Although new generation antidepressant drugs have replaced tricyclic antidepressants as first line treatment for major depressive disorder, no one drug is superior to the other in terms of safety and effectiveness. The choice of therapy is mainly determined by patient’s choice and cost of the drugs, according to researchers from the Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, who did a critical review of pharmacotherapy for this disorder.

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 symptoms.

However, recent 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): 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): 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): 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 patients.

• Tricyclic antidepressants (TCAs) – Amitriptyline, 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 such 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 arrhythmias.

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.

Despite numerous 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 perforatum) 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 care provider.

Reference: 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 24.

Source-Medindia