Depressive Disorder: Treatment

With appropriate treatment, the symptoms of a depressive disorder often disappear. Mild depression can be treated using general support and psychotherapy. Moderate and severe depression is treated with medication, psychotherapy or a combination of them, and sometimes with the use of electroconvulsive therapy. Some patients need more than one medication or combination of drugs. To improve the condition, it may take 1 to 4 weeks for the drug to be taken at the recommended dose. Depression, especially in patients who have had more than one episode, is prone to reappearance; therefore, in severe cases, prolonged maintenance medication of depressive disorder is necessary.

Most patients with depression are treated on an outpatient basis. Patients with severe suicidal intentions, especially if there is insufficient support from the family, need to be hospitalized; also hospitalization is necessary in the presence of psychotic symptoms or physical exhaustion.

In patients whose depressive symptoms are associated with the use of psychoactive substances, symptoms are resolved within a few months after discontinuation of the use of surfactants. If depression is caused by somatic disease or toxicity of pharmacological agents, treatment should primarily be directed to these disorders. If the diagnosis is questionable, if symptoms disrupt functioning or if suicidal tendencies occur, a sense of hopelessness, trial treatment with antidepressants or mood stabilizers may prove useful.

[1], [2]

Initial support

The doctor needs to see the patient weekly or bi-weekly to support him, give the necessary information and monitor changes in the condition. Telephone calls can complement visits to the doctor. The patient and his family may be concerned about the thought of having a mental disorder. In this situation, the doctor can help, explaining that depression is a serious medical condition caused by biological disorders and requiring specific treatment, and that depression most often ends on its own and the prognosis is good. The patient and his relatives need to be convinced that depression is not a character flaw (for example, laziness). Explaining to the patient that the path to recovery will not be easy, will help him later cope with feelings of hopelessness and improve cooperation with the doctor.

Encouraging the patient to gradually expand daily activities (eg walks, regular exercise) and social interactions should be balanced with the recognition of the desire of patients to avoid activities. The doctor should recommend the patient to avoid self-incrimination and explain that gloomy thoughts are part of the disease and they will pass.

Psychotherapy

Individual psychotherapy, often in the form of cognitive-behavioral therapy (individual or group therapy), is in itself often effective in mild forms of depression. Cognitive-behavioral therapy is increasingly used to overcome the inertia and self-blaming thinking of depressed patients. However, cognitive-behavioral therapy is most effective if used in combination with antidepressants for the treatment of moderate and severe depression. Cognitive-behavioral therapy can improve coping skills and increase the benefits of support and guidance provided through the removal of cognitive distortions that impede adaptive action and through encouraging the patient to gradually restore social and professional roles. Family therapy can help in reducing disharmony and tension between spouses. Long-term psychotherapy is not mandatory, except in cases where the patient has a prolonged interpersonal conflict or there is no response to short-term therapy.

Selective serotonin reuptake inhibitors (SSRIs)

These drugs block the re-uptake of serotonin [5-hydroxytryptamine (5-HT)]. SSRIs include citalopram, escitalopram, fluoxetine, paroxetine and sertraline. Although these drugs have a similar mechanism of action, differences in their clinical properties determine the importance of choice. SSRIs have broad therapeutic boundaries; they are relatively simple in the appointment, rarely need a dose adjustment (with the exception of fluvoxamine).

Blocking presynaptic reagent 5-HT, SSRIs lead to an increase in 5-HT stimulation of postsynaptic serotonin receptors. SSRIs act selectively on the 5-HT system, but are not specific for various types of serotonin receptors. Therefore, they not only stimulate 5-HT receptors, which is associated with antidepressant and anxiolytic effects, they also stimulate 5-HT, which often causes anxiety, insomnia, sexual dysfunction, and 5-HT-receptors, which usually leads to nausea and headache. Thus, SSRIs can act paradoxically and cause anxiety.

Some patients may appear more agitated, depressed and anxious for a week after starting treatment with SSRIs or increasing the dose. The patient and his relatives should be warned about this possibility and instructed about the call to the doctor if the symptoms worsen during treatment. This situation needs to be closely monitored, since in some patients, especially in children and adolescents, the risk of suicide increases if agitation, increased depression and anxiety are not recognized and do not stop in time. Recent studies show that the number of suicidal thoughts, actions and suicidal attempts in the first few months of SSRIs is increasing in children and adolescents (similar caution should also be exercised for the modulators of serotonin, serotonin-noradrenaline reuptake inhibitors and dopamine-noradrenaline reuptake inhibitors) ; the doctor needs to maintain a balance between clinical necessity and risk.

Sexual dysfunction (especially the difficulty of achieving orgasm, decreased libido and erectile dysfunction) are observed in 1/3 or more patients. Some SSRIs cause an excess of body weight. Others, especially fluoxetine, cause loss of appetite in the first few months. SSRIs have a small anticholinergic, adrenolytic effect and effect on cardiac conduction. Sedation is minimal or unimportant, but during the first weeks of treatment, some patients have a tendency to daytime sleepiness. Some patients experience stool loosening and diarrhea.

Drug interactions are relatively rare; however, fluoxetine, paroxetine, and fluvoxamine can inhibit CYP450 isoenzymes, which can lead to marked drug interactions. For example, fluoxetine and fluvoxamine may inhibit the metabolism of certain beta-blockers, including propranolol and metoprolol, which can lead to hypotension and bradycardia.

Modulators of serotonin (5-HT-blockers)

These drugs block mainly 5-HT-receptors and inhibit the re-uptake of 5-HT and norepinephrine. Modulators of serotonin include nefazodone, trazodone and mirtazapine. Modulators of serotonin have antidepressant and anxiolytic effects and do not cause sexual dysfunction. Unlike most antidepressants, nefazodone does not suppress REM-sleep and promotes a sense of rest after sleep. Nefazodone significantly interferes with the liver enzymes involved in the metabolism of drugs, its use is associated with hepatic insufficiency.

Trazodone is close to nefazodone, but does not inhibit presynaptic reuptake of 5-HT. Unlike nefazodone, trazodone causes priapism (in 1 out of 1000 cases) and, like norepinephrine blocker, can lead to orthostatic (postural) hypotension. It has pronounced sedative properties, therefore use in antidepressant doses (> 200 mg / day) is limited. Most often it is prescribed in doses of 50-100 mg before bedtime in depressed patients with insomnia.

Mirtazapine inhibits the reuptake of serotonin and blocks adrenergic autoreceptors, as well as 5-HT and 5-HT receptors. As a result, more effective serotonergic activity and increased noradrenergic activity without sexual dysfunction and nausea are observed. It has no cardiac side effects, minimal interaction with hepatic enzymes involved in the metabolism of drugs and the drug is generally well tolerated, with the exception of sedation and weight gain mediated by the blockade of histamine H-receptors.

Inhibitors of reuptake of serotonin and norepinephrine

Such drugs (for example, venlafaxine, duloxetine) have a dual mechanism of action on 5-HT and noradrenaline, as well as tricyclic antidepressants. However, their toxicity approaches that of SSRIs; nausea is the most common problem during the first two weeks. Venlafaxine has some potential advantages over SSRIs: it may be more effective in some patients with severe or refractory depression, and due to the low degree of binding to proteins and virtually no interaction with hepatic enzymes involved in the metabolism of drugs, has a low risk of interactions with concomitant administration with other drugs. However, with a sudden withdrawal of the drug, withdrawal symptoms are often observed (irritability, anxiety, nausea). Duloxetine is similar to venlafaxine in effectiveness and side effects.

Dopamine-norepinephrine reuptake inhibitors

Through not completely studied mechanisms, these drugs have a positive effect on catecholaminergic, dopaminergic and noradrenalinergic functions. These drugs do not affect the 5-HT system.

Currently, bupropion is the only drug in this class. It is effective in depressed patients with concomitant attention deficit hyperactivity disorder, cocaine dependence and those who are trying to quit smoking. Bupropion causes hypertension in very few patients and does not have other effects on the cardiovascular system. Bupropion can provoke seizures in 0.4% of patients taking more than 150 mg three times a day [or 200 mg of sustained-release (SR) 2 times a day, or

450 mg of prolonged action (XR) 1 time per day]; the risk rises in patients with bulimia. Bupropion has no sexual side effects and it interacts little with other drugs, although it inhibits hepatic enzymes CYP2D6. Agitation, which occurs frequently, is weakened by the use of delayed or sustained release forms. Bupropion can lead to a dose-dependent disturbance of short-term memory, which is restored after a dose reduction.

[3], [4], [5], [6], [7],

Heterocyclic antidepressants

This group of drugs, previously the basis of therapy, includes tricyclic (tertiary amines amitriptyline and imipramine and secondary amines, their metabolites, nortriptyline and desipramine), modified tricyclic and heterocyclic antidepressants. These drugs increase the availability of norepinephrine and, to a certain extent, 5-HT, blocking their re-uptake in the synaptic cleft. Long-term decrease in the activity of the a-adrenergic receptors of the postsynaptic membrane, perhaps, is a common result of antidepressant activity. Despite inefficiency, these drugs are now rarely used, since they are toxic in overdose and have many side effects. The most common side effects of heterocyclic antidepressants are associated with their muscarinoblocking, histamine-blocking and a-adrenolytic effects. Many heterocyclics have pronounced anticholinergic properties and therefore are not suitable for elderly patients, patients with benign prostatic hyperplasia, glaucoma or chronic constipation. All heterocyclic antidepressants, especially maprotiline and clomipramine, reduce the threshold of convulsive readiness.

Inhibitors of monoamine oxidase (MAOI)

These drugs inhibit oxidative deamination of 3 classes of biogenic amines (noradrenaline, dopamine and serotonin) and other phenylethylamines. MAOIs have no effect l because they have little effect on normal mood. Their main importance is effective action when other antidepressants are ineffective (for example, with atypical depression when SSRIs do not help).

MAOIs registered as antidepressants in the US market (phenelzine, tranylcypromine, isocarboxazide) are irreversible and non-selective (MAO-A and MAO-B inhibit). They can cause hypertensive crises if simpatomimeticheskie means or food containing tyramine or dopamine are used simultaneously. This effect is called a cheese reaction, since ripe cheese contains a lot of tyramine. MAOIs are not widely used because of fears of such a reaction. More selective and reversible MAOIs (such as moclobemide, befloxaton) that block MAO-A are not yet common in the US; these drugs practically do not cause such interactions. To prevent hypertensive and febrile crisis, patients taking MAOI should avoid sympathomimetic agents (eg pseudoephedrine), dextromethorphan, reserpine, meperidine, as well as malt beer, champagne, sherry, liqueurs, some foods containing tyramine or dopamine (for example, bananas, beans, yeast extracts, canned figs, raisins, yoghurt, cheese, sour cream, soy sauce, salted herring, caviar, liver, highly marinated meat). Patients should have at least 25 mg chlorpromazine tablets and, once symptoms of hypertension appear, take 1 or 2 tablets before reaching the nearest emergency room.

Frequent side effects are erectile dysfunction (less common in granilcipromine), anxiety, nausea, dizziness, leg cramps and weight gain. Do not use MAOI in conjunction with other classical antidepressants, should be at least 2 weeks (5 weeks for fluoxetine, as it has a long half-life) between taking drugs of two classes. The use of MAOI with antidepressants that affect the serotonin system (eg, SSRIs, nefazodone) can cause malignant neuroleptic syndrome (malignant hyperthermia, muscle decay, renal failure, convulsions, death in severe cases.) Patients taking MAOI and in need of anti-asthmatic, antiallergic treatment, local or general anesthesia, should be treated by a psychiatrist and an internist, dentist or anesthesiologist with experience in neuropsychopharmacology.

The choice and purpose of the drug for the treatment of depression

When choosing a drug, one can be guided by the nature of the response to the previously used specific antidepressant. In other words, SSRIs are the drugs of the initial choice. Although the various SSRIs are approximately equally effective in typical cases, the properties of a particular drug determine their greater or lesser suitability in specific patients.

If one of the SSRIs is ineffective, another drug of this group can be used, but antidepressants of other classes are more likely to be effective. Tranylcypromine in high doses (20-30 mg orally 2 times a day) is often effective in refractory depression after the sequential administration of other antidepressants; he should be appointed by a doctor who has experience with MAOI. In cases of refractory depression, psychological support of the patient and his loved ones is especially important.

Insomnia, a frequent side effect of SSRIs, is treated by lowering the dose or by adding a small amount of trazodone or another sedative antidepressant. The nausea and loosening of the chair that arise at the beginning of treatment usually pass, while the severe headache does not always go away, requiring the prescription of another class. SSRIs should be withdrawn in case of agitation (more often with fluoxetine). With a decrease in libido, impotence, anorgasmia due to SSRIs, a reduction in the dose or administration of a drug of another class can help.

Antidepressants

A drug	Initial dose	Maintenance dose	Caveats
Heterocyclic			Contraindicated in patients with coronary artery disease, certain arrhythmias, zakratougolnoy and glaucoma, benign prostatic hyperplasia, esophagous hernia; can cause orthostatic hypotension, leading to falls and fractures; potentiate the effects of alcohol; increase the level of antipsychotics in the blood
Amitriptyline	25 mg 1 time	50 mg 2 times	Causes an increase in body weight
Amoxapine	25 mg 2 times	200 mg 2 times	May cause extrapyramidal side effects
Clomipramine	25 mg 1 time	75 mg 3 times	Reduces convulsive threshold at a dose> 250 mg / day
Desipramine	25 mg 1 time	300 mg 1 time	Not used in patients younger than 12 years
Doxepin	25 mg 1 time	150 mg 2 times	Causes an increase in body weight
Imipramine	25 mg 1 time	200 mg 1 time	May cause increased sweating and nightmarish dreams
Maprotiline	75 mg once a day	225 mg 1 time	-
Nortriptyline	25 mg 1 time	150 mg 1 time	Effectively act in the therapeutic window
Protryptiline	5 mg 3 times	20 mg 3 times	Difficult to dose due to complex pharmacokinetics
Trimipramine	50 mg 1 time	300 mg 1 time	Causes an increase in body weight
MAOI			When taken together with SSRIs or nefazodone, the development of serotonin syndrome is possible; possible hypertensive crises when co-administered with other antidepressants, sympathomimetic or other selective drugs, certain foods and beverages
Isocarboxazide	10 mg 2 times	20 mg 3 times	Causes orthostatic hypotension
Fenelzin	15 mg of Zraza	30 mg 3 times	Causes orthostatic hypotension
Tranylcypromine	10 mg 2 times	30 mg 2 times	Causes orthostatic hypotension; has an amphetamine-like stimulating effect, there is a risk of abuse
SIZE
Escitalopram	10 mg 1 time	20 mg 1 time	-
Fluoxetine	10 mg 1 time	60 mg 1 time	Has a very long half-life. The only antidepressant with proven effectiveness in children
Fluvoxamine	50 mg 1 time	150 mg 2 times	May cause clinically significant increases in the levels of theophylline, warfarin, clozapine in the blood
Paroxetine	20 mg 1 time 25MrCR1 times	50 mg once every 62.5 times MrCR1 times	Has a greater likelihood of interactions between active metabolites and TCAs, carbamazepine, antipsychotics, antiarrhythmics 1C type than other SSRIs; can cause a marked suppression of ejaculation
Sertraline	50 mg 1 time	200 mg 1 time	Among the SSRIs, the greatest occurrence of loosening of the stool
Citalopram	20 mg 1 time	40 mg 1 time per day	Reduces the possibility of drug interactions due to a smaller effect on the enzymes CYP450

Inhibitors of reuptake of serotonin and norepinephrine

Duloxetine	20 mg 2 times	30 mg 2 times	Moderate dose-dependent increase in systolic and diastolic blood pressure; can cause slight urinary tract disorders in men
Venlafaxine	25 mg 3 times 37.5MrXR1 times	125 mg of Zraz in 225MrXR1 times	Moderate dose-dependent increase in diastolic blood pressure Rarely an increase in systolic blood pressure (not dose-dependent) Symptoms of cancellation with rapid discontinuation

Modulators of serotonin (5-HT blockers)

Mirtazapine	15 mg 1 time	45 mg 1 time	Causes weight gain and sedation
Nefazodone	100 mg 1 time	300 mg 2 times	May cause hepatic impairment
Trazodone	50 mg 3 times	100-200 mg 3 times a day	Can cause priapism May cause orthostatic hypotension

Dopamine and norepinephrine reuptake inhibitors

Bupropion	100 mg 2 times	150 MrSR Zraza	Contraindicated in patients with bulimia and a tendency to convulsions;
	150MrSR1 times	450 mg XL 1 time	Can interact with TCAs, increasing the risk of seizures; may cause
	150 mg XL 1 time		Dose-dependent memory impairment for recent events

MAOI monoamine oxidase inhibitors, TCA tricyclic antidepressants, CR-continuous release, XR-prolonged release, 5-HT-5-hydroxytryptamine (serotonin), SR-sustained release, XL-extended release.

SSRIs that tend to stimulate many depressed patients should be administered in the morning. If the full dose of a heterocyclic antidepressant is taken before going to bed, then there will be no increased sedation, side effects will be minimized in the daytime and the complex will improve. MAOIs are usually given in the morning or before lunch to avoid excessive stimulation.

The therapeutic response to most antidepressants is observed in the 2-3 weeks (sometimes from the 4th day to the 8th week). At the first episode of mild or moderate depression, antidepressants should be taken for 6 months, then gradually reduced for 2 months. If there has been a severe or repeated depressive episode or a suicidal risk has been expressed, a dose that contributes to complete remission should be taken during maintenance treatment. In psychotic depression, the maximum doses of venlafaxine or heterocyclic antidepressants (eg, nortriptyline) should be given within 3-6 weeks; if necessary, antipsychotics (for example, risperidone, ranging from 0.5-1 mg orally 2 times a day, gradually increasing to 4-8 mg once daily, olanzapine, starting at 5 mg orally once a day and gradually increasing to 10-20 mg once a day, quetiapine, starting from 25 mg orally 2 times a day and gradually increasing to 200-375 mg orally 2 times a day). To prevent the development of late dyskinesia, the antipsychotic should be given at the lowest effective dose and discontinued as soon as possible.

To prevent exacerbations, maintenance therapy with antidepressants from 6 to 12 months (up to 2 years in patients older than 50 years) is usually necessary. Most antidepressants, especially SSRIs, should be phased out gradually (reducing the dose by 25% per week) rather than suddenly; a single-stage withdrawal of SSRIs can lead to serotonin syndrome (nausea, chills, muscle pain, dizziness, anxiety, irritability, insomnia, fatigue).

Some patients use medicinal herbs. St. John's wort can be effective in mild depression, although these data are contradictory. St. John's wort can interact with other antidepressants.

Electroconvulsive therapy in the treatment of depressive disorder

In the treatment of severe depression with suicidal thoughts, depression with agitation or psychomotor retardation, depression during pregnancy, in the case of ineffectiveness of previous therapy, electroconvulsive therapy is often used. Patients who refuse to eat need electroconvulsive therapy to prevent a fatal outcome. Electroconvulsive therapy is also effective in psychotic depression. Efficacy for 6-10 sessions of electroconvulsive therapy is high, and this method can be salutary for life. After electroconvulsive therapy, there are exacerbations, so supportive medication is needed after the end of electroconvulsive therapy.

[8], [9], [10], [11], [12], [13], [14],

Phototherapy in the treatment of depressive disorder

Phototherapy can be used in patients with seasonal depression. Treatment can be done at home using lamps 2500-10 000 lux at a distance of 30-60 cm for 30-60 minutes per day (longer with less intense light sources). For patients who go to bed late at night and wake up in the late morning, phototherapy is most effective in the morning, sometimes with an additional exposure of 5-10 minutes between 15 and 19 hours.