Psychiatry Psychiatry and psychopharmacotherapy named after. P.B. Gannushkina No. 03 2000

Since 1990 TCA antidepressants are replaced with SSRI antidepressants. With relatively the same level of effectiveness, SSRIs are safer than TCAs. However, SSRIs have side effects that may affect your treatment.

Tolerability and side effects are different, but very closely related concepts. One of the main reasons for stopping treatment with antidepressants is the severity of their side effects. 43% of people with depression stop taking antidepressants due to side effects. Patients taking TCAs are more likely to discontinue treatment and experience more side effects than patients taking SSRIs.

More information about the main side effects:

Bleeding

– SSRIs are thought to influence hemostasis by affecting the uptake of serotonin by platelets. The more strongly antidepressants act on serotonin uptake, the higher the risk of bleeding. This applies to SSRIs and venlafaxine, the antidepressant with the most potent serotonergic effect of the SSRI group.

– SSRIs increase the risk of gastrointestinal bleeding.

– The risk of bleeding is increased by SSRIs, but not by TCAs.

– The risk of bleeding increases the simultaneous use of SSRIs and aspirin, SSRIs and non-steroidal anti-inflammatory drugs.

Explain in simple terms - how do antidepressants work?

Antidepressants are a group of psychotropic medications that affect the levels of neurotransmitters (they transmit nerve impulses between cells in the human brain), thereby helping to treat depression. We are talking about three hormones: serotonin, dopamine and norepinephrine. According to the prevailing point of view in scientific circles, with depression their concentration noticeably decreases, which is why the interaction between neurons is disrupted. Modern antidepressants help reverse this process, returning the brain to normal functioning. Thanks to this, patients experience the following improvements: improved mood, improved vitality, decreased anxiety and apathy, and normalized sleep and appetite.

Side effects on the cardiovascular system

– SSRIs were originally introduced as a safe alternative to TCAs. Recently, there is emerging evidence that SSRIs produce cardiovascular side effects, such as prolonging the QT interval, thereby increasing the risk of ventricular arrhythmias. However, TCAs prolong the QT interval more significantly than SSRIs. Among the SSRIs, citalopram has the strongest effect on the QT interval.

– TCAs are more likely to cause cardiovascular adverse reactions than SSRIs; Mirtazapine has a very low risk of these types of side effects; SSRIs have the highest risk of increasing blood pressure; among SSRIs, venlafaxine (at a dosage of 150 mg/day) has the highest risk of increasing blood pressure; Increased blood pressure due to SSRI use is very rare.

– All antidepressants except SSRIs increase resting heart rate and reduce heart rate variability; This effect is most significant when taking TCAs.

How do you know which antidepressant is best to start with?

Initially, the doctor prescribes the drug that, in his opinion, is best suited for a particular patient. It is impossible to know for sure what will work more effectively, but there are some factors that you can focus on: the type and symptoms of depression, side effects of medications, the general health of the patient, and concomitant diseases.

If you have family members with depression and certain medications work well for them, chances are the same medications will work for you.

Antidepressants can be prescribed during pregnancy and breastfeeding, but with caution. The doctor must carefully weigh the possible risks.

Hepatotoxicity

– The weakness of MAO and TCA antidepressants was considered to be their hepatotoxicity. Recent research confirms this idea and, in addition, shows the presence of a risk of hepatotoxicity with new antidepressants.

– The risk of hepatotoxicity is relatively higher when taking nefazadone, bupropion, duloxetine, agomelatine; the risk is relatively lower when taking citalopram, escitalopram, paroxetine, fluvoxamine.

– In the TCA group, clomipramine and amitriptyline have high hepatotoxicity.

– Agomelatine has the highest risk of hepatotoxicity.

– Milnacipran increases the risk of hepatotoxicity more significantly than duloxetine.

– SSRIs, compared with other antidepressants, do not significantly increase the risk of hepatotoxicity.

Global trends

Since the early 2000s, the use of antidepressants has increased in almost all countries. In 2000, residents of Iceland were the most likely to use these drugs: 71 people out of a thousand admitted to regularly using them, and in 2011 this number increased to 106 people per thousand. In Canada and Australia, the figures are not much better: in 2011, 86 and 89 people out of a thousand, respectively, resorted to using medications against depression. The Scandinavians and other Europeans lagged behind, but not by much. Residents of Eastern European countries avoid taking antidepressants constantly, but often use them once (to be honest, this does not make much sense for health). Women are treated for depression more often than men, and bisexuals are treated more often than homosexuals and heterosexuals. For Russia, alas, there is no exact data.

Convulsions

– Bupropion is considered the riskiest drug for seizures. But a lot depends on the dosage form. Bupropion IR (immediate release) at a dose greater than 450 mg increases the risk of seizures by 10-fold. Bupropion SR (extended release) at doses up to 300 mg increases the risk of seizures by only 0.01-0.03%. The same slight increase is observed when taking SSRIs.

– TCAs have a higher epileptogenic potential than bupropion, so antidepressants of this group are contraindicated in patients with a predisposition to seizures.

– Current research complicates the understanding of the risk of seizures. New evidence suggests that all antidepressants appear to increase the risk of seizures.

– The riskiest antidepressants: trazodone, lofepramine, venlafaxine. In the SSRI group, the greatest risk is when taking paroxetine and citalopram, the lowest when taking escitalopram and sertraline.

– According to other data, SSRIs are more dangerous than TCAs and the highest risk of seizures occurs when taking sertraline.

– Large studies, however, show that grand mal seizures occur more often in patients taking TCAs rather than SSRIs.

What happens if during treatment the patient stops taking the prescribed drug?

It all depends on the situation. If the withdrawal is abrupt, there is a high risk that the body will not have time to adapt to the new regime, and the side effects will increase exponentially. This is called withdrawal syndrome and can be expressed in different ways. Most often, patients complain of dizziness, headaches, sleep disorders, spasms and tremors in the limbs. There is also a rebound syndrome, in which untimely withdrawal from the drug provokes the return of all the negative symptoms of depression. With gradual withdrawal, such consequences do not occur, so it is extremely important to adhere to the dosage regimen prescribed by the doctor.

Suicide

– The FDA in 2004 required manufacturers of antidepressants to place a warning on their packaging about the increased risk of suicide in children and adolescents. The controversy of this rule is that the disease, which is treated with antidepressants, itself increases the risk of suicidal behavior. Limited data on the association of antidepressant use with suicide attempts still does not allow us to draw a clear conclusion.

– A relative increase in suicide risks is observed with venlafaxine, escitalopram, imipramine, duloxetine, fluoxetine and paroxetine.

“I heard that antidepressants change personality. Will they turn me into a “zombie”?

This is perhaps one of the most common and most ridiculous myths regarding antidepressants. They won't actually change your personality. You will remain the same person, you will be able to work normally, communicate with people around you, you will live a full life - your mood will simply stabilize and become normal. A far-fetched “side effect” in the form of personality changes is not something to be afraid of. You won't become a zombie.

The most important thing is to correctly determine whether you have indications for taking antidepressants and choose the appropriate drugs and dosages. Only a specialist can competently solve these problems. Trust an experienced doctor at the Cordia Clinic, contact us:

Overdose safety

– Among those who commit suicide, the most common mental disorder is depression. One in four patients with depression attempts suicide. For this reason, the safety of higher doses of antidepressants is very important.

– The highest hazard index (number of deaths per thousand poisonings with antidepressants) is for amoxapine, maprotiline, and desipramine. All SSRIs and SSRIs have a lower hazard index than TCAs.

– The proportion of deaths in the total number of poisonings for SSRIs is less than for venlafaxine and mirtazapine.

What to do if antidepressants don't help?

First of all, don’t panic. For some patients, antidepressants begin to help literally from the first days, but this is not always the case. In most cases, improvement occurs after weeks. An antidepressant is not a headache pill that works immediately after taking it. It is important to take them regularly, in the doses prescribed by your doctor.

Medicines may cause some side effects at first. For example, people who have just started taking SSRIs may experience headaches, nausea, dry mouth, and bowel dysfunction. After a period of adaptation, these symptoms disappear.

If the side effects are very strong, persist for too long, if you have been taking the drug for several weeks, but do not feel any improvement, you should not engage in amateur activities, consult your doctor.

Sexual dysfunction

– Sexual dysfunction in patients with depression is caused by the disease and the medications prescribed to treat it. All antidepressants that affect serotonin or norepinephrine uptake cause sexual dysfunction. There is no evidence that SSRIs and SSRIs are less effective in this area than TCAs.

– The most common causes of sexual dysfunction are citalopram, fluoxetine, paroxetine, sertraline and venlafaxine. Imipramine is the same, but weaker than the five named antidepressants.

– Bupropion has the weakest sexual side effects compared to other modern antidepressants.

Antidepressants

The most important role in the process of drug treatment of depression is played by antidepressants - drugs that systemically improve the patient’s condition, relieving symptoms of depression: emotional disorders, motor and cognitive disorders (memory, attention, thinking), as well as somatic and autonomic manifestations of depression.

Antidepressants can also be effective in the treatment of anxiety, eating disorders, obsessive disorders, vegetative crises, and in eliminating pain of various origins, for example, rheumatism, since antidepressants usually increase the threshold of pain sensitivity.

The choice of antidepressant for the treatment of depression is primarily determined by the clinical picture of the disease, although it should be kept in mind that those antidepressants that have been effective in the past or have successfully helped family members of the patient are likely to be most useful. Often, selecting an antidepressant that is adequate to the patient’s condition can take quite a long time and on average takes two to three weeks; if the dosage is adjusted, this period can increase to six to eight weeks. Patience is required from both the doctor and the patient, both in terms of the timing of the expected effect and reasonable tactics in case of side effects. Usually the latter occur in the first days of therapy, and their severity can be reduced by changing the dose of the drug or prescribing correctors.

Basic criteria for choosing an antidepressant:

1. Clinical picture of depression based on the leading modality of affect
2. Effectiveness of an antidepressant in relieving past episodes of depression
3. The effectiveness of an antidepressant in relieving depression in close relatives of the patient
4. Minimal side effects, tolerance to specific side effects
5. No somatic contraindications
6. Results of hormonal, neurophysiological, pathopsychological and neuropsychological studies
7. Economic feasibility
8. Balanced effects on the serotonergic and noradrenergic neurotransmitter systems
9. Patient's age
10. No negative interactions with other medications used to treat the patient

In practice, the main difficulties in using antidepressants are that their dose is not insufficient in patients with severe depression and not too high in patients with questionable and mild depression (Bochner F., et al., 2000).

The effect of an antidepressant usually appears 2 weeks after its administration, but a more pronounced therapeutic effect may require 6 weeks or more.

In more than a third of patients suffering from depression, the main reason for stopping taking antidepressants and, therefore, an important factor contributing to the formation of stable chronic depression are side effects that develop during the first stage of taking antidepressants. Among the side effects that are the most common reasons for stopping therapy are usually: constant feeling of nausea, weight gain, palpitations, drowsiness or insomnia, sexual disorders, weakness, headache. Often, a person suffering from depression agrees to treatment only with an antidepressant that has a minimum number of side effects. Such tactics for treating depression are usually ineffective.

The main reasons for stopping taking an antidepressant are:

1. Side effects of therapy, especially gastrointestinal (nausea, vomiting, flatulence, etc.), cardiological (palpitations, arrhythmias, orthostatic hypotension, etc.), neurological (headache, tremor, sweating, etc.) endocrinological (weight gain, changes in the menstrual cycle etc.), manifestations of sexual dysfunction.
2. Decrease in the patient’s quality of life due to taking an antidepressant (the need for long-term use of the drug, its high cost, refusal to drink alcohol, etc.).
3. Lack of rapid therapeutic effect of the drug, its inadequate dosage.
4. Concerns regarding the development of dependence with long-term use of the drug.
5. Negative interaction with other medications (tranquilizers, antipsychotics, cardiovascular drugs, etc.).
6. Temporary improvement in the patient's condition.
7. There is no information about the required duration of antidepressant therapy, including the stage of long-term maintenance therapy and therapy aimed at preventing relapse of depression.
8. Negative suggestibility of the patient regarding the occurrence of possible side effects of the drug (annotations on the drugs, opinions of other patients, close relatives, etc.).
9. Belief in one's own strength to combat depression, psychologization of depression, orthodox religiosity, or belief in the effectiveness of psychotherapy.
10. Adherence to alternative methods of therapy (non-traditional therapy).

In cases of a negative result, the doctor may increase the dose of the drug, and it should be remembered that the most common mistakes in the treatment of depression are treatment with low doses of an antidepressant and its rapid discontinuation after the patient’s condition improves.

For treatment-resistant depression, a psychiatrist may replace one antidepressant with another, use a combination of them, intensify psychotherapeutic intervention, or use another biological treatment method, such as electroconvulsive therapy. In the case of particularly resistant conditions, clarification of the diagnosis and active treatment of concomitant diseases are required: cardiovascular, gastroenterological, endocrine, etc. Particular caution during antidepressant therapy should be exercised in the presence of pregnancy, liver disease, kidney disease, or indications of cardiovascular disorders. It is important to emphasize that antidepressants are not always combined with the medications that are used in the treatment of the above diseases. Quite common in depression is the tendency to haphazardly take various drugs, especially painkillers and sleeping pills; tranquilizers that relieve panic attacks. All these medications may not be combined with antidepressants, cause significant side effects, distort the effect of the drugs or neutralize it completely.

There have been cases of incompatibility of antidepressants with a number of nutritional supplements and medicinal herbs. Alcohol, when combined with antidepressants, on the one hand causes a feeling of weakness, on the other hand, reduces the effectiveness of the antidepressant, however, the rare intake of small amounts of alcoholic beverages is quite acceptable and safe.

The reason for the resistance of depression to therapy in 20-30% of cases is the patient’s hidden resistance to the therapy process: a conditional “benefit from the disease.” The reason for the persistence of depression can also be: the cohesion of the symptoms of the disease with the patient’s personality, the presence of concomitant somatic diseases, fear of psychotropic drugs, categorical refusal to take them (religious views, peculiar ideas about a healthy lifestyle, imaginary opinion about the possibility of developing dependence due to long-term use of antidepressants) attempts independently reduce or increase the dose of antidepressants, non-compliance with the treatment regimen regarding the time of its administration or duration, independent discontinuation of the drug after a temporary improvement in the condition. Finally, due to the severity of his condition, the appearance of absent-mindedness or despair, the patient may forget about taking the medication and lose faith in its effectiveness.

Patients may have a negative attitude towards treatment with psychotropic drugs and antidepressants, in particular, due to those false myths that are widespread in society. These myths include:

• the belief that you will have to take antidepressants for life;
• recognition of weakness due to the inability to independently cope with the manifestations of depression;
• an unfounded belief that these drugs cause addiction, negatively affect a person’s thinking and memory, change his personality and limit creative activity.

The doctor needs to explain to the patient that for many diseases there is a need for long-term medication, that antidepressants cannot change a person’s character, do not cause drug addiction, do not negatively affect his mental abilities, but, on the contrary, contribute to the restoration of mental health. Before starting antidepressant therapy, it is necessary to identify the diseases that the patient suffers from, since the use of many drugs used to treat these diseases may be incompatible with the effects of any antidepressants.

Typically, a patient with depression is interested in questions regarding the use of antidepressants: the name of the drug, its cost, side effects and complications, including possible allergic reactions, contraindications, the required dose, the mechanism of action of the antidepressant, the exact time of taking the medication, dietary features during treatment, the possibility of drinking alcohol during antidepressant therapy. The patient is also interested in the possibility of combining an antidepressant with other medications, especially hypnotics and painkillers, tactics in case of temporary cessation of medication, the ability to drive vehicles and perform certain types of work, duration of medication, methods for determining its concentration in the blood, the likelihood of a positive effect and start time the effects of the drug, the first signs of improvement and the time of final recovery from depression. There is no doubt that correct answers to these questions are only possible if the doctor is sufficiently qualified and has experience in treating depression.

To exclude a recurrence of depression, it is necessary that the duration of taking an antidepressant is about nine months for the initial episode of depression, and almost two years for the second episode. It is almost impossible to do without prescribing antidepressants if the patient has a combination of depression with hallucinations and delusions.

Modern antidepressants, as a rule, are classified according to their chemical structure (Table 2) and mechanism of action (Table 3) (Kharkevich M.Yu., 1996; Mashkovsky M.D., 1997; Puchinsky S., 2000).

Table Classification of antidepressants by chemical structure

Table Classification of antidepressants by mechanism of action

Based on the chemical structure, a large number of groups of drugs are distinguished:

• tricyclic antidepressants (amitriptyline, imipramine, clomipramine),
• atypical tricyclic derivatives (tianeptine),
• tetracyclic drugs (mianserin, mirtazepine, maprotiline, pirlindole),
• bicyclics (sertraline, paroxetine, trazadone, citalopram),
• monocyclic (fluoxetine, fluvoxamine, venlafaxine, milnacipran),
• adenosyl-methionine derivatives (5 - adenosyl - methionine),
• benzamide derivatives (moclobemide),
• carbohydrazine derivatives (isocarbohydrazide),
• cyclopropylamine derivatives (tranylcypromine),
• hydrazine derivatives (phenylzine, nialamide, iproniazid).

The pharmacological action of antidepressants is due to the following mechanisms:

• delayed recovery of norepinephrine, serotonin and dopamine;
• sodium antagonistic effects;
• blockade of muscarinogenic acetylcholine receptors;
• block of histamine (H1) receptors, blockade of alpha-1 receptors, blockade of serotonin-2 (5-HT2) receptors and blockade of dopamine dopamine D2 receptors (Kasper S., Moller H., Muller-Spahn F., 1997).
• Antidepressants can mediate those intracellular signaling mechanisms that control neurotrophic processes, which ensures the functional viability of the neuronal systems of the brain.

Based on the mechanism of action of antidepressants, the following groups are distinguished:

• selective serotonin reuptake inhibitors (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram),
• monoamine oxidase inhibitors (nialamide),
• reversible inhibitors of monoamine oxidase type A (pirazidol, moclobemide),
• selective norepinephrine reuptake blockers (mianserin, maprotiline),
• selective serotonin and norepinephrine reuptake inhibitors (venlafaxine, milnacipran),
• noradrenergic and serotonergic antidepressant (mirtazapine),
• selective serotonin reuptake stimulator (tianeptine).

Currently, there are drugs that selectively affect the metabolism of the precursor of norepinephrine - dopamine (bupropion).

The pharmacological properties of antidepressants have different effects on the clinical manifestations of depression. Blockade of norepinephrine reuptake by nerve endings leads to a reduction in depressive symptoms (psychomotor retardation, low mood), but at the same time causes a number of side effects (tremor; tachycardia; sexual dysfunction in men; weakening of the effect of a number of drugs that lower blood pressure). Blockade of serotonin reuptake leads to a weakening of other manifestations of depression (anhedonia, circadian manifestations of depression, anxiety). Blockade of dopamine reuptake increases psychomotor activity and has an antiparkinsonian effect, but at the same time can increase the manifestations of psychosis. Blockade of histamine receptors - enhances the effect of alcohol, barbiturates, neuroleptics, tranquilizers, leading to drowsiness, weight gain and hypotension. Blockade of muscarinic receptors (anticholinergic effect) contributes to the occurrence of such side effects as: blurred vision, dry mouth, tachycardia, constipation, urinary retention, memory impairment. Blockade of some adrenergic receptors leads to increased antihypertensive effects of adrenergic blockers, orthostatic hypotension, dizziness, and reflex tachycardia. Inhibition of monoamine oxidase type A (deamination of serotonin, norepinephrine, dopamine) has a stimulating effect (psychomotor activation, weakening of depression), and anxiety, insomnia, headache, neurotoxic disorders, the effect of sympathomimetic amines (adrenaline) may increase, and tyramine (“cheese”) symptoms may occur. ") reactions. Inhibition of monoamine oxidase type B (deamination of phenylethylamine, benzylamine and dopamine) causes hemodynamic disorders, impaired liver function, antiparkinsonian and antihypertensive effects.

Antidepressants are heterogeneous in terms of their effect on various manifestations of depression, in particular, sadness, apathy, anxiety and motor agitation. The nature of the effect on these components of depression underlies the clinical classification of antidepressants (Roose S., et.al. 1994).

We can highlight:

• antidepressants with a weak effect, relieving anxiety and a moderate effect on psychomotor agitation - amitriptyline, imipramine, clomipramine, moclobemide;
• antidepressants with a pronounced anxiolytic and sedative effect without a noticeable effect on psychomotor agitation - doxepin (Sinequan), trimipramine - (Surmontil), and among relatively new drugs - fluvoxamine and paroxetine;
• antidepressants without a pronounced sedative and anti-anxiety effect, but with a disinhibiting effect on reduced psychomotor activity - desipramine (Pertofran), nortriptyline (Pamelor), protriptyline.

In clinical practice, the basis for choosing an antidepressant is the difference in the clinical picture of depression, in the structure of its syndromes: for example, motor and intellectual retardation is better served by the action of melipramine, and anxiety by the sedative effect of amitriptyline (Nuller Yu.L., Mikhalenko I.N., 1973 ; Avrutsky G.Ya., Sinitsky V.I., 1986; Neduva A.A., 1988,).

The specific effect of some antidepressants is primarily associated with improving mood and sedation (thymoleptics), others with a stimulating, motor-activating effect (thimeretics), and others with a noticeably mood-enhancing effect (thymoanaleptics). Antidepressants and stimulants include melipramine, petilin, pyrazidone, cefedrine, nialamide, transamine; to antidepressants - sedatives: amitriptyline, fluoroacyzine, azafen, gerfonal, oxylidine.

The main antidepressants include drugs whose action is due to inhibition of the uptake of monoamines, which play the role of carriers of mediators of the central nervous system, in particular, norepinephrine and (or) serotonin. The relative activity of antidepressants to block norepinephrine uptake relative to serotonin influences the spectrum of activity and side effects of these drugs. An example of a sequential series of antidepressants that have a greater effect on the metabolism of norepinephrine than serotonin is the following list of drugs: maprotiline, melipramine, amitriptyline, clomipramine, fluoxetine.

Antidepressants have different effects on different receptors in the brain. Thus, in particular, dopamine metabolism is influenced to a greater extent by melipramine than by amitriptyline.

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Weight gain

– Previously, it was believed that SSRIs and SSRIs contributed to excess weight gain. Among the SSRIs, the riskiest in this regard is paroxetine, and among the TCAs, amitriptyline. However, on average, weight gain occurs similarly with amitriptyline, sertraline, and fluoxetine.

– SSRIs and SSRIs may be associated with weight loss. After 4 months of treatment, this effect disappears, and paroxetine begins to contribute to the gain of extra pounds.

– Amitriptyline and mirtazapine promote weight gain in short-term and long-term treatment.

– Imipramine and bupropion promote weight loss or relatively slow weight gain in short-term and long-term treatment.

– In general, the latest evidence suggests that weight gain occurs to some extent when taking all antidepressants.

Does taking antidepressants guarantee a complete cure for depression?

Unfortunately no. Often, the causes of depressive disorders lie not in physiology, but in human psychology, so drug therapy has only a temporary effect, which gradually fades away after discontinuation of the drug. Knowing this, doctors usually use antidepressants as part of a comprehensive treatment that also includes psychotherapy sessions. However, some patients only need medication to recover. On the contrary, they don’t help some people. Depression is a very complex disorder, so doctors select their own treatment methods for each specific case.

Hyponatremia, sleep disturbances, sweating

– The first reports of hyponatremia due to antidepressants involved TCAs. But the risk of hyponatremia is higher with SSRIs than with TCAs.

– The highest risk in the SSRI group is citalopram and escitalopram.

– Venlafaxine has the same risk as SSRIs or higher.

– The risk of hyponatremia when taking antidepressants increases in elderly patients and in cases of concomitant use of diuretics.

– The effect of antidepressants on sleep can vary greatly. The duration of sleep may be reduced, or it may be increased.

– Venlafaxine reduces the REM sleep phase, which is why it is prescribed in the treatment of narcolepsy.

– Many TCAs have a very strong sedative effect.

– Bupropion may cause insomnia.

– Increased sweating occurs with TCAs, SSRIs, and SSRIs.

– Sweating is observed in 10% of patients taking SSRIs, venlafaxine, TCAs.

Are antidepressants compatible with alcohol?

During drug treatment of depression, alcohol consumption should be avoided. At the same time, different groups of antidepressants interact with alcohol in different ways. Mixing some (for example, tricyclic antidepressants) with alcohol can lead to serious consequences, including death. More modern drugs are not so dangerous in this regard. But MAO inhibitors, for example, can affect vasoconstriction (and therefore, indirectly, on erection), and can also enhance the effect of strong drinks and provoke, for example, damage to the liver or nervous system. Exactly how the drug interacts with alcohol is always written in the instructions. And in most cases this interaction is undesirable.

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