressants that do not act through the serotonergic system would be reboxetine and bupropion.
Bupropion acts selectively on noradrenergic and dopaminergic neurons. The symptoms that seem to depend on a deficit of dopamine would respond quite well to bupropion: psychomotor retardation, anhedonia, hypersomnia, psychomotor and craving lentificación (that can be translated by crave for or crave after, also imperious desire).
When some patients do not tolerate or do not respond to SSRIs, they can be replaced or enhanced by bupropion, perhaps due to the different neurochemical action profile.
It may be useful to eliminate side effects of SSRIs, especially sexual dysfunction. Also the improvement of the dopaminergic activity would contribute to its effect in the decrease of the nicotine appetite. While its noradrenergic action can cause hyperactivity, restlessness and insomnia. Several studies show its usefulness in the depressive episode of bipolar disease.
Reboxetine is a drug that works by selectively inhibiting the reuptake of noradrenaline and would be more potent than desipramine.
4. Blocking of 5-HT2 receptors with serotonin reuptake block. The drug that currently captures the attention of this family is nefadozone. This antidepressant is similar to SSRIs with a particular difference, since it blocks or antagonizes the 5-HT2 receptors, which are stimulated by the former. Another drug in this family is trazodone.
5. Inhibitors of the reuptake of serotonin, noradrenaline and dopamine. The only representative is venlafaxine. Its action is dependent on the dose; at low doses it functions as an SSRI, at medium and high doses it has norepinephrine reuptake inhibitory action and would act as a tricyclic, while at higher doses it could show a weak ability to inhibit dopamine reuptake and perhaps could function as bupropion.
6. Blocking alpha adrenergic receptors and blocking 5-HT2 and 5-HT3 receptors. The only representative of this group is mirtazapine, which has noradrenergic and serotonergic action. The first is due to blockade of alpha 2 autoreceptors of the presynaptic neuron leading to an increase in the release of noradrenaline, with a marked central and non-peripheral effect.
It also blocks 5-HT2 receptors, making it similar to nefazodone, relieving insomnia, anxiety and without interfering with sexual function. On the other hand the blockade of 5-HT3 receptors would lead to no gastrointestinal discomfort.

-HOW TO AVOID DEPRESSION:

You must communicate the problems. It is the way of not enclosing yourself and thus avoid entering a depressed state.
There are some risk factors, the risk is higher in working women and with small children and the overload of social functions. All these factors can, in many cases, be solved by looking for solid social supports.
There are moments in the life of a woman where there is more risk, as are the dependents of the menstrual cycle, or taking oral contraceptives, in the puerperium and in menopause. You should consult your doctor if you notice important changes in your mood.
Caring for the image is important in order to be well with oneself. Exercise and watch your diet.
Find out about this disease. Depression can appear masked in the form of physical illnesses, so 20 out of 100 people who go to their family doctor may have depression.
He must learn to recognize the symptoms in oneself. The most frequent manifestations are: sadness, anxiety, insomnia, loss or increase of appetite and loss of interests and ability to enjoy.
You should go to the doctor when the symptoms are lasting or make life difficult depression, after cancer, among all diseases, is the one that most affects the quality of life. Do not look for magic formulas, or easy escapes (alcohol, gambling, shopping, TV, …)
You have to lose the fear of going to the psychiatrist. Depression has an effective treatment, both biological and social and psychological.
Depression has consequences on the family, work environment and in general on the whole world of the person’s relationship. If you see a friend or family member in these circumstances, calmly explain that they are sick, encourage them to go to the doctor, and make them see that the disease prevents them from seeing life as it is.
Know that organic disease, especially chronic disease, is associated with depression in 30% of cases. Consult your doctor if you have symptoms.

-New antidepressants:

-Pristiq: desvelanfaxina, 50 and 100mg. is an antidepressant that belongs to a group of medicines called selective serotonin and norepinephrine reuptake inhibitors (SNRIs). This group of medicines is used to treat depression.
People with depression may have low levels of serotonin and noradrenaline (also known as norepinephrine) in the brain. It is not completely known how antidepressants work, but they can help increase the levels of serotonin and noradrenaline in the brain. Pristiq is a treatment for adults.
-Brintellix: vortioxetine, 5 and 10mg. it can be stopped abruptly increases the activity of the receptor and serotonin transporter.
-Valdoxan 25mg: agomelatine is a melatoninergic agonist (MT1 and MT2 receptors) and a 5-HT2C antagonist, which is the serotonin receptor. In the studies of union it is indicated that agomelatine has no effects on the uptake of monoamines and has no affinity for the adrenergic receptors Alpha or β, histaminergic, cholinergic, dopaminergic and benzodiazepine.
Agomelatine resynchronizes circadian rhythms in animal models of altered circadian rhythm. Agomelatine increases the release of dopamine and noradrenaline, specifically in the frontal cortex, and has no influence on the extracellular levels of serotonin.
These last two valdoxan (vortixetina) and brintellix (agomelatine), together with bupropion (elontril), should be used preferably in case of sexual dysfunction, caused by other antidepressants.

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