Selective serotonin reuptake inhibitors

Serotonin syndrome is the accumulation of too much serotonin in the body, which leads to a number of consequences. When a person takes a combination of drugs that contain serotonin (commonly prescribed antidepressants such as Zoloft, Lexapro, SSRIS and Effexor, SNRI), they are at high risk of developing serotonin syndrome.

Sometimes taking one drug to increase serotonin levels can also lead to serotonin syndrome in susceptible people. Before taking any medications, it is very important to discuss all medications you are taking with your doctor to avoid this potentially fatal condition.

What is serotonin?

Serotonin is a chemical produced by the body that helps regulate mood, social behavior, sex drive, sleep and appetite. As a neurotransmitter, serotonin transmits signals between nerve cells.

Serotonin is produced in the gut and brain, but is also present in the central nervous system (CNS) and blood platelets. As a result, serotonin is thought to influence a wide range of psychological and bodily functions.

Fluvoxamine

Fluvoxamine (fevarin), as a selective serotonin reuptake inhibitor, has a distinctly activating, mood-enhancing effect, it calms, stabilizes the activity of the autonomic system and can be recommended for a combination of depression and anxiety. In addition, the positive aspect of fluvoxamine treatment is its relatively rapid onset and smooth action, which, as a rule, contributes to the establishment of a good relationship between the patient and his attending physician.

Fluvoxamine is prescribed in a dose of 50 mg. per day once in the evening. The dose of the drug can be increased to 100 mg. (average dose of effectiveness) for 5-7 days. If necessary, the dosage of the drug can be further increased at intervals of 2-4 weeks (maximum daily dosage - 500 mg), starting with a dose of 150 mg. the drug is prescribed several times a day.

The active metabolites of fluvoxamine are unknown. The average half-life is 20 hours, plasma concentrations are not proportional to the dose taken

In most cases, symptoms of an anxiety disorder are eliminated earlier than those of a depressive disorder. This was clinically manifested by an improvement in the general condition of the patients, leading them to greater composure, confidence and external calm. The effectiveness of this drug is noted in patients with obsessive disorders and social phobia, in particular in childhood.

Adding fluvoxamine to atypical neuroleptics can reduce the severity of primary negative symptoms in patients with chronic schizophrenia. At the same time, comparative studies have shown that among the group of selective serotonin reuptake inhibitors, it has the greatest number of side effects (Freemante N., et al., 2000), sertraline has the least (Edwards J., Anderson I., 1999 ).

Symptoms of excess serotonin

If you start taking serotonin-related drugs, increase your dosage, or start taking other drugs in combination with the drug you are already taking and too much serotonin builds up within a few hours, you will feel its effects.

Symptoms can range from mild to severe and depend on the level of serotonin in your body. At best, the signs and symptoms of serotonin are unpleasant; at worst, they can cause extreme anxiety and require intensive treatment.

The following symptoms are signs that you are experiencing serotonin syndrome:

• headache;
• shiver;
• goosebumps;
• heavy sweating;
• fearlessness;
• excitement;
• dilated pupils;
• confusion;
• diarrhea;
• fast pulse;
• high blood pressure;
• muscle stiffness;
• loss of muscle coordination, muscles twitch.

If you experience these symptoms, contact your doctor as soon as possible to discuss the best course of action.

However, severe serotonin syndrome can be life-threatening, and if you experience any of the symptoms listed below, you should seek emergency medical help immediately:

• Irregular heartbeat
• High temperature (>103 F/40 C)
• Seizures
• Unconsciousness

How long does serotonin syndrome last?

The duration of serotonin syndrome depends on the level of serotonin in the body. In cases where serotonin syndrome is present only in a mild form, symptoms may be relieved within 24 hours of stopping the serotonin-inducing drug. However, some antidepressants may take longer to cause symptoms because serotonin levels may take weeks to return to normal.

How common is serotonin syndrome?

According to the American Association of Poison Control Centers, in 2004, 8,187 people were diagnosed with serotonin toxicity as a result of using selective serotonin reuptake inhibitors (SSRIs). Of these, 103 people died.

However, given that statistics on serotonin syndrome are limited, they are likely to be much more common than the data suggests, as those who suffer from mild to moderate serotonin toxicity are often undiagnosed or unreported.

Fluoxetine

One of the first serotonin reuptake inhibitors was fluoxetine (Prozac), which has been actively used since the early 80s to treat various depressive spectrum disorders. In addition, its positive effect in the treatment of bulimia was noted.

Fluoxetine is prescribed at a dose of 20 mg. once a day in the morning, if necessary, increase the dose to 40-80 mg. (in addition to tablet forms, a special solution of fluosetine 4 mg/ml is used abroad).

The drug is well absorbed when administered orally and is demethylated in the liver to form inactive metabolites and pharmacologically active norfluoxetine. Due to the peculiarities of metabolism, the effect of fluoxetine is quite significantly reflected in the functional capabilities of the liver (Bergstrom M., Lemberg L, et al., 1988). It suppresses the activity of hepatic cytochromes P4502D6, and therefore slows down the metabolism of a number of psychotropic drugs, including TCAs, with an increase in their concentration in plasma, which determines the possibility of toxic effects (Creve N., et.al., 1992).

The maximum concentration in the blood when taking fluoxetine is achieved after 6 hours. It has the longest half-life of all SSRIs, which in this case is two to three days, and the half-life of its active metabolite, norfluoxetine, reaches 7-9 days. This circumstance provides an advantage in the treatment of patients who may occasionally forget to take the next dose, but, on the other hand, it complicates the replacement of the drug with other antidepressants (especially MAOIs). It takes several weeks to achieve a stable concentration of the active substance. It was noted that, despite the anxiolytic effect, fluoxetine can increase the manifestations of anxiety and agitation at the initial stage of therapy.

In terms of its spectrum of action, fluoxetine is more reminiscent of the profile of imipramine, since it has a disinhibitory effect and can, as noted above, increase the manifestations of anxiety and restlessness (Caley Ch., 1993; Pujynski S., et al., 1994; Montgomery S., Johnson F., 1995). There is a point of view according to which, due to the disinhibitory effect, fluoxetine should not be used for anxiety, restlessness, motor disinhibition, insomnia, suicidal thoughts and tendencies, however, recent studies have shown that taking fluoxetine does not increase the risk of suicide (Freemante N., et.al ., 2000).

Fluoxetine (Prozac), compared to other SSRIs, eliminates signs of depression much more slowly (within 2-3 weeks), however, its final effect turned out to be similar to the effect of other drugs of this class (Edwards J., Anderson I., 1999). There are observations that fluoxetine is approximately equal to TCAs in its effectiveness in relieving symptoms of depression (Beasley C., et al., 1991).

At the same time, there is a point of view according to which fluoxetine is inferior to other SSRIs in its ability to relieve general manifestations of depression (Williams J., et al., 2000).

In the first days of using fluoxetine, and possibly also at further stages of treatment, nausea, akathisia, headaches, impaired visual acuity, and allergic skin reactions may be observed. Sexual dysfunctions have been reported when taking fluosetine (Guthrie S., 1991; De Vane C. 1994; Pujynski S., 1996).

Causes

Serotonin syndrome most often occurs when two serotonin-related drugs are combined, although in some cases taking one drug that increases serotonin levels can cause this condition in some people.

For example, serotonin syndrome can occur if antidepressants are combined with opioid medications.

What medications cause serotonin syndrome?

Some medications and supplements that may cause serotonin syndrome when taken together or in high doses include the following:

1. Selective serotonin repeat inhibitors: antidepressants such as citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft).
2. Serotonin norepinephrine repeat inhibitors (SNRIs), antidepressants such as trazodone, duloxetine (Cymbalta), and venlafaxine (Effexor).
3. Tricyclic antidepressants such as amitriptyline and nortriptyline (Pamelor)
4. Antimigraine drugs
5. Pain medications: Opioid medications including codeine (Tylenol with codeine), fentanyl (Durage), hydrocodone meperidine (Demerol), oxycodone (OxyContin, Percocet, Percodan), and tramadol (Ultra).
6. Lithium
7. Street drugs: LSD, cocaine, ecstasy and amphetamines.
8. Anti-nausea medications
9. Cough and cold medicines
10. Herbal Supplements: St. John's wort, ginseng and nutmeg.
11. Cannabinoids can also affect serotonin.

Is Serotonin Syndrome Deadly?

If you don't seek medical help when serotonin levels become too high, severe serotonin syndrome can lead to unconsciousness and death. Intentional overdose of serotonin using antidepressants is one of the cases where serotonin syndrome can be fatal without prompt medical treatment.

Can Serotonin Syndrome Be Reversed?

Symptoms of serotonin syndrome usually disappear when you stop taking the medications that cause the symptoms. Fortunately, there are generally no long-term or lasting complications of serotonin syndrome, although you should be aware to avoid serotonin syndrome in the future. Talk to your doctor about prevention, especially if you are taking multiple medications that contain serotonin.

The neurobiological basis of depression is not fully understood. At the same time, the monoamine hypothesis, which appeared in the 70s of the last century, remains relevant and very convincing, according to which mood disorders are associated with disruption of the synaptic transport of serotonin, norepinephrine and dopamine. The validity of this hypothesis is proven not only by modern research, but also by the clinical effects of antidepressants1​᠎.

Antidepressants used in modern psychiatric practice can be systematized (taking into account different classifications) approximately as follows​2​᠎.

— tricyclic antidepressants (TCAs):

imipramine, clomipramine, amitriptyline;

— tetracyclic antidepressants:

maprotiline;

— monoamine oxidase inhibitors (MAOIs)

​3​᠎
):
pirlindol, moclobemide;

- and reuptake inhibitors

,
SARI ):
trazodone, nefazodone;

— selective serotonin reuptake inhibitors (SSRIs):

fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram;

— Selective serotonin and norepinephrine reuptake inhibitors (SNRIs):

venlafaxine, duloxetine, milnacipran;

— norepinephrine reuptake inhibitors:

atomoxetine​4​᠎, reboxetine, viloxazine;

— norepinephrine and dopamine reuptake inhibitors:

bupropion;

- noradrenergic and specific serotonin antidepressants

,
NaSSA ):
mirtazapine, mianserin;

— serotonin modulators and stimulants:

vilazodone, vortioxetine;

— melatonergic antidepressants:

agomelatine.

The disadvantage of the modern classification of antidepressants is its eclecticism: some groups of drugs are distinguished based on the predominant type of pharmacological action (for example, suppression of presynaptic uptake of serotonin), others based on structural features. The TCA group is heterogeneous in terms of the pharmacological properties of the drugs: for example, clomipramine and imipramine predominantly inhibit the reuptake of serotonin and to a much lesser extent interfere with the presynaptic uptake of norepinephrine, while amitriptyline has a balanced effect on both of these neurotransmitters. The imperfect and somewhat arbitrary nature of the above taxonomy is also manifested in the fact that, for example, mirtazapine in different classifications is classified as both a TCA (in terms of chemical structure) and NaSSA (based on the characteristics of pharmacological mechanisms). Although SSRIs are considered to be selective serotonergic antidepressants, all six drugs in this group also (to varying degrees) affect the synaptic transport of norepinephrine and dopamine.

The presented list begins with TCAs and MAOIs as first-generation antidepressants, although, in accordance with modern international and many national clinical guidelines, SSRIs are the first choice drugs in the treatment of depression and anxiety-related disorders, which is determined by the optimal balance of their effectiveness and tolerability.

Of course, for the successful treatment of depression, improving the interneuronal transmission of three key monoamines - serotonin, norepinephrine and dopamine - is important, but it is believed that increased serotonin neurotransmission plays a special role in the clinical effectiveness of modern antidepressants [1].

The following groups of drugs have serotonergic properties: TCAs, tetracyclic antidepressants, MAOIs, SARIs, SSRIs, SNRIs, NaSSA, as well as serotonin modulators and stimulants.

TCAs—especially clomipramine—show significant ability to facilitate synaptic transport of serotonin and demonstrate high efficacy in the treatment of depression, including its most severe, including psychotic, forms. Significant disadvantages of TCAs include frequent side effects (including cardiotoxicity and the ability to provoke the development of type 2 diabetes) and low overall tolerability.

SSRIs, as first-line drugs in the treatment of depression and anxiety-related disorders, are tolerated by patients much better than TCAs and other first-generation antidepressants, but are also not completely free from adverse effects; A typical reason for premature discontinuation of SSRIs is sexual dysfunction - most often decreased libido and deterioration of erection (in men).

SARIs, most notably trazodone5​᠎, occupy an intermediate position between TCAs and SSRIs.

Trazodone is the first serotonergic antidepressant, proposed for clinical use in the treatment of depression in 1981 and preceded the appearance seven years later of fluoxetine, followed by other SSRIs. On the Russian pharmaceutical market, trazodone is presented under the name trittico.

Trazodone affects various types of serotonin receptors. The predominant pharmacological effect of trazodone is considered to be an antagonistic effect on serotonin 5-HT2A and 5-HT2C receptors7​᠎; A certain importance in the antidepressant effect of the drug is also attached to the suppression of serotonin reuptake, which brings trazodone closer to SSRIs and SNRIs. The complex effects of trazodone on serotonin neurotransmission allow it to be considered as a multifunctional serotonergic antidepressant [2].

Trazodone is used in many countries as a treatment for major depressive disorder in adults. Clinical studies indicate significant effectiveness of trazodone in the treatment of depression, comparable to that of TCAs, SSRIs and SNRIs [3]. Pronounced thymoanaleptic properties and proven clinical effectiveness make it possible to prescribe trazodone for depression of varying severity; in addition, the drug is used to augment (strengthen) the action of other antidepressants, including SSRIs, such as fluoxetine [4].

If the combination of two antidepressants is common in clinical practice, then the advisability of simultaneous prescribing of three antidepressants seems controversial to many specialists and causes debate, mainly due to the increase in the total risk of side effects of therapy. Highlighting the controversial nature of the simultaneous use of three antidepressants, R. Lopes et al. [15] described a case of successful treatment of treatment-resistant depression by adding trazodone to the ineffective combination of paroxetine and mirtazapine.

Due to its multifunctional effects on serotonin receptors, trazodone is particularly effective in the treatment of depression accompanied by insomnia and anxiety [6]. According to E. Frecska [7], the introduction into widespread practice of treating depression of trazodone, which has a hypnotic and anxiolytic (anti-anxiety) effect, can reduce the need to prescribe benzodiazepines as an additional component of antidepressant therapy.

The wide range of pharmacological effects of trazodone has provided the basis for its use in clinical practice in a number of countries, along with the treatment of depression for additional indications and primarily for the treatment of insomnia. The drug is most often used in the treatment of sleep disorders in the USA8​᠎; trazodone is invariably included in the list of antidepressants that have a hypnotic effect, and is often the leader in this list [8, 9].

In addition to treating depression and insomnia, trazodone is used in the treatment of generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, bulimia nervosa, alcohol dependence and benzodiazepine dependence, as well as neuropathic pain and other chronic pain syndromes [7, 10]. .

According to some data, trazodone has a moderate beneficial effect on the negative symptoms of schizophrenia, and also in some cases helps reduce delusional disorders that are resistant to antipsychotics [7, 11]. In the practice of treating elderly patients, the ability of trazodone not only to mitigate the negative symptoms of schizophrenia, but also to reduce the manifestations of tardive dyskinesia has been noted [12].

Improved sleep under the influence of trazodone expands the indications for its use in combination therapy for depression: on the one hand, the drug is prescribed in addition to other antidepressants in order to augment their thymoanaleptic effect, and on the other, it is used as a corrective to eliminate anxiety and insomnia caused by other antidepressants , including fluoxetine, bupropion, and monoamine oxidase inhibitors [7].

It should be noted that the apparent hypnotic effect of trazodone has led to certain undesirable consequences: many doctors have ceased to perceive the drug as a significant treatment for major depressive disorder and prescribe it mainly for the treatment of insomnia, which does not allow the full therapeutic potential of trazodone and significantly narrows the range of patients who may benefit from this antidepressant; in other words, trazodone can and should be prescribed for the treatment of depression, regardless of whether it is accompanied by sleep disorders or not.

While demonstrating comparable effectiveness in treating depression as other antidepressants, trazodone is superior in tolerability not only to TCAs, but also to drugs of new generations; its use as an alternative to SSRIs allows one to avoid such undesirable effects associated with the use of the latter, such as anxiety, insomnia and sexual dysfunction [3].

The high adherence of patients to trazodone therapy is largely due to the lack of ability to worsen sexual functions. On the contrary, trazodone is capable of increasing libido (in both men and women) and even, in some cases, causing priapism; however, the frequency of this side effect does not exceed 0.01% [13–17]. Unlike a number of antidepressants, trazodone does not cause or worsen movement disorders, in particular restless legs syndrome and periodic limb movements [18]. A significant advantage of trazodone compared to some newer generation antidepressants, which promotes adherence to therapy (especially in women), is the absence of its effect on body weight [7].

Unlike TCAs, which can increase insulin resistance and provoke the development of type 2 diabetes and aggravate its course, trazodone does not have an adverse effect on carbohydrate metabolism [16].

The effect on anxiety and sleep disorders, combined with good tolerability, including in elderly patients, allows us to consider trazodone one of the drugs of choice for the treatment of depression in late life; in addition, depression comorbid with dementia or psychomotor agitation is an indication for trazodone; An improvement in the quality of life of patients suffering from cerebral atrophy under the influence of trazodone was also noted [6].

Proven clinical efficacy comparable to that of TCAs, SSRIs and SNRIs, combined with good tolerability, warrants re-opening .

rediscovering) of trazodone for the treatment of depression [3].

Summarizing data from various studies, A. Fagiolini et al. [3] concluded that trazodone is an effective and well-tolerated antidepressant that plays an important role in the modern treatment of major depressive disorder, either as monotherapy or as a component of combination treatment. They emphasize that trazodone controls a wide range of depressive symptoms and does not have a negative effect on sleep, but rather has the ability to significantly improve sleep function.

In conclusion, we can add that trazodone, the high clinical effectiveness of which was actively discussed in scientific publications of the 80s and 90s of the previous century, has now, for a number of reasons, turned out to be undeservedly forgotten, although the pharmacological spectrum of this drug provides every reason for its successful use in the treatment of depression (as well as a number of other mental disorders) as an alternative to both TCAs and newer generations of antidepressants.

Conflict of interest: the article was prepared with the support of Pharmaceutical.

Of course, the pathogenesis of depression is extremely complex, associated with many factors and is by no means reduced to a violation of the neurotransmission of monoamines.

Not all of the listed drugs are registered in the Russian Federation.

This list contains only selective and reversible MAO-A inhibitors.

Atomoxetine is the only drug listed here that is not used to treat depression, but as a means of correcting attention deficit hyperactivity disorder.

Another SARI representative, nefazodone, is absent from the Russian pharmaceutical market, which can hardly be considered a significant loss for domestic clinical practice: due to its pronounced hepatotoxic effect, nefazodone in the United States is labeled with the so-called “Black Box Warning” by the FDA.

As mentioned above, antidepressants of early generations already had pronounced serotonergic activity, for example, the powerful tricyclic antidepressant clomipramine, but trazodone is the first drug whose clinical effectiveness is determined by its multimodal effect on the neurotransmission of serotonin.

Some authors, including those cited in the text by A. Schatzberg and C. DeBattista [4], classify trazodone (together with nefazodone) as HT2 receptor antagonists, which, in our opinion, does not fully reflect the spectrum of its pharmacological activity.

The undoubted advantage of trazodone over benzodiazepines, which determines its widespread use in the United States as a treatment for insomnia, is the absence of a negative effect on cognitive functions, as well as the ability to cause addiction and dependence.

Insomnia and anxiety are often at the root of benzodiazepine abuse; Due to its hypnotic and anxiolytic effects, trazodone can successfully replace benzodiazepines and similar hypnotic-sedative drugs.

Citalopram

Citalopram has a significantly higher level of selectivity for serotonin transporters compared to norepinephrine and dopamine transporters.

The drug is prescribed in a dose of 20 mg. per day once a day in the morning. For most patients, this dose is the most effective; the maximum daily dose of the drug is 60 mg.

Citalopram practically does not enter into drug interactions, due to the fact that it has little effect on the activity of some liver enzymes (cytochrome P450 enzyme system). Therefore, it is often used in the treatment of depressive conditions that develop as a result of chronic somatic diseases. Interdrug interactions of the drug are minimal. Under the influence of cytochrome P450, citalopram is converted into two main metabolites: demethylcitalopram and didemethylcitalopram. These metabolites have pharmacological activity, but much less than that of citalopram itself. The half-life of citalopram is 30 hours. It is characterized by a linear dependence of plasma concentrations depending on the dose in the therapeutic interval. For the treatment of severe depression, the dose of the drug should be increased.

The use of citalopram is recommended in general medical practice, in elderly patients and persons who have suffered a cerebral stroke.

When prescribing citalopram, the percentage of men with sexual dysfunction, a side effect that is relatively common when prescribing drugs in this group, turned out to be extremely small. Headache and nausea were the most common side effects of citalopram treatment during the first two weeks of treatment.