How Antidepressants Work

So, what causes MDD? The exact cause is unknown, but research has focused on the balance of certain chemicals called neurotransmitters, specifically serotonin, norepinephrine (also called noradrenaline) and dopamine. These neurotransmitters, especially serotonin, are prevalent in the areas of the brain -- like the limbic system and upper brainstem -- that control mood and emotions. See How Your Brain Works for more information.

Research indicates that patients with MDD either do not have enough serotonin or norepinephrine in these areas of the brain or have an imbalance between the two types of neurotransmitters. Antidepressants are designed to increase the levels of these neurotransmitters in the limbic system. So, to understand how antidepressants work, we must look at the process of neurotransmission.

Note Many addictive drugs (like cocaine, methamphetamines, LSD, heroin and marijuana) affect the same pathways and neurotransmitters as MDD does.

Your brain and nervous system are made of nerve cells, or neurons. Like wires in your home's electrical system, nerve cells make connections with one another in circuits called neural pathways. Unlike wires in your home, nerve cells do not touch, but they come close together at synapses. At the synapse, the two nerve cells are separated by a tiny gap, or synaptic cleft. The sending neuron is called the presynaptic cell, while the receiving one is called the postsynaptic cell. Nerve cells send chemical messages called neurotransmitters in a one-way direction across the synapse from presynaptic cell to postsynaptic cell.

Next, we'll look at this process using serotonin as an example.­

Let's see how the nerve communication process works.

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1. The presynaptic cell (sending cell) makes serotonin (5-hydroxytryptamine, 5HT) from the amino acid tryptophan and packages it in vesicles in its end terminals.
2. An electrochemical nerve signal passes down the presynaptic cell into its end terminals.
3. The nerve signal stimulates the vesicles containing serotonin to fuse with the cell membrane and dump serotonin into the synaptic cleft.
4. Serotonin passes across the synaptic cleft, binds with special proteins called receptors on the membrane of the postsynaptic cell (receiving cell) and sets up a new electrochemical signal in that cell (the signal can stimulate or inhibit the postsynaptic cell). Serotonin fits with its receptor like a lock and key.
5. The remaining serotonin molecules in the cleft and those released by the receptors after use get destroyed by enzymes in the cleft (monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT)). Some get taken up by specific transporters on the presynaptic cell (reuptake). In the presynaptic cell, the absorbed serotonin molecules get destroyed by MAO and COMT. This enables the nerve signal to be turned "off."

A similar process occurs for norepinephrine, which is also implicated in mood, emotions and MDD. Serotonin, norepinephrine and dopamine are chemically similar and belong to a class of neurotransmitters called monoamine neurotransmitters. Because these chemicals are structurally similar, they are all recognized by the enzymes MAO and COMT.

Now let's look at how antidepressants work.

Stephen Chernin/Getty Images Prozac is one of the most prescribed antidepressants.

Antidepressants are designed to block various aspects of the synaptic transmission process in serotonin, norepinephrine and dopamine-containing neurons in the brain. This increases the levels of these neurotransmitters. By increasing the levels of these neurotransmitters, mood and emotions should stabilize and perhaps return to normal. However, because some of these neurotransmitters (like norepinephrine) are contained in neural pathways in other parts of the brain and nervous system, some antidepressants can have side effects (like changes in blood pressure and saliva production). Also, because the pathways involved in MDD are in the lower brain and brainstem, antidepressants may interfere with other functions, like appetite, sleep and sexual function.

Antidepressants are classified according to which neurotransmitters they affect and how they affect them. Let's look at the different types of antidepressants.

Selective Serotonin Reuptake Inhibitors (SSRI)
SSRIs, the most frequently prescribed antidepressants, were introduced in the mid-1980s. SSRIs block the transport of serotonin back into the presynaptic cell. This action increases the concentration of serotonin in the synaptic cleft, increasing stimulation of the postsynaptic cells. SSRIs include the following drugs:

• fluoxetine (Prozac^TM)
• paroxetine (Paxil^TM)
• sertraline (Zoloft^TM)
• fluvoxamine (Luvox^TM)
• citalopram (Celexa^TM)
• escitalopram (Lexapro^TM)

The various SSRIs are equally effective and equally tolerated by patients. Not everyone reacts in the same way, however, so some patients may experience more side effects with one type of SSRI than with another. Most of the time, patients have to take antidepressants more than once per day. However, fluoxetine has a longer half-life -- it remains in the body longer, so patients can usually take it once a day. This lowers the chance of missing a dose. At high doses, paroxetine and sertraline will interfere with dopamine and serotonin neurotransmission.

To minimize side effects that might cause a patient to stop using the drug, primary health-care providers usually start SSRIs at low doses and slowly increase to the target dose over four to six weeks. Such side effects include nausea, dizziness, vertigo, vomiting, insomnia, anorexia, anxiety and sexual dysfunction.

Tricyclic Antidepressants and Selective Norepinephrine Reuptake Inhibitors
Tricyclic antidepressants were introduced in the late 1950s and early 1960s. Like SSRIs, these compounds block the reuptake of norepinephrine by the presynaptic cell, thereby increasing its concentration in the synaptic cleft. Tricyclic antidepressants include:

• nortryptiline (Pamelor^TM)
• maprotiline (Ludiomil^TM)
• desipramine (Norpramine^TM)
• amitryptiline (Elavil^TM)
• clomipramine (Anafranil^TM)
• imipramine (Trofranil^TM)

Tricyclic antidepressants affect heart rate and blood pressure because norepinephrine is also used in the autonomic nerves that control these functions. Their side effects include postural hypotension (drop in blood pressure upon standing), tachycardia (rapid heart rate), dry mouth, urinary retention and blurry vision. Tricyclic antidepressants are not used often because they are toxic and easily overdosed. However, for patients who do not tolerate SSRIs or other antidepressants, tricyclics are effective. Physicians must monitor the patient closely for toxic side effects.

Tric­yclic antidepressants are nonselective inhibitors of norepinephrine reuptake because their chemical structures look like norepinephrine. Reboxetine (Edronax^TM­) is a more specific reuptake inhibitor because it binds better to the reuptake transporter, but it isn't available in the United States.

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Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
These drugs were introduced in the mid-1990s and block the reuptake of both serotonin and norepinephrine by binding to the transporters of these neurotransmitters on the presynaptic cell. SNRIs include:

• bupropion (Wellbutrin^TM) -- blocks dopamine and norepinephrine reuptake as well
• duloxetine (Cymbalta^TM)
• venlafaxine (Effexor^TM)

The side effects of these drugs are similar to, but less than, those of SSRIs. Bupropion and duloxetine, in particular, have minimal side effects in the areas of sexual dysfunction and weight gain.

Monoamine Oxidase Inhibitors (MAOI)
An enzyme called monoamine oxidase can degrade serotonin and norepinephrine in the synaptic cleft and presynaptic cell. MAOIs block this degradation, increasing the concentration of the neurotransmitters. MAOIs include:

• phenelzine (Nardil^TM)
• tranylcypromine (Parnate^TM)
• selegiline (Eldepryl^TM)
• isocarboxazid (Marplan^TM)
• moclebemice (Manerix^TM)

Because these drugs can interfere with norepinephrine, they can have cardiovascular side effects. Most commonly, patients must limit their consumption of foods containing tyramine because the drugs interact with tyramine to cause hypertension (high blood pressure). Tyramine can be found in foods like soy sauce, sauerkraut, chicken and beef livers, aged cheese, sausage, cured meat and fish, yogurt, raisins, figs and sour cream. Patients also have to refrain from consuming alcohol when on these antidepressants. Because of these interactions, doctors do not prescribe this class of antidepressants as frequently as others.

Noradrenergic and Specific Serotonin Antidepressants (NaSSA)
Some of these compounds were introduced in the mid-1980s and others even more recently. NaSSAs block negative feedback effects on norepinephrine and serotonin secretion by the presynaptic cell. This action increases the concentrations of these neurotransmitters in the synaptic cleft. They also block some serotonin receptors on the postsynaptic cell, which enhances serotonin neurotransmission. These compounds include

• Mirtazipine (Remeron^TM)
• Trazodone (Desyrel^TM)
• Nefazodone (Serzone^TM)
• Mianserin (Bolvidion^TM)

The most common side effects are drowsiness, dry mouth, increased appetite and weight gain.

Remember that the available antidepressants are about equally effective in treating MDD. So, choices are based on patient's age, family history, drug tolerance, side effects and past response to antidepressants.

On the next page, we'll look at the role of antidepressants in MDD treatment.

There is no cure for MDD, so doctors must manage their patients with the goals of reducing the patient's symptoms, improving the quality of life and minimizing any risks of suicide. Ideally, treatment requires a combination of psychotherapy, medications and patient education. MDD treatment has been divided into three phases: acute, continuation and maintenance [source: Mann].

Arif Ali/AFP/Getty Images A survivor of the Kashmir earthquake in 2005 receives antidepressant drops at a medical center.

Acute phase
Here, the goal is to get the patient into remission (a state with minimal symptoms). This usually involves beginning antidepressant therapy. Usually, SSRIs are the drug of choice, especially for children and older patients, because they can be used in lower dosages with the fewest side effects. It takes about four to six weeks for any antidepressant to show effects.

Augmenting Antidepressants Sometimes MDD patients show other symptoms (changes in mood, delusions, hallucinations, changes in energy metabolism) partially due to antidepressant side effects or to other types of depression (like bipolar disorder -- periods of happiness interspersed by periods of severe depression). So, primary care providers may add other medications to antidepressant therapy. Mood stabilizers: lithium, latmotriguine (LamictalTM), valproic acid (DepakeneTM, DepakoteTM) Antipsychotic agents: chlorpromazine (ThorazineTM) or haloperidol (HaldolTM) Thyroxine: thyroid hormone to increase metabolism

The physician and patient start by rating the severity of the untreated symptoms to establish a baseline. During the first four to six weeks on antidepressants, patients may undergo psychotherapy and side-effect monitoring. The physician reassesses the severity of the symptoms and compares them to the baseline. If, after eight weeks, the reduction in severity is less than 25 percent, that antidepressant is considered to offer no improvement. The primary care provider may choose to change the dosage or class of medication, augment the medication or combine classes of antidepressants. If successful, the acute phase of treatment may six to 10 weeks.­­

Continuation phase
After remission begins, doctors try to eliminate remaining symptoms, restore the patient to his or her level of function before the MDD episode and prevent recurrence of further MDD episodes. During this time, the levels of antidepressant therapy and psychotherapy used to achieve remission are maintained. If, after six months, there is no relapse, medication might be discontinued gradually over several weeks. The continuation phase of treatment could last six to 12 months.

Maintenance phase
This phase is most important for patients with annual episodes of depression. During this time, patients should be monitored regularly. Antidepressant therapies sometimes have to be reinitiated. Psychotherapy and patient education are especially important. The maintenance phase can last one to three years.

Special populations and depression therapy
When deciding on therapy, some clinically depressed patients require special considerations:

• Bipolar disorder -- these patients have extreme mood swings (periods of excessive high spirits followed by severe depressive episodes). Typically, the antidepressants are augmented with mood stabilizers.
• Children/adolescents -- The SSRI fluoxetine is the only effective (and approved) antidepressant for this age group. There have been reports that children on antidepressants are more likely to commit suicide than those who are not on antidepressants; while some data suggest that this may be true, it has not been proven conclusively. Primary care providers need to weigh the risks of antidepressant therapy versus untreated depression. Most often, treatment carries fewer risks of suicide than non-treatment.
• Pregnant/postpartum women -- Depression can be a common symptom during pregnancy and postpartum -- it usually corrects itself, but sometimes severe depression must be treated (in about 10 percent of pregnant/postpartum women). Antidepressants can pass to the fetus and through breast milk. The effects of antidepressants on the developing fetus and newborn are not well known. Therefore, doctors should carefully consider the risks and benefits of treatment.

Treatment for depression is not a short-term process but a long-term project with specific goals of remission and maintenance. Multiple approaches of medication, psychotherapy and patient education are most effective in the treatment of MDD. Close consultation with a physician and/or psychiatrist can provide the best treatment options.

Next, we'll learn about direct-to-consumer marketing by pharmaceutical companies, which has greatly affected patient choice in the past few years.

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Saint-John's Wort Saint-John’s-wort is an herb that has been used since ancient times for treating depression. It is available over the counter without a prescription, but its clinical effectiveness for treating depression has been controversial. Studies in Europe have indicated that it is about as good as tricyclic antidepressants in treating mild depression. However, studies in the United States have indicated that this herbal supplement is not effective and should not be used for treating severe depression. Because Saint-John’s-wort is an herb, it is not governed by the FDA, but studies have shown that it interferes with ­liver enzymes that are critical for the metabolism and actions of other drugs (like HIV medications, cyclosporine and oral contraceptives). Therefore, the FDA has warned consumers not to take Saint-John’s-wort when taking other medications.

Traditionally, pharmaceutical companies have not had direct contact with consumers. Physicians and health care providers would get information about treatments and medications from pharmaceutical representatives, in a process called physician detailing. In 1996, the FDA relaxed the rules on direct-to-consumer advertising of prescription drugs (only the United States and New Zealand allow this practice). Pharmaceutical companies claimed that such advertising would benefit patients by educating them about conditions and available medications, enhancing communication between the primary care provider and the patient. So, you can now see full ads about various prescription medications, including antidepressants, in print media and on television [source: Frosch] estimate that consumers see up to 16 hours of ads for prescription drugs each year). Pharmaceutical companies increased expenditures on DTCA from about $11 billion in 1996 to about $30 billion in 2005.

DTCA has been a controversial idea. Pharmaceutical companies claim that it helps patient education, but opponents claim that:

• Patients do not receive adequate education (especially in 45-second TV spots)
• In response to inquiries/pressure from patients, physicians are more likely to prescribe expensive name brands when generics or alternate treatments are available.
• The FDA has not enforced regulations regarding the accuracy of DTCA for prescription drugs, especially in TV spots.

The result is higher health care costs for medications without necessarily improving the quality of patient care.

In one study, investigators had groups of actors portray patients with MDD [source: Kravitz et al]. The actors visited more than 150 health care providers in Sacramento, Calif., San Francisco and Rochester, N.Y. In some visits, the actors would describe symptoms and request an advertised antidepressant, and others didn't mention brands or make requests. The investigators found that physicians were more likely to prescribe brand names when the patient requested a brand or when the patient requested a general antidepressant than when the patient made no requests at all. The investigators concluded that patients have a large influence on the prescribing patterns of health care providers when it comes to antidepressants. In contrast, another study concluded that physician detailing had more influence in prescribing name brands than did DTCA [source: Donohue et al]. So, the influence of DTCA remains controversial.

For more information about antidepressants, check out the links on the next page.