Antidepressants

Contents of antidepressants

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1. Introduction to Antidepressant drugs

2. Classes of antidepressant drugs

Tricyclic and related antidepressant drugs
MonoamineOxidase Inhibitirs (MAOIs)
Selective Serotinin Reuptake Inhibitors (SSRIs)
Other antidepressant drugs.

3. Mechanisms of actions of antidepressants

4. Common side effects of antidepressants

5. Tricyclic and related antidepressant drugs

Amitriptyline Hydrochloride
Amoxapine
Clomipramine Hydrochloride
Dosulepin Hydrochloride
Doxepin
Imipramine Hydrochloride
Lofepramine
Nortriprtyline
Trimipramine

6. Monoamine Oxidase Inhibitors

Phenelzine
Isocarboxazid
Tranylcypromine
Moclobemide

7. Selective Serotonin Reuptake Inhibitors

Citalopram
Escitalopram
Fluoxetin
Fluvoxamine maleate
Paroxetine
Sertraline

8. Other antidepressant drugs

Flupentixol
Mirtazapine
Reboxetine
Tryptophan
Venlaflaxine

9. Drug interactions

Drugs interactions with Tricyclic and related antidepressant drugs
Drugs interactions with MonoamineOxidase Inhibitirs (MAOIs)
Drugs interactions with Selective Serotinin Reuptake Inhibitors (SSRIs)
Drugs interactions with other antidepressant drugs.

10. New developments

Introduction to Antidepressant drugs

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Antidepressant drugs are effective in the treatment of major depression ofmoderate and severe degree including major depression associated with physical illness and that following child birth; they are also effective for dysthymia (low grade chronic depression).antidepressant drugs are not generally effective in milder forms of acute depression but trial may be considered in cases of refractory to psychological treatment.

Choice of antidepressant should be based on the individualpatient’srequirements, including the presence of concomitant diseases, exixting therapy, suicide risk, and previous response to antidepressant therapy.

Either trycyclic and related antidepressants or SSRIs are generally preferred because MAOIs may be less effective and show dangerous interaction with some foods and drugs.

Patient should be reviewed every 1-2 weeks at the start of anideprassant treatment. Treatment should be continued for at least 4 weeks (6 weeks in elderly) before considering whether to switch antidepressant due to lack of efficiency.

Following remission, antidepressant treatment should be continued at the same dose for at least 4-6 months (about 12 months in elderly).

Failure to respond to an initial course of antidepressant, may be necessitate an increase in the dose, switching to a different antidepressant class, or in patient with ‘atypical’ major depression, the use of a MAOIs. Failure to respond to a second antidepressant may require the addition of an augmenting drug such as lithium or liothyronine.

Tricyclic and related antidepressant drugs

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This section covers tricyclic antidepressants(TCA) and also 1-, 2-, and 4-ring structured drugs with broadly similar properties.

These drugs are most effectve for treating moderate to severe endogenous depression associated with psychomotor and psychological changes such as loss of appetite and sleep disturbances; improvement in slepp is usually the first benefit of therapy. Since there may be an interval of 2 weeks before the antidepressant action takes place electroconvulsive treatment may be required in severe depression when delay is hazardous or intolerable.

Some tricyclic antidepressants are also effective in the management of panic disorders as well.

About 10 to 20% of patients fail to respond to tricyclic and related antidepressant drugs and inadequate dosage may be account for some these failures. It is important to use doses that are sufficiently high for effectve treatment but not so high as to cause toxic effects. Low doses should be used for initial treatment in the elderly.

TCA and related antidepressant drugs can be roughly divided into those with additional sedative properties and those which are less so. Agitated and anxious patients tent to respond best to the sedative compounds whereas withdrawn and apathetic patients will often obtain most benefit from the less sedative ones.

Common TCAs are;

1. Amitriptyline Hydrochloride
2. Amoxapine
3. Clomipramine Hydrochloride
4. Dosulepin Hydrochloride
5. Doxepin
6. Imipramine Hydrochloride
7. Lofepramine
8. Nortriprtyline
9. Trimipramine

Related antidepressants are;

1. Maprotiline Hydrochloride
2. Mianserin Hydrochloride
3. Trazodone Hydrochloride

MonoamineOxidase Inhibitirs (MAOIs)

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Monoamine oxidase inhibitors are used much less frequently than tricyclic and related antidepressants, or SSRIs and related antidepressants because of the dangers of dietary and drug interactions and the fact that it is easier to prescribe MAOIswhen tricyclic antidepressants have been unsuccessful than vice versa.

Phobic patients and depressed patients with atypical, hypochondriacal, or hysterical features are said to respond best to MAOIs. However, MAOIs should be tried in any patients who are refractory to treatment with other antideoressants as there is occasionally dramatic response.

MAOis inhibits monoamine oxidase, thereby causing an accumulation of amine neurotransmitters. The metabolism of some amine drugs such as interact acting sympathomimetics is also inhibited and their pressor action may be potentiated.

Other antidepressants should notbe started for 2 weeks after treatment with MAOIs has been stopped. Conversely, a MAOIs should not be started for at least 2 weeks after a previous MAOI has been stopped.

Common MAOIs are;

1. Phenelzine
2. Isocarboxazid
3. Tranylcypromine
4. Moclobemide

Selective Serotinin Reuptake Inhibitors (SSRIs)

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This is a newer class of antidepressants. SSRIs should be used with caution in patients with epilepsy (avoid if poorly controlled, discontinue if convulsuin develop), concurrent electroconvulsive therapy (prolonged seizures reported with fluoxetin), history of mania, cardiac disease, diabetes mellitus, angle closure glaucoma, concomitant use of drugs that increase risk of bleeding, history ofbleeding disorders 9especially gastrointestinal bleeding), hepatic and renal impairment, pregnancy and breast feeding.

Common SSRIs are;

1. Citalopram
2. Escitalopram
3. Fluoxetin
4. Fluvoxamine maleate
5. Paroxetine
6. Sertraline

Other antidepressant drugs

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Serotonin-norepinephrine reuptake inhibitors (SNRIs)
Noradrenergic and specific serotonergic antidepressants (NASSAs)
Norepinephrine (noradrenaline) reuptake inhibitors (NRIs)
Norepinephrine-dopamine reuptake inhibitors (NDRIs)

1. Flupentixol
2. Mirtazapine
3. Reboxetine
4. Tryptophan
5. Venlaflaxine

Mechanisms of actions of antidepressants

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Mechanism of actions of antidepressants is based on a theory which explains why depressant occurs. According to the theory, there is a low level of monoamine in the brain in depressed persons. Main monoamines found in the brain are dopamine, noradrenalin and serotonin. Even though there are lots of monoamine found in the brain, these are the main monoamine related to depression.

Therefore any chemical compound which is capable of increasing monoamine level in the brain will be an antidepressant. Followings are the main methods of increasing monoamine in the brain;

prevention of reuptake of monoamine into synaptic nerve endings from synaptic cleft (tricyclic antidepressants)
prevention of serotonin reuptake into synaptic nerve endings from synaptic cleft (SSRI)
prevention of noradrenalin and serotonin reuptake into synaptic nerve endings from synaptic cleft (SNSRI)
prevention of noradrenalin and serotonin reuptake into synaptic nerve endings from synaptic cleft and serotonin (5HT2A) receptor antagonists (Nefazodone, Trazodone).
prevention of monoamine destruction (MAOI)

Common side effects of antidepressants

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1. withdrawal

gastrointestinal symptoms of nausea, vomiting and anorexia, accompanied by headache, giddiness, chills and insomnia, and sometimes by hypomania, panic-anxiety, and extreme motor restlessness may occur if an antidepressant (particularly MAOIs) is stopped suddenly after regular administration for 8 weeks or more. Therefore the dose should preferably be reduced gradually over about 4 weeks.

2. Cardiovascular side effects

Arrhythmias and heart block (tricyclic and relate antidepressants)

3. Central nervous system side effects

Convulsion (tricyclic and relate antidepressants)

4. Hepatic and renal effects

5. Other side effects

Amitriptyline Hydrochloride

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structure of the amitriptyline

Indications

Depressive illness, particularly where sedation is required.
Nocturnal enuresis in children.

Cautions to be considered

cardiac diseases (arrhythmias)
Epilepsy
Pregnancy and breast feeding.
Elderly
Hepatic impairment
Thyroid diseases
Phaeochromocytoma
History of mania
Angle closure glaucoma
History of urinary retention

Contraindications (where you have to avoid Amitriptyline)

recent myocardial infarction
arrhythmias (particularly heart block)
severe liver disease

Side-effects

Dry mouth
sedation
blurred vision
constipation
cardiovascular side-effects (ECG changes, arrythmias)
syncope
behavioral disturbances
interference with sexual function
testicular enlargement
gynaecomastia

Dose

Depression; initially 75mg (elderly and adolescents 30-75mg)daily in divided doses or as a single dose at bed time increased gradually as necassary to 150-200mg; child under 16 years not recommended fordepression.
Nocturnal enuresis; child 7-10years 10-20mg: 11-16years 25-50mgat night. maximum period of treatment (including gradual withdrawal) 3 months, need a full physical examination before further course.

Amitriptyline preparations

tablets, coated, amitriptyline hydrochloride 10mg.
oral solution, amitriptyline hydrochloride 25mg/5ml.

Amoxapine

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structure of the amoxapine

Indications

depressive illness

Cautions to be considered

cardiac diseases (arrhythmias)
Epilepsy
Pregnancy and breast feeding.
Elderly
Hepatic impairment
Thyroid diseases
Phaeochromocytoma
History of mania
Angle closure glaucoma
History of urinary retention

Contraindications (where you have to stop the drug)

recent myocardial infarction
arrhythmias (particularly heart block)
severe liver disease

Side-effects

tardive dyskinesia
menstrual irregularities
breast enlargement
galactorrhoea in women
Dry mouth
sedation
blurred vision
constipation
cardiovascular side-effects (ECG changes, arrythmias)
syncope
behavioral disturbances
interference with sexual function
testicular enlargement
gynaecomastia

Dose

Initially 100-150mgdaily in divided doses or as a single dose at bedtime increased as necessary to maximum300mg daily; ELDERLY initially 25mg twice daily increased as necessary after 5-7 days to maximum 50mg three times daily: CHILD under 16 years not recommended.

Amoxapine preparation

tablets, amoxapine 50mg (orange, scored)

Clomipramine Hydrochloride

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Indications

depressive illness
phobic and obsessional states
adjuvant treatment of cataplexy associated with narcolepsy

Cautions to be considered

cardiac diseases (arrhythmias)
Epilepsy
Pregnancy and breast feeding.
Elderly
Hepatic impairment
Thyroid diseases
Phaeochromocytoma
History of mania
Angle closure glaucoma
History of urinary retention

Contraindications (where you have to avoid the drug)

recent myocardial infarction
arrhythmias (particularly heart block)
severe liver disease

Doses

depressive illness

Initially 10 mg daily, increased gradually as necessary to 30 – 150 mg in divided doses or as a single dose at bed time; maximum dose 250 mg daily.
ELDERLY; initially 10 mg daily, increased carefully over approximately 10 days to 30-75 mg daily.
CHILD; not recommended.

Phobic and obsessional states

Phobic and obsessional states, initially 25 mg daily (elderly; 10 mg daily) increased over 2 weeks to 100-150 mg daily. CHILD not recommended.

adjuvant treatment of cataplexy associated with narcolepsy

initially 10 mg daily gradually increased until satisfactory response (range 10-75 mg daily)

Clomipramine preparation

1. capsules; 10 mg
2. tablets (slow release); 75 mg

Dosulepin Hydrochloride

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Indications

Depressive illness, especially where sedation is required.

Cautions to be considered

cardiac diseases (arrhythmias)
Epilepsy
Pregnancy and breast feeding.
Elderly
Hepatic impairment
Thyroid diseases
Phaeochromocytoma
History of mania
Angle closure glaucoma
History of urinary retention

Contraindications (where you have to avoid the drug)

recent myocardial infarction
arrhythmias (particularly heart block)
severe liver disease

Doses

Initially 75 mg (ELDERLY 50-75 mg) daily in divided doses or as a single dose at bed time. Increased gradually as necessary to 150 mg daily (ELDERLY 75 mg may be sufficient); up to 225 mg daily in some circumstances (eg. Hospital use). CHILD not recommended.

Dosulepin preparations

capsule; 25 mg
tablets; 75 mg

Doxepin

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Indications

Depressive illness, particularly where sedation is required.

Cautions to be considered

cardiac diseases (arrhythmias)
Epilepsy
Pregnancy and breast feeding.
Elderly
Hepatic impairment
Thyroid diseases
Phaeochromocytoma
History of mania
Angle closure glaucoma
History of urinary retention

Contraindications (where you have to avoid the drug)

recent myocardial infarction
arrhythmias (particularly heart block)
severe liver disease

Doses

Initially 75 mg daily in divided doses or as a single dose at bed time, increased as necessary to maximum 300 mg daily in three divided doses (up to 100 mg may be given as a single dose)

ELDERLY; initially 10-50 mg daily, range of 30-50 mg daily may be adequate

CHILD; not recommended

Doxepin preparations

1. capsule; 10 mg

Imipramine Hydrochloride (a Tricyclic antidepressant)

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Indications

1. depressive illness
2. nocturnal enuresis of children

Cautions to be considered

1. cardiac diseases (arrhythmias)
2. Epilepsy
3. Pregnancy and breast feeding.
4. Elderly
5. Hepatic impairment
6. Thyroid diseases
7. Phaeochromocytoma
8. History of mania
9. Angle closure glaucoma
10. History of urinary retention

Contraindications (where you have to avoid the drug)

1. recent myocardial infarction
2. arrhythmias (particularly heart block)
3. severe liver disease

Doses

1. depression

Initially up to 75 mg daily in divided doses increased gradually to 150-200 mg (up to 300 mg in hospitalized patients); up to 150 mg may be given as a single dose at bed time.

ELDERLY; initially 10 mg daily, increased gradually up to 30-50 mg daily.

CHID; not recommended for depression.

2. nocturnal enuresis

CHILD up to 7years 25 mg, 8-11 years 25-50 mg, over 11 years 50-75 mg at bed time. Maximum period of treatment (including gradual withdrawal) 3 months, full physical examination before further course.

Preparations

1. tablets, red brown, 10 mg and 25 mg.

Lofepramine (a Tricyclic antidepressant)

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Indications

1. depressive illness

Cautions to be considered

1. cardiac diseases (arrhythmias)
2. Epilepsy
3. Pregnancy and breast feeding.
4. Elderly
5. Hepatic impairment
6. Thyroid diseases
7. Phaeochromocytoma
8. History of mania
9. Angle closure glaucoma
10. History of urinary retention

Contraindications (where you have to avoid the drug)

1. recent myocardial infarction
2. arrhythmias (particularly heart block)
3. severe liver disease

Side-effects are lesser than that of other tricyclic antidepressants.

Doses

140-120 mg daily in divided doses.

ELDERLY; may respond to lower doses.

CHILD; not recommended.

Preparations

1. tablets; 70 mg, brown violet
2. oral suspension; 70mg/5ml.

Nortriprtyline (a Tricyclic antidepressant)

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Indications

1. depressive illness
2. nocturnal enuresis of children

Cautions to be considered

1. cardiac diseases (arrhythmias)
2. Epilepsy
3. Pregnancy and breast feeding.
4. Elderly
5. Hepatic impairment
6. Thyroid diseases
7. Phaeochromocytoma
8. History of mania
9. Angle closure glaucoma
10. History of urinary retention

Plasma level of the drug should be monitored if the dose is above 100 mg.

Contraindications (where you have to avoid the drug)

1. recent myocardial infarction
2. arrhythmias (particularly heart block)
3. severe liver disease

Doses

1. depression

Low dose initially increased as necessary to 75-100 mg daily in divided doses or single dose (max. 150 mg daily)

ADOLESCENT and ELDERLY; 30-50 mg daily in divided doses

CHILD; not recommended for depression

2. nocturnal enuresis

CHILD 7 years 10 mg, 8-11years 10-20 mg, over 11 years 25-35 mg, at night; maximum period of treatment (including gradual withdrawal) 3 months, full physical examination before further course.

Preparations

1. tablets; 10 mg, pink

Trimipramine (a Tricyclic antidepressant)

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Indications

1. depressive illnesses, particularly where sedation is required

Cautions to be considered

1. cardiac diseases (arrhythmias)
2. Epilepsy
3. Pregnancy and breast feeding.
4. Elderly
5. Hepatic impairment
6. Thyroid diseases
7. Phaeochromocytoma
8. History of mania
9. Angle closure glaucoma
10. History of urinary retention

Contraindications (where you have to avoid the drug)

1. recent myocardial infarction
2. arrhythmias (particularly heart block)
3. severe liver disease

Doses

Initially 50-75 mg daily in divided doses or as a single dose at bed time, increased as necessary to 150-300 mg daily.

ELDERLY; initially 10-25 mg three times daily, maintenance half adult dose may be sufficient.

CHILD; not recommended

Preparations

1. capsules; 50 mg, green/white
2. tablet; 10 mg

Phenelzine

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Isocarboxazid

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Tranylcypromine

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Moclobemide

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Citalopram

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Escitalopram

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Fluoxetin

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Fluvoxamine maleate

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Paroxetine

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Sertraline

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Flupentixol

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Mirtazapine

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Reboxetine

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Tryptophan

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Venlaflaxine

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Drugs interactions with TCAs

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Drugs interactions with MAOIs

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Drugs interactions with SSRIs

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Drugs interactions with other antidepressant drugs

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New developments

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