Antidepressants are a class of psychotherapeutic drugs that are used to treat major depression. The therapeutic effect of antidepressants aims at the restoration of mood and behavior. The major types of drugs included in this class are the monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors and atypical antidepressants.

• What is Depression?
• History of Antidepressants
• Behavioral Effects in Humans
• Mechanisms of Action
• Current Theories of Depression
• Thought Questions and Quick Quiz
• Additional Sources of Information

Major depression is one of the most common psychiatric disorders afflicting humankind. It has been estimated that 7 to 12% of men and 20 to 25% of women will experience a major depressive episode in their lifetime. However, because of stigma, misunderstandings about the seriousness and treatability of the disorder, and the tendency of both patients and physicians to focus on physical rather than psychological symptoms, it often goes undiagnosed and untreated. The cost of depression in terms of loss of function, work missed and treatment has been estimated to be $16 billion per year in the United States alone. The human cost is significant as well, with as many as 80% of attempted suicides attributed to major depression.

It is important to distinguish major depression from normal fluctuations in mood in response to daily events. Although nearly everyone experiences a depressed mood on occasion, major depression is characterized by extreme and inappopriate, or chronic and unremitting changes in mood and behavior. The diagnosis of major depression is based on clinical symptoms. To be considered 'clinically' depressed, individuals must exhibit at least five symptoms from a list of nine depressive symptoms (DSM-IV). At least one of the symptoms must be either (1) depressed mood, or (2) loss of interest or pleasure.

Major depression is believed to arise from disturbances in brain neurotransmitter systems. As stated in recent public service announcements by the National Alliance for Research on Schizophrenia and Depression (NARSAD), depression is a "flaw in chemistry, not character". Antidepressant drugs help restore the chemistry of the brain so that normal mood and behavior can take place.

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The first two classes of drugs used to treat major depression, the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants were discovered by serendipity. Iproniazid, the first modern antidepressant, was originally developed as an antitubercular drug in the early 1950's. In addition to its ability to treat tuberculosis, iproniazid was observed to elevate mood and stimulate activity in many patients. These effects led researchers to investigate the ability of iproniazid to treat the symptoms of depression. After promising preliminary findings reported in 1957, iproniazid was prescribed widely to patients with major depression. Within the first year it was available as an antidepressant, four hundred thousand depressed people were treated with iproniazid. Subsequent studies demonstrated the ability of this drug to block the activity of monoamine oxidase, the enzyme that destroys the monoamine neurotransmitters (norepinephrine, serotonin and dopamine). Although iproniazid is no longer used as an antidepressant because of toxic side-effects, the effectiveness of this drug led to further interest in the idea that depression might be alleviated by appropriate drugs.

The first tricyclic antidepressant, imipramine, was originally developed in a search for drugs useful in the treatment of schizophrenia. Although clinical trials demonstrated a lack of effect in treating schizophrenia, an astute clinician decided to examine its effectiveness in depressed patients. Early studies in 1957 and 1958 reported that imipramine significantly alleviated symptoms in patients with major depression. Interestingly, although imipramine elevated mood and increased energy in depressed patients, the drug proved to be sedating in individuals without major depression. These effects led to the idea that imipramine was selectively reversing the depression, rather than simply producing a general activating effect. Subsequent biochemical studies on imipramine demonstrated that this drug increased the activity of the monoamine neurotransmitters, norepinephrine and serotonin, by inhibiting their reuptake into neurons.

The monoamine oxidase inhibitors and tricyclic antidpressants, although having different modes of action, have as their primary effect an increase in the activity of monoamines in the brain. This observation, together with other findings, led to monoamine theory of depression -- the idea that depression arises from a deficit in norepinephrine and/or serotonin activity, and that antidepressants work by normalizing this deficit. This theory led to the development of the next major class of antidepressants, the selective serotonin reuptake inhibitors (SSRIs). In order to develop an antidepressant that worked effectively on the symptoms of depression, but that did not have the side effects of the MAOIs or the tricyclics, a systematic search was begun for drugs that selectively enhanced activity of one monoamine, but not others. The first SSRI, fluoxetine (Prozac) was released in 1987. This drug and other SSRIs, as the name implies, selectively inhbit the reuptake of serotonin, and thereby increase serotonin activity in the brain.

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Monoamine Oxidase Inhibitors

The MAO inhibitors are effective drugs for the treatment of major depression, atypical depression and panic or phobic disorders. The efficacy of MAO inhibitors is generally equivalent to the other classes of antidepressant drugs, and like other antidepressants, MAOIs may take anywhere from two to six weeks to produce therapeutic effects.

Tricyclic antidepressants

The name tricyclic is a little misleading, referring to the three ring chemical structure of many of the drugs of this class. Drugs included in this class may actually contain anywhere from one to four rings. From the 1960's until the late 1980's, tricyclic antidepressants were the drugs of choice for the treatment of depression in the United States, and they are still widely used for moderately to severely depressed patients. Tricyclic antidepressants elevate mood, increase physical activity, normalize appetite and sleep patterns, and reduce morbid preoccupation in 60% - 70% of patients with major depression. Like the other classes of antidepressants, therapeutic effects of the tricyclics may take from two to six weeks to appear. Often, the first symptom to subside is insomnia, followed a few days later by an increase in activity and an improvement in concentration and memory. Improvement in mood does not usually occur until later.

Selective serotonin reuptake inhibitors (SSRIs) represent a relatively new class of antidepressant drugs. These drugs are refered to as "clean" drugs because they primarily affect only serotonin (in contrast to MAOIs and tricyclics which affect other monoamines). Because SSRIs are more targeted, they have a lower incidence of some of the side effects associated with tricyclic antidepressants and MAOIs (e.g., blurred vision, dizziness, constipation, dry mouth). More important to their current popularity, SSRIs have less potential for overdose than the tricyclics or MAOIs, and are therefore considered safer than these other drug classes. Although some reports suggest that SSRIs may have more rapid actions than the tricyclics or the MAOIs, this does not appear to be the case. Like the other classes of antidepressants clinical response to the SSRIs may take anywhere from two to six weeks to appear.

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Monoamine Oxidase Inhibitors

This class of drugs inhibits the activity of monoamine oxidase (MAO), the enzyme that destroys monoamine neurotransmitters (norepinephrine, dopamine or serotonin) in synapses. The inhibition of this enzyme allows these neurotransmitters to remain active in the brain longer, thereby correcting a presumed deficit in monoamine function.

Unfortunately, MAO inhibitors have the potential for producing a harmful side effects known as the "cheese effect". Some foods, such as aged cheeses and red wines contain pressor amines, substances similar to catecholamines. These amines are normally deactivated by a form of MAO that is present in the blood. The cheese effect occurs when a person treated with MAO inhibitors eats food containing pressor amines. These amines simulate the sympathetic nervous system, increasing heart rate and blood pressure. This reaction can cause blood pressure to increase enough to produce intracranial bleeding or cardiovascular collapse. Therefore, unless strict dietary guidelines are followed, risk of hypertensive crisis is significant. However, when appropriate precautions are exercised, MAOIs are safe and effective antidepressants.

The three MAOIs marketed in the U.S. irreversibly inhibit both forms of monoamine oxidase found in the body, MAO-A and MAO-B. MAO-A preferentially destroys norepinephrine and serotonin, while MAO-B selectively destroys phenethylamine. When administered initially, MAO inhibitors transiently elevate the cytoplasmic and vesicular concentrations of neorpinephrine, dopamine, and serotonin. This activates a feedback loop that reduces the synthesis of these monoamines. If administration continues, there is a reduction in the number and activity of ß-adrenergic receptors, as well as in the number of alpha2-adrenergic and serotonergic receptor sites.

Generic Name	Trade Name
Phenelzine	Nardil
Tranylcypromine	Parnate
Isocarboxazid	Marplan

Tricyclic antidepressants inhibit the reuptake of the neurotransmitters serotonin and norepinephrine into their respective nerve terminals. Reuptake is the first step in the process of deactivating these neurotransmitters in the brain. After serotonin and norepinephrine are released from neurons, they are removed from the extracellular space by transporters (also known as reuptake sites) located on the cell membrane. The tricyclic antidepressants block these transporters. By inhibiting reuptake, the drugs allow serotonin and norepinephrine to remain active in the synapse longer, thereby correcting a presumed deficit in the activity of these neurotransmitters.

Generic Name	Trade Name		Generic Name	Trade Name
Imipramine	Tofranil		Trimipramine	Surmontil
Desipramine	Norpramin		Protriptyline	Vivactil
Amitriptyline	Elavil Endep		Maprotiline	Ludiomil
Nortriptyline	Pamelor Aventyl		Amoxapine	Asendin
Doxepin	Adapin Sinequan		Clomipramine	Anafranil

The SSRIs, as their name implies, inhibit reuptake of serotonin. Reuptake is the first step in the process of deactivating this neurotransmitter in the brain. After serotonin is released from neurons, it is removed from the extracellular space by transporters, or reuptake sites, located on the cell membrane. SSRIs block serotonin reuptake sites, allowing serotonin to remain active in the synapse longer, thereby correcting a presumed deficit in the activity of this neurotransmitter.

Generic Name	Trade Name
Fluoxetine	Prozac
Fluvoxamine	Luvox
Paroxetine	Paxil
Sertraline	Zoloft

Atypical Antidepressants

Generic Name	Trade Name
Bupropion	Wellbutrin
Venlafaxine	Effexor
Trazodone	Desyrel
Nefazodone	Serzone

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Monoamine Hypothesis

Shortly after the first antidepressant drugs were introduced they were demonstrated to increase the availability of the monoamine neurotransmitters, norepinephrine and serotonin. Monoamine oxidase inhibitors (MAOIs), as the name implies, inhibit the enzyme monoamine oxidase (MAO). This enzyme is the primary enzyme responsible for the inactivation of monoamines after they are released from neurons. Blockade of MAO therefore increases the ability of norepinephrine and serotonin to act in the brain.

Tricyclic antidepressants inhibit reuptake of norepinephrine and serotonin, while selective serotonin reuptake inhibitors (SSRIs) inhibit reuptake of serotonin selectively. Following release from neurons, norepinephrine and serotonin are actively transported back into the neurons from which they are released, in a process known as reuptake. In addition to inactivation by MAO, reuptake is one of the most important processes by which monoamines are inactivated in the brain. Blockade of reuptake therefore increases the ability of norepinephrine and/or serotonin to act in the brain.

The majority of antidepressants thus have as their principal effect an increase in the activity of serotonin and/or norepinephrine. These findings form the basis of the monoamine hypothesis of depression. Since antidepressant drugs increase the activity of monoamines, this hypothesis suggests that depression is primarily the result of a monoamine deficit.

Although the monoamine hypothesis is pleasing in its simplicity, it has several major flaws. First, it has been difficult to detect consistent abnormalities in monoamine function in depressed patients. Additionally, some antidepressants, such as iprindole and bupropion, are at best weak inhbitors of monoamine uptake. Finally, this hypothesis does not account for the temporal discrepancy between the acute effects of the antidepressant drugs on monoamine systems, which occur within minutes to hours, and the therapeutic benefits which typically occur only after two to six weeks of administration.

Because of these flaws in the classical monoamine hypothesis other hypotheses have been proposed. The majority of these hypotheses still suggest a disturbance in monoamine function, however the disturbance is considered to be more complex than a simple deficit in brain monoamines. Chronic administration of antidepressants is thought to produce adaptations in monoamine systems, correcting the disturbance responsible for depression. These hypotheses therefore account for the need to administer antidepressants for several weeks to achieve therapeutic benefits.

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Thought Questions

• It is believed that long-term administration of antidepressants produces adaptations in brain monoamine systems, and it is these adaptations, rather than the acute effects of antidepressants that are responsible for the therapeutic benefits. What are some potential adaptions in monoamine systems that might be produced by chronic antidepressant administration?

• There is no widely accepted animal model of major depression, making it difficult for researchers to understand how antidepressants produce their therapeutic effects. Given the lack of an animal model of depression, how would you study antidepressants in the laboratory?

Quick Quiz

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