Antidepressant and Antimanic Medications: Monoamine-Releasing Agents
Monoamine-releasing agents are also categorized as psychostimulants and primarily include amphetamine, methamphetamine, methylphenidate, and pemoline. They cause the release of and weakly block the reuptake of NE, DA, and serotonin. Amphetamine was available on an over-the-counter basis until the FDA reclassified it as a prescription drug in 1938 and further restricted its availability in 1951 due to widespread misuse and abuse.

The literature on the use of monoamine-releasing agents in the treatment of depression is surprisingly large and disappointingly poorly controlled given the beneficial effects usually reported. Almost all large, controlled trials were conducted before 1970, and different studies used different dosing strategies, diagnostic methods, and outcome measures. No long-term studies have been conducted. More recent studies have focused on medically ill or geriatric patients with MDE.

Monoamine-releasing agents are rapidly metabolized into inactive compounds and generally have relatively short half-lives (4-8 hours). The most common side effects are insomnia, drowsiness, restlessness, nausea, weight loss, weight gain, and hypertension. At high doses these agents can cause a characteristic paranoid psychosis. These drugs are generally well tolerated in the clinical dosage range (e.g., 5-30 mg/day dextroamphetamine), with most patients experiencing no side effects and with insomnia being the most common side effect reported.

A unique feature of this group of agents is that the onset of action is usually much more rapid than with other agents. Improvement can often be seen within hours or days of treatment initiation but frequently wanes as the plasma levels decline following each dose, resulting in an uneven response. The use of higher doses or of longer-acting preparations frequently causes nighttime activation with resulting insomnia.

Neurotransmitter Receptor Agonists
Few drugs with receptor agonist properties have been found to have antidepressant properties despite the fact that we now have relatively selective compounds for most known neurotransmitter receptors and their pharmacological subtypes. This may be because receptor agonists stimulate receptors in a nonphysiological manner. The natural transmitter is released in a pulsatile fashion as the nerve cell fires and then is rapidly taken back up (reuptake) into the nerve cell through uptake pumps and repackaged into vesicles or metabolized by MAO. The natural transmitter has a broad profile of action, binding to all subtypes of receptors for it. In contrast, a pharmacological agonist constantly stimulates certain subtypes of receptors and is not usually taken up or locally metabolized. This leads to adaptive changes in the receptors or in the coupling mechanisms and second-messenger systems (downregulation).

The use of benzodiazepine receptor agonists as antidepressants has been studied for many years. The earlier studies primarily investigated diazepam and chlordiazepoxide, whereas more recent studies have focused primarily on alprazolam. The Depression Guideline Panel (1993b) surveyed previous acute-treatment studies evaluating the efficacy of diazepam (11 studies), chlordiazepoxide (4 studies), and alprazolam (22 studies). Meta-analysis of these data revealed little efficacy for diazepam and chlordiazepoxide but modest evidence of effectiveness for alprazolam in mild to moderately depressed outpatients. The lack of data regarding continuation and maintenance and the potential for tolerance and withdrawal led the Depression Guideline Panel to recommend that these agents not be used routinely for the treatment of depression.

Check also:
Antidepressant and Antimanic Medications
Depression-Focused Psychotherapies
Psychodynamic Psychotherapies
Combined Medication and Psychotherapy
Electroconvulsive Therapy
Light Therapy
Treatment-Resistant Mood Disorders
Treatment of Mood Disorders in the Medically Ill Patient
Strategies and Tactics in the Treatment of Depression