Depression Management: Pharmacotherapy

ABSTRACT: Pharmacologic approaches to the treatment of depression can relieve symptoms in up to 75% of patients with major depressive disorder.

Major depressive disorder is more common in primary care than any condition other than hypertension, affecting 20 million adults each year. The leading cause of disability in the country, depression will be the second most disabling condition worldwide by 2020 — second only to cardiovascular disease.

However, once identified, depression can usually be successfully treated, stresses UAB psychiatrist Jack G. Modell, MD, who outlines the goals of treatment as relieving the symptoms of depression, returning patients to their previous ability to function socially and in the workplace, and reducing the likelihood of recurrence. "Medications are the most common form of therapy and eventually can provide significant relief of symptoms for up to 75% of people," he reports.

Antidepressant Drugs
Modell recounts that the first antidepressants, monoamine oxidase inhibitors (MAOIs), were discovered accidentally during the 1950s by researchers who were trying to develop new drugs to treat tuberculosis. While MAOIs did not help tuberculosis, they did elevate mood.

Since 1988, when fluoxetine (Prozac®) became part of the national vocabulary, new antidepressant drugs have been hitting the market at record pace. Annual sales of selective serotonin-reuptake inhibitor (SSRI) antidepressants in the United States now top $6 billion.

Prior to SSRIs, drug options were basically limited to tricyclic antidepressants (TCAs) and MAOIs, Modell relates. "These older drugs, while clearly effective, require frequent physician monitoring to avoid toxicity and are associated with side effects such as dry mouth, blurred vision, hand tremors, dizziness, sedation, hypotension or hypertension, tachycardias, or arrhythmias," he says, adding that the elderly, 15% of whom suffer from depression, are particularly susceptible to such adverse reactions.

Mode of Action
"While antidepressants' mode of action is complex and only partly understood, most of these drugs heighten the level of a target neurotransmitter at the neuronal synapse," he reveals, by either: boosting neurotransmitter synthesis, blocking its degradation, preventing its reuptake from the synapse into the presynaptic neuron, or mimicking its binding to postsynaptic receptors.

To make matters more complicated, he adds, many antidepressants affect more than one neurotransmitter, and recent research indicates that the antidepressants also affect gene transcription (and therefore intracellular protein synthesis and activity), which could affect mood.

"First-line" Choices
Most psychiatrists favor the newer antidepressants as "first-line" medications, because of their ease of use, more manageable side effects, and safety in overdoses, Modell reports. Among these agents, 4 SSRIs have been approved by the Food and Drug Administration for treatment of depression: fluoxetine (Prozac® and, newly introduced for the treatment of premenstrual dysphoric disorder, Sarafem®), sertraline (Zoloft®), paroxetine (Paxil®), and citalopram (Celexa®). A fifth SSRI, fluvoxamine (Luvox®), is approved for obsessive-compulsive disorder (OCD), yet is used off-label for depression.

"SSRIs can cause nausea, diarrhea, headache, tremor, daytime sedation, sexual dysfunction, nervousness, insomnia, and a possible increase in bleeding time," he maintains. "The incidence of treatment-related suicidal thoughts for the SSRIs is low and probably comparable to the rate observed for other antidepressants, despite reports to the contrary."

"Atypical" Antidepressants
In addition to the major classes of antidepressants are several "atypical antidepressants," specifically mirtazepine (Remeron®), nefazodone (Serzone®), venlafaxine (Effexor®), and bupropion (Wellbutrin-SR® and Zyban® to aid with smoking cessation).

Mirtazepine blocks 2 types of serotonin receptors, the 5-HT2 and 5-HT3 receptors, as well as noradrenergic alpha-2 receptors. It is also a potent antihistamine, which is responsible for the frequent (and sometimes desirable) side effects of sedation and weight gain. Nefazodone has unique and incompletely understood effects at serotonin receptors and, like mirtazepine, is sedating and may be useful for patients with troublesome insomnia. Both drugs have a low incidence of adverse sexual side effects.

Venlafaxine blocks the reuptake of both serotonin and norepinephrine and has side effects similar to those of the SSRIs, though with less chance of sexual dysfunction. Modell points out that some clinicians feel that venlafaxine's apparent dual-mechanism of action can be useful in treating severe or refractory cases of depression, although this is largely unproven.

At the high-end of the dosage range, venlafaxine may cause significant, though usually not hazardous, increases in blood pressure. "With this exception, and in contrast to the TCAs and MAOIs, all of these newer agents and the SSRIs generally have no adverse cardiovascular effects, and each can be a reasonable choice for first-line treatment of depression," he advises.

Modell describes bupropion as an interesting agent that increases synaptic concentrations of norepinephrine and, to a lesser extent, dopamine. "Because bupropion has mild stimulant properties, it may be particularly useful in treating anergic or apathetic depressed patients, and may cause less 'switching' into mania in patients with bipolar (manic-depressive) illness than many of the other antidepressants," he says. Side effects can include sympathomimetic-like effects, such as anxiety, shakiness, or insomnia.

"In premarketing studies, bupropion was associated with an increased incidence of seizures in certain patients, which was greatly exaggerated," he concludes. "With the introduction of a sustained-release formulation of the drug, the incidence of seizures, at usual therapeutic doses, is the same as with placebo. Interestingly, bupropion lacks the adverse sexual effects of most of the other antidepressants and may, in some cases, actually have prosexual side effects."

For more information:
Dr. Jack Modell
1.800.UAB.MIST
mist@uabmc.edu