Pharmacological Treatment of Depression

Citalopram

• Dosage is 20-40 mg once daily, generally taken in the morning. For the elderly, the initial dose is 10 mg and the maintenance dose is 20 mg.
• Not for patients with prolonged QT interval, and not to be combined with drugs that prolong QT interval.
• Half-life is about 36 h.
• There are no significant interactions with other drugs, although when used concomitantly with some neuroleptics an increase in citalopram concentration has been observed, which is of no apparent practical significance.
• Caution should be exercised in the treatment of patients with epilepsy.

Escitalopram

• Escitalopram is the S-enantiomer of citalopram, and it is a highly specific inhibitor of serotonin reuptake.
• Dose is 10-20 mg once daily, generally taken in the morning.
• Half-life is about 30 h.
• There are no significant interactions with other drugs, although when used concomitantly with some neuroleptics an increase in citalopram concentration has been observed, which is of no apparent clinical significance.
• Caution should be exercised in the treatment of patients with epilepsy.
• Not for patients with prolonged QT interval, and not to be combined with drugs that prolong QT interval.

Fluoxetine Fluoxetine Versus other Types of Pharmacotherapy for Depression

• Dose for depression is 20-40 mg per 24 h, divided into 1-2 doses to be taken in the morning and during the day. The dose for bulimia is 60 mg per 24 h, generally as a single dose in the morning.
• Half-life is 2-4 days; the half-life of the active metabolite is considerably longer.
• Renal or hepatic insufficiency can increase the half-life of fluoxetine.
• When switching to MAO inhibitors a "wash out" period of at least 5 weeks is needed.
• Increases considerably the concentrations of many drugs that are metabolized by the liver, e.g. tricyclic antidepressants, long-acting benzodiazepines, carbamazepine and valproate.
• Quinidine may significantly increase the concentration of fluoxetine.

Fluvoxamine

• Dose is 100-200 mg, up to 300 mg per 24 h.
• Doses exceeding 150 mg are usually divided into 2-3 doses. The starting dose is taken in the evening.
• Average half-life is 20 h.
• Adverse effects of Fluvoxamine are those typical for this drug group, i.e. nausea, vomiting, insomnia or drowsiness, headache, tremor and dizziness.
• Slows the clearance of drugs that are metabolized by the liver. Has significant interactions with e.g. melatonin, beta-blockers, haloperidol, phenytoin, quinidine and warfarin.
• May increase the plasma concentrations of tricyclic drugs.
• Raised liver enzymes and creatinine have been documented.
• Caution should be exercised in the treatment of patients with epilepsy as susceptibility to seizures may increase.

Paroxetine Paroxetine Versus other Anti-Depressive Agents for Depression

• The initial dose is 20 mg in the morning. The dose may be increased in increments of 10 mg up to 50 mg. Maximum of 40 mg for patients over 65 years of age. Safe dose for those with liver or renal malfunction is about 20 mg per 24 h. Not to be used in children or adolescents due to an increased risk of self-destructive or hostile behaviour.
• Half-life of Paroxetine averages at 24 h but varies individually.
• Interactions with numerous antidepressants, phenothiazine-type antipsychotic drugs, warfarin, cimetidine, antiarrhythmic drugs belonging to class 1A and 1C (quinidine, flecainide), phenytoin and other antiepileptics.

Sertraline

• The initial dose is 50 mg once a day, morning or evening. If necessary, the dose may be increased gradually over several weeks up to 200 mg.
• Half-life averages at 26 h.
• No particular effect on psychomotor performance.
• Sertraline does not significantly affect the clearance of drugs metabolized by the liver.
• May have minor interactions with some drugs, e.g. the dose of lithium should be kept as small as possible; also, INR value should be monitored during warfarin treatment as it may increase.
• Caution should be exercised in the treatment of patients with epilepsy.

Moclobemide

Agomelatin Agomelatine Versus other Antidepressive Agents for Major Depression

• Chronobiological drug that stimulates melatonin receptors (MT1 and MT2) and inhibits serotonin receptor 5-HT_2C
• Therapeutic dose in the treatment of depression is 25 mg at bedtime.
• After 2 weeks the dose may be increased to 50 mg if the patient's condition has not improved.
• The drug is not recommended for patients less than 18 years of age and it must not be used in patients over 74 years of age.
• Agomelatin must not be used in patients with liver failure or in patients whose plasma aminotransferase (AST/ALT) concentrations are more than 3 times the upper limit of the normal range.
• Before the treatment is started the patient must be informed about the symptoms of liver damage and advised to immediately stop the medication if such symptoms should appear.
• Liver function tests are required before the treatment is started, then at 3 and 6 weeks and 3 and 6 months after the outset, always when the dosage is increased applying the same time intervals as at outset, and otherwise as necessary. If aminotransferase levels increase, they must be determined again within 48 hours. The use of agomelatin has to be discontinued if clinical signs of liver dysfunction appear or if the plasma concentration of liver aminotransferases is more than 3 times the upper limit of the normal range. The normalization of the concentrations has to be ensured with repeated follow-up tests.
• Special attention must be paid to patients with overweight, heavy alcohol use, other medications increasing the risk of liver damage, fatty liver, diabetes, or other factors predisposing to liver damage.
• There are interactions especially with drugs that inhibit the enzymes CYP1A2 (e.g. oestrogens, propranolol, grepafloxacin, enoxacin) and CYP2C9/19. The use of agomelatin is especially contraindicated concomitantly with strong CYP1A2 inhibitors (e.g. fluvoxamine and ciprofloxacin).
• Adverse effects include e.g. nausea, dizziness, drowsiness and anxiety.
• Adverse effects that are typical for many other antidepressants, such as sexual dysfunction, weight gain or cardiovascular harms, are not seen with agomelatin.

Bupropion

• Selective noradrenaline and dopamine reuptake inhibitor, with only marginal effect on serotonin reuptake and no effect on either of the two monoamine oxidases
• Initial dose in the treatment of depression is 150 mg. The drug may cause insomnia, and it should be taken well before bedtime.
• The drug starts to show effect 14 days after the initiation of treatment. If there is no improvement in 4 weeks with the 150 mg dose, the dose may be increased to 300 mg once daily. There should always be an interval of 24 hours between the doses. The treatment should be continued for at least 6 months in order to prevent recurrence of depression.
• The treatment should be discontinued with care because of possible rebound or withdrawal symptoms.
• If the patient has a mild to moderate hepatic or renal failure, the recommended daily dose is 150 mg.
• Bupropion has an eliminatory half-life of approximately 20 hours, but some of the metabolites may have half-lives up to almost twice as long.
• The drug must not be prescribed to patients less than 18 years of age. Some elderly patients may be exceptionally sensitive to the effects of bupropion.
• The drug should be discontinued if the patient experiences seizures during the treatment.
• Contraindications include in particular susceptibility to seizures for any reason, a CNS tumour, liver cirrhosis, actual or a history of bulimia or anorexia nervosa as well as use of a MAO inhibitor.
• Caution is required if the patient is concurrently on any medication that lowers the threshold for seizures. Even severe hypersensitivity reactions have been described in patients using bupropion. Special carefulness is required with patients who have cardiovascular diseases, and their blood pressure should be controlled at the start and during the treatment.
• The patients should be carefully followed up due to the potential danger of suicide especially at the initial phase of treatment.
• Bupropion inhibits the CYP2D6 enzyme system and thus has interactions with drugs that use the same metabolic route. Enzyme inhibition lasts for at least one week after the intake of the last dose. Caution is required with patients who are on levodopa or amantadine. Alcohol should not be used during bupropion treatment. When the drug is used concurrently with a nicotine patch it raises blood pressure.
• During pregnancy, bupropion should only be used on especially weighty grounds, and the mother must not breast-feed when using the drug.
• The most common adverse effects include insomnia and headache. Others include e.g. hypersensitivity reactions, restlessness, anxiety, depression, anorexia, dizziness, tremor, concentration difficulties, disturbances of taste, blood pressure increase that may sometimes even be severe, blushing, sweating, skin rash, itching, chest pain, fever, lack of strength, dryness of the mouth and abdominal symptoms.

Duloxetine Duloxetine Versus other Anti-Depressive Agents for Depression

• Serotonin and noradrenalin reuptake inhibitor, also a weak dopamine reuptake inhibitor. No significant effect on histaminergic, dopaminergic, cholinergic or adrenergic receptors.
• Other indications: generalized anxiety disorder and treatment of diabetic neuropathic pain in adults
• Starting dosage is 60 mg a day, maximal dosage 120 mg a day divided in equal doses.
• Treatment response is usually reached within 2 to 4 weeks. There is no clinical evidence that a bigger dose would improve the response, if no response was achieved with the starting dosage.
• The dose does not usually have to be adjusted when treating elderly people, but care must be taken especially when maximal dose (120 mg) is used.
• Adverse effects include nausea, dryness of the mouth, constipation, sleeplessness, sleepiness and dizziness.
• Not for children or adolescents
• Not during pregnancy or lactation
• Not for patients suffering from liver insufficiency or severe renal insufficiency
• Not to be combined with strong CYP₁A₂-inhibitors like fluvoxamine, ciprofloxacin, enoxacin
• Concomitant use of quinidine may increase the concentration of duloxetine.
• Not together with MAO-inhibitors

Mianserin

• Causes fewer adverse effects than tricyclic drugs.
• Usually taken in the evening.
• Considerable but transient fatigue, which sometimes presents at the early stages of treatment, may discourage compliancy.
• Has not caused lethal intoxications.
• Adverse effects
  • Because of reports of bone marrow depression, which were mainly cases of agranulocytosis and granulocytopenia, patients are advised to see their physician immediately should signs of infection appear. Previous recommendation was to routinely check leucocytes on weeks 4 and 6 after starting treatment.
  • Quinidine may significantly increase the concentration of mianserin.

Milnacipran (available only with special permit)

• Serotonin and noradrenaline reuptake inhibitor
• Usually administered 50 mg twice daily (morning and evening).
• Dose should be decreased in renal insufficiency.
• Half-life about 8 h. Steady state will be achieved after 2-3 days.
• Eliminated mainly unchanged, via the renal route. Hepatic insufficiency does not significantly affect the pharmacokinetics of the drug.
• In sleep disorders and anxiety, symptomatic treatment is generally needed.
• It always is important to be careful with suicidality. Patient's psychomotor activity may increase before depression has alleviated.
• Must not be used
  • with MAO-inhibitors, triptanes (especially sumatriptan), digoxin, epinephrine, norepinephrine, clonidine and similar drugs
  • in prostatic hyperplasia and other urogenital diseases
  • during pregnancy and lactation.
• The most usual adverse effects of milnacipran include dizziness, hyperhidrosis, anxiety, hot flushes and dysuria. Also nausea, vomiting, anticholinergic adverse effects, tremor, palpitations and agitation may occur. Cardiovascular adverse effects occur more often in those with coexisting cardiovascular diseases.

Mirtazapine

• Starting dose is 15 mg, which is then slowly increased as needed. 15-45 mg is the average effective dose. The dose for the elderly is the same as that for adults, but the response and possible adverse effects should be closely monitored.
• The drug is usually taken as a single dose at bedtime or sometimes in equally divided doses in the morning and the evening.
• The treatment response is likely to be best when the symptoms include features of the somatic syndrome of depression: anhedonia, psychomotor inhibition, sleep disorders, lack of interest, suicidal thoughts and a better mood in the evening than in the morning.
• Half-life, which is 20-40 h, is lengthened by renal or hepatic insufficiency.
• Mirtazapine may increase the effects of alcohol and benzodiazepines.
• Must not be used with MAO inhibitors.
• May impair concentration and alertness.
• Adverse effects include: increased appetite and weight, fatigue, (orthostatic) hypotension, mania, seizure attacks, tremor, myoclonus, oedema, acute bone marrow depression, increased plasma level of aminotransferases and exanthema.

Reboxetine (available only with special permit)

• Reboxetine is a selective and potent noradrenaline reuptake inhibitor. The drug also acts as a very weak serotonin reuptake inhibitor.
• The initial dose for adults is 4 mg twice daily. The daily dose can be increased up to 10 mg after 3-4 weeks. The maximum daily dose is 12 mg. The drug should not be used in the elderly.
• The drug is activating rather than hypnotic.
• Adverse effects include dryness of mouth, constipation, insomnia and hyperhidrosis.
• The drug is not suitable for patients with epilepsy or those with severe somatic diseases. Caution is warranted if used for patients with benign prostatic hyperplasia, glaucoma and cardiac diseases.
• The drug should be used cautiously with drugs that are metabolized through enzymes other than CYP₂D₆.
• Should not be combined with MAO inhibitors.
• Contraindicated during pregnancy and lactation
• The effectiveness of the drug has not been reliably verified through research.

Sulpiride

• A neuroleptic with an antidepressant effect
• The most effective adult dose is between 50-400 mg daily.
• Administered in the morning and daytime because an evening dose may cause sleep disorders.
• Adverse effects include milk secretion caused by increased prolactin secretion, increased appetite and weight gain, and occasional motor restlessness (akathisia).
• Tardive dyskinesia may develop during long-term use, particularly in the elderly. If it persists for a prolonged period it may become permanent. Smacking of the lips is usually the first sign of tardive dyskinesia. It is usually reversible upon immediate discontinuation of sulpiride.

Trazodone

• Indicated for patients with mild to moderate depression and for whom tricyclic antidepressants are not suitable.
• Cardiovascular effects are milder compared with tricyclic antidepressants.
• Adverse effects of trazodone include orthostatic hypotension and priapism.
• Maximum dose is 600 mg per 24 h divided into three doses.

Venlafaxine

• Venlafaxine is started with the smallest possible dose. The usual initial dose is 75 mg once daily, which is also the usual therapeutic dose. If necessary, the dose may be increased by 75 mg at a minimum of 2-week intervals up to 225 mg or, in severely depressed patients, up to 375 mg. The maximum recommended dose is 125 mg three times daily. Particular caution and care should be exercised in the treatment of the elderly.
• Treatment should be withdrawn cautiously and with decreasing doses over at least 2 weeks. Withdrawal symptoms may include nausea, dizziness, headache, sleep disorders, general malaise, anxiety and muscle spasms.
• Must not be used together with MAO inhibitors.
• May raise blood pressure, which is why routine blood pressure monitoring is recommended for all patients on venlafaxine. Particular caution should be exercised with cardiac patients, even though sudden cardiac deaths appear to be no more common among venlafaxine users than in patients using some other antidepressants.
• Regular check-ups are necessary for patients with disturbances in micturition, acute angle-closure glaucoma, raised intraocular pressure, low blood pressure or cardiac complaints. The depressive period of manic-depressive psychosis may change to mania during venlafaxine treatment.
• Possible adverse effects include dizziness, insomnia, drowsiness, nervousness, GI-tract symptoms, headache, cardiovascular symptoms (including increased blood pressure), increased appetite and weight gain, CNS symptoms, accommodation disturbances, increased voiding frequency, sexual disturbances, sweating and weakness.
• Venlafaxine should be stopped at least 1 week before switching to MAO inhibitors.
• There are interactions with many drugs that are metabolized by the liver, such as quinidine, paroxetine, erythromycin, verapamil and cimetidine.

Vortioxetine Vortioxetine for Depression in Adults

• Vortioxetine is indicated for the treatment of severe depressive disorders.
• The mechanism of action is supposed to be based on modulation of serotonergic receptor function and on inhibition of serotonin transport.
• The initial dose for patients 18 to 65 years of age is 10 mg. This can be modified according to treatment response and increased up to 20 mg per day. The efficacy and safety of vortioxetine in the treatment of patients less than 18 years of age has not been confirmed. In patients over 65 years of age, the initial dose must always be 5 mg, and doses over 10 mg require particular caution.
• The peak concentration of vortioxetine is reached within 7 to 11 hours, the elimination half-life is 66 hours, and a steady-state concentration is achieved in about two weeks.
• The medication can be abruptly discontinued without gradual tapering.
• Adverse effects include e.g. nausea and vomiting, diarrhoea or constipation, pruritus, dizziness and abnormal dreams. Night sweats are a rather rare adverse effect.
• The frequency of sexual disturbances has been at the same level as with placebo at doses of 5 to 15 mg, but they are more frequent than with placebo when the dose is 20 mg.
• Concomitant use with e.g. duloxetine, fluoxetine, paroxetine, lithium, tryptophan, bupropion, St. John's wort, anticoagulants, platelet inhibitors or quinidine should be avoided.
• It may be necessary to adjust the dose of vortioxetine when used concomitantly with a broad cytochrome P450 inductor (e.g. rifampicin, carbamazepine or phenytoin).
• Dose adjustment is not needed in association with CYP3A4 and CYP2C9 inhibitors (ketoconazole, fluconazole).
• The concomitant use of vortioxetine together with non-selective MAO inhibitors and with selective MAO-A inhibitors is contraindicated.
• Convulsive seizures are possible, particularly if vortioxetine is used concomitantly with drugs that lower the seizure threshold (antidepressants, antipsychotic drugs, mefloquine and bupropion). Particular caution is required when treating patients with epilepsy.
• Concomitant use of vortioxetine with serotonergic drugs (e.g. tramadol, triptans), drugs that inhibit serotonin metabolism (MAO inhibitors), antipsychotic drugs or other dopamine antagonists may lead to potentially life-threatening serotonin or neuroleptic malignant syndrome Neuroleptic Malignant Syndrome (Nms).
• Particular caution is required when treating patients with bipolar disorder, and the medication must be immediately discontinued should hypomanic or manic symptoms appear.
• Abnormal bleeding or hyponatraemia may occur.
• Particular attention must be paid when treating patients with liver or kidney failure.
• Vortioxetine should not be used during pregnancy or breastfeeding if its use is not absolutely necessary.

St. John's wort

• St. John's wort (Hypericum perforatum) extract is more effective than placebo and appears to be similarly effective as standard antidepressants for treating mild to moderate depressive symptoms St John's Wort for Major Depression.
• The extract may lower the serum concentration and thus the efficacy of concomitantly used drugs such as ciclosporin, digoxin, oral contraceptives, theophylline, warfarin, and indinavir. Patients using these drugs should not use St. John's wort products. Check also local recommendations.