Major depressive disorder (MDD) is a common and disabling illness that significantly reduces the
quality of life. It can strike anyone irrespective of age, race, gender or
socio-economic status. This disorder is characterized by low mood, low self
esteem and loss of interest in normally enjoyable activities.
It is believed
that MDD is caused by chemical changes in the brain due to a genetic problem.
The genetic problems are said to arise due to stressful events, cognitive and
environmental factors or even a combination of unknown causes.
The neural circuits in the brain responsible for the regulation
of moods, thinking, sleep, appetite, and behavior fail to function properly
leading to imbalance in the critical neurotransmitters, viz., serotonin,
norepinephrine, and dopamine present in the central nervous system which assist
in communication between nerve cells. Serotonin regulates other
neurotransmitter systems, therefore, decreased serotonin activity makes the
other systems act in erratic ways. Depression may arise when low serotonin
levels promote low levels of norepinephrine. This is the basis of 'monoamine
hypothesis' which postulates that a deficiency of certain neurotransmitters is
responsible for the corresponding features of depression -
- norepinephrine may be related
to alertness and energy as well as anxiety, attention, and interest in life;
- serotonin is related to
anxiety, obsessions, and compulsions; and
- dopamine is related to
attention, motivation, pleasure, and reward, as well as interest in life.
This hypothesis is supported by the mechanism of
action of antidepressants, that is, agents that elevate the levels of these
neurotransmitters in the brain are effective in the alleviation of depressive
studies have shown that the mood-enhancing effect of
monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake
inhibitors (SSRIs) takes weeks of treatment to develop, but the available
monoamine levels are boosted within hours.
Drug treatment of major depressive disorder involves
antidepressant medication such as -
• Selective serotonin reuptake inhibitors (SSRIs):
include fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and
fluvoxamine. They work by selectively blocking the reuptake of serotonin to
increase the amount of serotonin available in synapses in the brain. They are
effective, have fewer and milder side effects. Fluoxetine and escitalopram are
the only antidepressants recommended for treatment of MDD in adolescents (aged
12-17 years), and fluoxetine is also approved for children aged 8 years and
older. Side effects of SSRIs include dry mouth, nausea, sleepiness, dizziness,
sweating, constipation, decreased appetite, and insomnia. Taking SSRIs in the
morning generally avoids the insomnia issues.
• Monoamine oxidase inhibitors (MAOIs):
(phenelzine, isocarboxazid, tranylcypromine, and selegiline) are prescribed
when either other types of antidepressants do not help or in cases of severe
depression. They act by inhibiting monoamine oxidase thereby increasing
norepinephrine and serotonin levels. The effect of MAOIs last up to 2 to 3
weeks. However, selective MAOIs have severe side effects and require restrictive
dietary rules and care to avoid serious drug interactions. The interaction of
tyramine with MAOIs can sharply increase blood pressure leading to stroke.
Other side effects of MAOIs include orthostatic hypotension (temporary
lowering of blood pressure due usually to suddenly standing up or a few seconds
of disorientation), drowsiness, dizziness, insomnia and sexual dysfunction.
Pregnant women should avoid these drugs since they can cause birth defects.
• Serotonin-norepinephrine reuptake inhibitors (SNRIs):
venlafaxine, duloxetine, and desvenlafaxine - inhibit reuptake of serotonin and
norepinephrine and are effective in patients who do not respond to standard
antidepressants or in patients with chronic pain. Duloxetine may cause liver or
kidney disease, so patients who take lot of alcoholic drinks should not use
this drug. Venlafaxine and desvenlafaxine cause elevated blood pressure in some
• Tricyclic antidepressants (TCAs)
nortriptyline, imipramine, desipramine, doxepin, and protriptyline are TCAs
that inhibit the reuptake of serotonin and norepinephrine at the synaptic
cleft. However, TCAs, especially desipramine, tend to cause heart rhythm
disturbances for patients with certain heart diseases. Common side effects include
dry mouth, constipation, blurred vision, sexual dysfunction, weight gain,
difficulty urinating (especially in patients with benign prostatic
hyperplasia), drowsiness, dizziness, and orthostatic hypotension.
• Central alpha2-receptor antagonists
as Mirtazapine enhance central noradrenergic and serotonergic activity. Side
effects include orthostatic hypotension, impaired cognition, blurred vision,
eye fatigue, photosensitivity, malaise or lassitude, increased appetite and
subsequent weight gain, dry mouth, and constipation.
• Norepinephrine and dopamine reuptake inhibitors
such as bupropion work by
inhibiting the reuptake of dopamine and norepinephrine. About 25 percent of
patients lose weight initially. Side effects include restlessness, agitation,
sleeplessness, headache, and stomach pain, and sometimes seizures which
increase with higher doses. High doses may also cause dangerous heart
In January 2011, the FDA approved vilazodone hydrochloride
(Viibryd) for the treatment of major depressive disorder in adults. It is said
to enhance serotonergic activity in the central nervous system through
selective inhibition of serotonin reuptake. The most common side effects are
diarrhea, nausea, vomiting, sexual dysfunction, and insomnia. Do not use this
drug with MAOIs as it may cause drug interactions with serotonergic drugs.
advances in the pharmacological treatment of depression, many patients remain
ill despite initial treatment. Patients who do not
respond to antidepressants are usually prescribed 'augmentation' or 'adjunctive
treatment'. The only FDA-approved regimen for treatment-resistant depression is
the olanzapine - fluoxetine combination. Aripiprazole and quetiapine are
approved as adjunctive agents.
Although a clinical trial conducted by the National
Institutes of Health (NIH) revealed that St. John's wort (Hypericum
) extract was not effective in the treatment of adult MDD, it is
extensively used in the treatment of mild to moderate depression.
Whatever your choice of drug treatment, it is essential to
continue medications regularly as directed even if symptoms are seemingly
resolved. Do not discontinue medication or take any new prescription or
nonprescription drug or herbal remedies without first talking to the health
Dupuy JM, Ostacher MJ, Huffman J, Perlis RH,
Nierenberg AA. A critical review of pharmacotherapy for major depressive
disorder. Int J Neuropsychopharmacol. 2011 Nov;14(10):1417-31. Epub 2011 Feb