Depressive Disorder - Treatment

With appropriate treatment, the symptoms of depressive disorder often resolve. Mild depression can be treated with general support and psychotherapy. Moderate to severe depression is treated with medication, psychotherapy, or a combination of both, and sometimes with electroconvulsive therapy. Some patients require more than one medication or combination of medications. Improvement may require 1 to 4 weeks of medication at the recommended dose. Depression, especially in patients who have had more than one episode, tends to recur; therefore, long-term maintenance medication for depressive disorder is necessary in severe cases.

Most patients with depression are treated on an outpatient basis. Patients with severe suicidal intent, especially with insufficient family support, require hospitalization; hospitalization is also necessary if psychotic symptoms or physical exhaustion are present.

In patients whose depressive symptoms are associated with substance use, symptoms resolve within a few months after stopping substance use. If depression is due to a somatic disorder or drug toxicity, treatment should primarily target these disorders. If the diagnosis is in doubt, if symptoms impair functioning, or if suicidal tendencies or feelings of hopelessness are present, a trial of antidepressants or mood stabilizers may be helpful.

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Initial support

The physician should see the patient weekly or every other week to provide support, information, and monitoring for changes in the patient’s condition. Telephone calls can supplement the visits to the physician. The patient and his or her family may be concerned about the possibility of a mental disorder. The physician can help by explaining that depression is a serious medical condition caused by biological disorders and requiring specific treatment, and that depression most often resolves on its own and the prognosis is good with treatment. The patient and his or her family should be reassured that depression is not a character flaw (e.g., laziness). Explaining to the patient that the road to recovery will not be easy will help the patient cope with the feeling of hopelessness later on and improve cooperation with the physician.

Encouraging the patient to gradually increase daily activities (e.g., walking, regular exercise) and social interactions should be balanced with acknowledging the patient's desire to avoid the activity. The physician should encourage the patient to avoid self-blame and explain that negative thoughts are part of the illness and will pass.

Psychotherapy

Individual psychotherapy, often in the form of cognitive-behavioural therapy (individual or group), is often effective on its own for mild depression. Cognitive-behavioural therapy is increasingly used to overcome the inertia and self-blaming thinking of depressed patients. However, cognitive-behavioural therapy is most effective when used in combination with antidepressants for the treatment of moderate to severe depression. Cognitive-behavioural therapy can improve coping skills and enhance the benefits of support and guidance by addressing cognitive distortions that interfere with adaptive action and by encouraging the patient to gradually re-establish social and occupational roles. Family therapy can help reduce disharmony and tension between spouses. Long-term psychotherapy is not necessary unless the patient has protracted interpersonal conflict or does not respond to short-term therapy.

Selective serotonin reuptake inhibitors (SSRIs)

These drugs block the reuptake of serotonin [5-hydroxytryptamine (5-HT)]. SSRIs include citalopram, escitalopram, fluoxetine, paroxetine, and sertraline. Although these drugs have similar mechanisms of action, differences in their clinical properties make the choice important. SSRIs have wide therapeutic margins; they are relatively easy to prescribe and rarely require dose adjustments (with the exception of fluvoxamine).

By blocking the presynaptic 5-HT reuptake, SSRIs lead to increased 5-HT stimulation of postsynaptic serotonin receptors. SSRIs act selectively on the 5-HT system, but not specifically on the different types of serotonin receptors. Therefore, not only do they 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 during the week following initiation of SSRI treatment or dose escalation. Patients and their loved ones should be warned of this possibility and instructed to call their physician if symptoms worsen during treatment. This situation should be closely monitored because some patients, particularly children and adolescents, may be at increased risk of suicide if agitation, worsening depression, and anxiety are not recognized and treated promptly. Recent studies suggest that suicidal ideation, actions, and suicide attempts increase in children and adolescents during the first few months of SSRI use (similar caution should be exercised with serotonin modulators, serotonin-norepinephrine reuptake inhibitors, and dopamine-norepinephrine reuptake inhibitors); the physician must balance clinical need with risk.

Sexual dysfunction (especially difficulty achieving orgasm, decreased libido, and erectile dysfunction) occurs in one-third or more patients. Some SSRIs cause weight gain. Others, especially fluoxetine, cause loss of appetite during the first few months. SSRIs have small anticholinergic, adrenolytic, and cardiac conduction effects. Sedation is minimal or insignificant, but some patients experience daytime sleepiness during the first weeks of treatment. Loose stools and diarrhea occur in some patients.

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

Serotonin modulators (5-HT blockers)

These drugs block predominantly 5-HT receptors and inhibit the reuptake of 5-HT and norepinephrine. Serotonin modulators include nefazodone, trazodone, and mirtazapine. Serotonin modulators have antidepressant and anxiolytic effects and do not cause sexual dysfunction. Unlike most antidepressants, nefazodone does not suppress REM sleep and promotes a feeling of rest after sleep. Nefazodone significantly interferes with the work of liver enzymes involved in drug metabolism; its use is associated with liver failure.

Trazodone is closely related to nefazodone but does not inhibit presynaptic 5-HT reuptake. Unlike nefazodone, trazodone causes priapism (in 1 in 1000 cases) and, as a norepinephrine blocker, can cause orthostatic (postural) hypotension. It has pronounced sedative properties, so its use in antidepressant doses (>200 mg/day) is limited. It is most often prescribed in doses of 50-100 mg before bedtime in depressed patients with insomnia.

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

Serotonin and norepinephrine reuptake inhibitors

Such drugs (eg, venlafaxine, duloxetine) have a dual mechanism of action on 5-HT and norepinephrine, similar to 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 its low protein binding and virtually no interaction with liver enzymes involved in drug metabolism, it has a low risk of interactions when co-administered with other drugs. However, withdrawal symptoms (irritability, anxiety, nausea) are common when the drug is suddenly discontinued. Duloxetine is similar to venlafaxine in its efficacy and side effects.

Dopamine-norepinephrine reuptake inhibitors

Through mechanisms that are not fully understood, these drugs positively affect catecholaminergic, dopaminergic, and noradrenergic functions. These drugs do not act on the 5-HT system.

Bupropion is currently the only drug in this class. It is effective in depressed patients with concomitant attention deficit hyperactivity disorder, cocaine dependence, and in those trying to quit smoking. Bupropion causes hypertension in a very small number of patients and has no other cardiovascular effects. Bupropion may precipitate seizures in 0.4% of patients taking more than 150 mg 3 times daily [or 200 mg sustained release (SR) twice daily, or

450 mg extended-release (XR) once daily]; the risk is increased in patients with bulimia. Bupropion has no sexual side effects and few drug interactions, although it inhibits the liver enzyme CYP2D6. Agitation, which is quite common, is reduced by using the slow-release or extended-release forms. Bupropion may cause dose-related impairment of short-term memory, which recovers with dose reduction.

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Heterocyclic antidepressants

This group of drugs, which previously formed 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 primarily norepinephrine and, to a certain extent, 5-HT, blocking their reuptake in the synaptic cleft. A long-term decrease in the activity of alpha-adrenergic receptors of the postsynaptic membrane is probably a common result of their antidepressant activity. Despite their ineffectiveness, these drugs are now rarely used, as they are toxic in overdose and have many side effects. The most common side effects of heterocyclic antidepressants are associated with their muscarinic blocking, histamine blocking and alpha-adrenolytic action. Many heterocyclics have pronounced anticholinergic properties and are therefore not suitable for use in the elderly, patients with benign prostatic hyperplasia, glaucoma, or chronic constipation. All heterocyclic antidepressants, especially maprotiline and clomipramine, lower the seizure threshold.

Monoamine oxidase inhibitors (MAOIs)

These drugs inhibit oxidative deamination of 3 classes of biogenic amines (norepinephrine, dopamine, and serotonin) and other phenylethylamines. MAOIs have little or no effect on normal mood. Their main value is their effectiveness when other antidepressants are ineffective (e.g., in atypical depression, when SSRIs fail).

The MAOIs marketed as antidepressants in the US (phenelzine, tranylcypromine, isocarboxazid) are irreversible and nonselective (inhibit MAO-A and MAO-B). They can cause hypertensive crises if sympathomimetic agents or foods containing tyramine or dopamine are taken concomitantly. This effect is called the cheese reaction, since ripened cheese contains a lot of tyramine. MAOIs are not widely used because of concerns about this reaction. More selective and reversible MAOIs (such as moclobemide, befloxatone), which block MAO-A, are not yet widely available in the US; these drugs rarely cause such interactions. To prevent hypertensive and febrile crises, patients taking MAOIs should avoid sympathomimetic agents (eg, pseudoephedrine), dextromethorphan, reserpine, meperidine, malt beer, champagne, sherry, liqueurs, and certain foods containing tyramine or dopamine (eg, bananas, beans, yeast extracts, canned figs, raisins, yogurt, cheese, sour cream, soy sauce, salted herring, caviar, liver, heavily marinated meats). Patients should carry chlorpromazine 25 mg tablets and take 1 or 2 tablets as soon as signs of a hypertensive reaction appear before reaching the nearest emergency department.

Common side effects include erectile dysfunction (less common with granylcypromine), anxiety, nausea, dizziness, swelling of the legs, and weight gain. MAOIs should not be used with other classical antidepressants; at least 2 weeks (5 weeks for fluxetine, as it has a long half-life) should pass between taking the drugs of the two classes. The use of MAOIs with antidepressants that affect the serotonin system (eg, SSRIs, nefazodone) may cause neuroleptic malignant syndrome (malignant hyperthermia, muscle breakdown, renal failure, seizures, and in severe cases, death). Patients taking MAOIs who require antiasthmatic, antiallergic treatment, local or general anesthesia should be treated by a psychiatrist and an internist, dentist, or anesthesiologist with experience in neuropsychopharmacology.

Selection and prescription of drugs for the treatment of depression

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

If one SSRI is ineffective, another SSRI may be used, but other classes of antidepressants are more likely to be effective. Tranylcypromine in high doses (20-30 mg orally twice daily) is often effective in refractory depression after successive use of other antidepressants; it should be prescribed by a physician experienced in the use of MAOIs. Psychological support for the patient and his or her loved ones is especially important in cases of refractory depression.

Insomnia, a common side effect of SSRIs, is treated by reducing the dose or adding a small amount of trazodone or another sedating antidepressant. Nausea and loose stools that occur early in treatment usually resolve, while severe headache does not always resolve, requiring a different class of drug. SSRIs should be discontinued if agitation occurs (most often with fluoxetine). If libido, impotence, or anorgasmia occur as a result of SSRIs, a dose reduction or a different class of drug may help.

Antidepressants

Preparation	Initial dose	Maintenance dose	Cautions
Heterocyclic			Contraindicated in patients with coronary artery disease, some arrhythmias, closed-angle glaucoma, benign prostatic hyperplasia, esophageal hernia; may cause orthostatic hypotension leading to falls and fractures; potentiate the effects of alcohol; increase blood levels of antipsychotics
Amitriptyline	25 mg 1 time	50 mg 2 times	Causes weight gain
Amoxapine	25 mg 2 times	200 mg 2 times	May cause extrapyramidal side effects
Clomipramine	25 mg 1 time	75 mg 3 times	Reduces seizure threshold at doses >250 mg/day
Desipramine	25 mg 1 time	300 mg 1 time	Not for use in patients under 12 years of age.
Doxepin	25 mg 1 time	150 mg 2 times	Causes weight gain
Imipramine	25 mg 1 time	200 mg 1 time	May cause excessive sweating and nightmares
Maprotiline	75 mg once a day	225 mg 1 time	-
Nortriptyline	25 mg 1 time	150 mg 1 time	Effective in the therapeutic window
Protriptyline	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 weight gain
IMAO			When taken together with SSRIs or nefazodone, serotonin syndrome may develop; hypertensive crises are possible when administered together with other antidepressants, sympathomimetic or other selective drugs, certain foods and drinks
Isocarboxazid	10 mg 2 times	20 mg 3 times	Causes orthostatic hypotension
Phenelzine	15 mg Zraza	30 mg 3 times	Causes orthostatic hypotension
Tranylcypromine	10 mg 2 times	30 mg 2 times	Causes orthostatic hypotension; has amphetamine-like stimulant effects, potential for abuse
SSRI
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 blood levels of theophylline, warfarin, clozapine
Paroxetine	20 mg 1 time 25MrCR1 time	50 mg 1 time per 62.5 MrCR1 time	Has a greater potential for interactions between active metabolites and TCAs, carbamazepine, antipsychotics, and type 1C antiarrhythmics than other SSRIs; may cause marked suppression of ejaculation
Sertraline	50 mg 1 time	200 mg 1 time	Among SSRIs, the highest incidence of loose stools
Citalopram	20 mg 1 time	40 mg 1 time per day	Reduces the potential for drug interactions due to lesser effect on CYP450 enzymes

Serotonin and norepinephrine reuptake inhibitors

Duloxetine	20 mg 2 times	30 mg 2 times	Moderate dose-dependent increase in systolic and diastolic blood pressure; may cause minor urinary disturbances in men
Venlafaxine	25 mg 3 times 37.5MrXR1 time	125 mg Zraza in 225MrXR1 times	Moderate dose-dependent increase in diastolic blood pressure Rarely, an increase in systolic blood pressure (not dose-dependent) Withdrawal symptoms when stopping rapidly

Serotonin modulators (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 liver failure
Trazodone	50 mg 3 times	100-200 mg 3 times a day	May 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 seizures;
	150MrSR1 times	450 mg XL 1 time	May interact with TCAs, increasing the risk of seizures; may cause
	150 mg XL 1 time		Dose-dependent impairments in recent memory

MAOIs - monoamine oxidase inhibitors, TCAs - tricyclic antidepressants, CR - continuous release, XR - extended release, 5-HT - 5-hydroxytryptamine (serotonin), SR - slow release, XL - extended release.

SSRIs, which tend to stimulate many depressed patients, should be given in the morning. If the full dose of a heterocyclic antidepressant is given before bed, there will be no increased sedation, daytime side effects will be minimized, and compliance will be improved. MAOIs are usually given in the morning or before lunch to avoid overstimulation.

Therapeutic response to most antidepressants is observed in 2-3 weeks (sometimes from day 4 to week 8). In the first episode of mild or moderate depression, antidepressants should be taken for 6 months, then gradually tapered over 2 months. If there has been a severe or repeated depressive episode or there is a pronounced risk of suicide, a dose that promotes complete remission should be taken during maintenance treatment. In psychotic depression, maximum doses of venlafaxine or heterocyclic antidepressants (eg, nortriptyline) should be prescribed for 3-6 weeks; If necessary, antipsychotics may be added (eg, risperidone, starting at 0.5-1 mg orally twice daily, gradually increasing to 4-8 mg once daily, olanzapine, starting at 5 mg orally once daily and gradually increasing to 10-20 mg once daily, quetiapine, starting at 25 mg orally twice daily and gradually increasing to 200-375 mg orally twice daily). To prevent the development of tardive dyskinesia, the antipsychotic should be prescribed at the minimum effective dose and discontinued as soon as possible.

Maintenance antidepressant therapy for 6 to 12 months (up to 2 years in patients over 50) is usually necessary to prevent relapses. Most antidepressants, especially SSRIs, should be tapered gradually (25% dose reduction per week) rather than abruptly; sudden withdrawal of SSRIs can lead to serotonin syndrome (nausea, chills, muscle pain, dizziness, anxiety, irritability, insomnia, fatigue).

Herbal remedies are used by some patients. St. John's wort may be effective for mild depression, although the evidence is conflicting. St. John's wort may interact with other antidepressants.

Electroconvulsive therapy in the treatment of depressive disorder

Electroconvulsive therapy is often used in the treatment of severe depression with suicidal thoughts, depression with agitation or psychomotor retardation, depression during pregnancy, and in cases where previous therapy has been ineffective. Patients who refuse to eat require electroconvulsive therapy to prevent death. Electroconvulsive therapy is also effective in psychotic depression. The effectiveness of 6-10 sessions of electroconvulsive therapy is high, and this method can be life-saving. Exacerbations may occur after electroconvulsive therapy, so maintenance drug therapy is necessary after the end of electroconvulsive therapy.

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Phototherapy in the treatment of depressive disorder

Phototherapy may be used in patients with seasonal depression. Treatment can be done at home using 2500-10,000 lux lamps at a distance of 30-60 cm for 30-60 min per day (longer with less intense light sources). For patients who go to bed late at night and wake up late in the morning, phototherapy is most effective in the morning, sometimes with an additional exposure of 5-10 min between 3 and 7 p.m.