Depression is a common and normal emotion and people naturally become depressed as a result of unfortunate domestic and social conditions. Sometimes, depression may be disproportionate to the precipitating factors or there may be no obvious cause at all.
Environmental factors may at times play a more prominent part and this is sometimes called reactive depression or depression neurosis.
Sometimes depression may alternate with attacks of mania. This is known as bipolar depression or manic-depressive psychosis. In depression the mood is lowest in the morning and improves throughout the day.
The patient is disinterested, may be irritable and anxious. The appetite is poor and vague symptoms including headache and odd pains are common.
Brain Neurotransmitters and depression
There is evidence that reduction in the amount of neurotransmitter
amines such as 5-HT (5-hydroxytryotamine; serotonin) or norepinephrine
at the junctions between neurons in the brain; as a major cause of
Many of the drugs used to treat depression increase the amount of these substances in the brain, thus providing some evidence that amines are connected with the changes in mood.
Although both brain abnormalities and circadian rhythms have been implicated as factors in depression, the predominant theory states that depression is caused by insufficient activity of monaminergic neurons within the brain, this belief is called the Biological Amine Theory of Depression or the MonoAmine Hypothesis.
It attempts to explain clinical depression in terms of a chemical imbalance within the brain, the specific areas or structures involved are still unknown.
The goals of antidepressant therapy, for major depression and dysthymia, are short-term effectiveness in controlling acute episodes of major depression and the prevention of their reoccurrence.
Antidepressants are classified into various classes as follows.
- Tricyclic antidepressants
- Tricyclic anxiolytics
- Selective serotonin re-uptake inhibitors (SSRIs)
- Monoamine oxidase inhibitors (MAOIs)
- Other antidepressants
TCAs were first manufactured in the 1950s through the modification of phenothiazines ( a group of antipsychotics). They possess a three-ring nucleus. The first commercially available drug was Imipramine.
Other TCAs include
- protriptyline and
These drugs are mixed norepinephrine and serotonin reuptake inhibitors though they also have several other properties that contribute to their side effects.
They are well absorbed after oral administration and undergo considerable breakdown in the liver; some of these metabolic products are therapeutically active.
Believed that they produce their action by preventing the reuptake of amines at the nerve endings in the brain; which increases the concentration of these substances available for receptor uptake
Imipramine And Amitriptyline
Imipramine was the first of these drugs to be used, amitriptyline is very similar to imipramine but rather more sedating.
Both of these drugs have a long duration of action and are only administered once a day.
They are usually given in the evening for their sedative action to help in sleep, which is often disturbed by depression.
After starting treatment the sleep disorders associated with depression usually respond fairly quickly. It may take several weeks before the depression itself is relieved.
Treatment should be continued for 6 weeks before deciding that the treatment has failed. About 80% of depressed patients will ultimately respond.
Bed wetting – Imipramine is used for nocturnal enuresis (bed wetting) in children. The effect may be delayed for 2-3 weeks and treatment should not usually be given for more than 3 months.
Adverse Effects Of Tricyclic Antidepressants
- Anticholinergic effects – Dry mouth can be troublesome, may be reduced by taking lemon juice. An elderly male may experience difficulty in micturition and constipation.
- Postural hypotension – A fall in BP with occasional faintness especially in elderly patients.
- Increased appetite and weight gain.
- In epilepsy – the tendency to have seizures is increased and the dose of antiepileptics may require alteration if tricyclic antidepressants are used.
- Heart – Tricyclic antidepressants depress conduction in the heart, and a number of sudden cardiac death have been reported.
- Overdose – Tricyclic antidepressants are dangerous in overdose, producing cardiovascular disturbance, seizures, and coma.
- Withdrawal symptoms – Develop if the drug is stopped suddenly.
Doxepin and Dosulepin
They are similar to tricyclic antidepressants but have a weaker antidepressant action. They are particularly useful when anxiety complicates mild depression. They are more rapidly effective than tricyclic antidepressants.
Adverse effects are similar to the tricyclic antidepressants but they are generally less marked.
Monoamine Oxidase Inhibitors
A few years after inception, the tricyclics were followed by the MonoAmine Oxidase Inhibitors (MAO inhibitors). These can further be sub-classified as:
- i) Hydrazides g. phenelzine and isocarboxazid (no longer marketed)
- ii) Non-hydrazides g. tranylcypromine.
Tranylcypromine retains some sympathomimetic activities of amphetamines.
Mechanism of action
- They inhibit the enzyme MAO and thus interfere with the breakdown of epinephrine, norepinephrine, and 5-HT in the brain, which leads to the accumulation of these substances.
- They produce mood change with an increase in cheerfulness, energy and well being in about half of the patients with depression.
- The main use of MAOIs in atypical antidepression and phobic anxiety states.
These older generation MAO inhibitors are non-selective inhibitors of both MAO-A and MAO-B.
Phenelzine and Isocarboxazid
These are irreversible inhibitors (they bind to MAO and do not detach themselves from it, so that a new enzyme has to be biosynthesized.
A reversible inhibitor (it binds and inhibits the action of MAO, but detaches itself so that the enzyme can resume its normal function of metabolizing amines.
All three drugs are taken orally in tablet form.
They are initially given in twice or three times daily and the dose is reduced depending on the patient’s response.
Postural hypotension, insomnia, nervousness, difficulty in micturition and jaundice.
- They may exaggerate the effects of CNS acting drugs like alcohol, cocaine, morphine, pethidine.
- They lead to an overreaction by vasopressors like epinephrine and amphetamine. This may result in headaches, hypertension, restlessness, coma, and death.
- Similar effects may also occur if these MAOIs are taken with various foods; including cheese, meat, yeast extracts, some wines and beers, broad bean pods, etc. This is because these foods contain vasopressor substances that are normally broken down by MAO. If this breakdown is inhibited; these vasopressors accumulate and hence the adverse effects.
- It is dangerous to combine MAOIs with tricyclic antidepressants or 5-HT reuptake inhibitors. There should be a gap of 5 weeks between treatment with fluoxetine and MAOIs.
- Rare side effects of MAOIs like phenelzine (brand name: Nardil) and tranylcypromine (brand name: Parnate) include hepatitis, heart attack, stroke, and seizures.
Atypical antidepressants (Heterocyclics)
Also called atypical antidepressants. They are subclassified as follows:
i) Second-Generation Antidepressants-g amoxapine, maprotiline, trazodone, bupropion
ii) Third Generation Antidepressants-g. mirtazapine, venlafaxine, nefazodone
Selective Serotonin Reuptake inhibitors (SSRIs)
5-HT is concerned with mood and behavior and a deficiency of 5-HT in the brain is believed to be a factor in depression. These drugs specifically inhibit the reuptake of 5-HT at the nerve junctions thus raising its concentration in the brain.