Antidepressants are used commonly in medical and psychiatric practice. As a class, antidepressants have in common their ability to treat major depressive illness. Most antidepressants are also effective in the treatment of panic disorder and other anxiety disorders. Some antidepressants effectively treat obsessive-compulsive disorder (OCD) and a variety of other conditions (see indications below).

The most commonly prescribed antidepressants are listed in Table 12-1. Antidepressants are subdivided into groups based on structure or prominent functional activity: selective serotonin reuptake inhibitors (SSRls), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOls), and other antidepressant compounds with a variety of mechanisms of action. Antidepressants are typically thought to act on either the serotonin or norepinephrine systems, or both. Choice of medications typically depends on diagnosis, history of response (in patient or relative), and the side-effect profile of the medication. Antidepressant effects are typically not seen until 2 to 4 weeks into treatment. Side effects must be carefully monitored, especially for TCAs and MAOls.

Indications

Table 12-2 lists the indications for antidepressants. The main indication for antidepressant medications is major depressive disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Antidepressants are used in the treatment of all subtypes of depression, including depressed phase of bipolar disorder, psychotic depression (in combination with an antipsychotic medication), atypical depression, and seasonal depression. Antidepressants also are indicated for the prevention of recurrent depressive episodes.

Antidepressant medications may be effective in the treatment of patients with dysthymic disorder, especially when there are clear neurovegetative signs or a history of response to antidepressants.

Panic disorder with or without agoraphobia has been shown to respond to SSRls, MAOls, TCAs, and high-potency benzodiazepines (alprazolam and clonazepam).

OCD has been shown to respond to the serotonin-selective tricyclic clomipramine (Anafranil) and to SSRIs at high doses (e.g., fluoxetine at 60-80mg/ day). Obsessions tend to be more responsive to pharmacotherapy than compulsions. Symptoms of OCD respond more slowly than symptoms of major depression. Trials of 12 weeks or more are needed before a medication can be ruled a failure for an OCD patient.

The binging and purging behavior of bulimia has been shown to respond to SSRls, TCAs, and MAOls in several open and controlled trials. Because SSRIs have the most benign side-effect profile of these medications, they are often the first-line psychopharmacologic treatment.

Mechanisms of Action

Antidepressants are thought to exert their effects at particular subsets of neuronal synapses throughout the brain. Their major interaction is with the monoamine neurotransmitter systems (dopamine, norepinephrine, and serotonin). Dopamine, norepinephrine, and serotonin are released throughout the brain by neurons that originate in the ventral brainstem, locus ceruleus and the raphe nuclei, respectively. These neurotransmitters interact with numerous receptor subtypes in the brain that are associated with the regulation of global state functions including appetite, mood states, arousal, vigilance, attention, and sensory processing.

SSRls act by binding to presynaptic serotonin reuptake proteins, thereby inhibiting reuptake and increasing the levels of serotonin in the synaptic cleft.

TCAs act by blocking presynaptic reuptake of both serotonin and norepinephrine. MAOls act by inhibiting the presynaptic enzyme (monoamine oxidase) that catabolizes norepinephrine, dopamine, and serotonin, thereby increasing the levels of these neurotransmitters presynaptically.

These immediate mechanisms of action are not sufficient to explain the delayed antidepressant effects (typically 2 to 4 weeks). Other unknown mechanisms must play a role in the successful psychopharmacologic treatment of depression.