Soon after the first successes with MAO inhibitors, another class of tricyclic compounds appeared. The mode of action of these agents is not fully understood, but there is evidence that they block the reuptake of amine neurotransmitters, both norepinephrine and serotonin. Blocking this amine pump mechanism (called the presynaptic plasma transporter), which ordinarily terminates synaptic transmission, permits the persistence of neurotransmitter substances in the synaptic cleft and does no more than support the hypothesis that endogenous depression is associated with a deficiency of noradrenergic or serotonergic transmission.
These medications have been divided into classes of tertiary amines (imipramine, amitriptyline and doxepin, trimipramine), which have activity as reuptake inhibitors of norepinephrine and serotonin, and the secondary amines (desipramine, amoxapine, maprotiline, nortriptyline, protriptyline), which have a preferential effect on reuptake of norepinephrine. Subsequently, a number of additional antidepressant drugs were introduced. A full account of these drugs, which will not be attempted here, can be found in the chapters by Baldessarini and Nelson listed in the references.
The tricyclic antidepressants and the serotonergic drugs discussed in the next section, are presently the most effective drugs for the treatment of patients with depressive illnesses, the former being particularly useful for those with anergic depressions, early morning awakening, and decreased appetite and libido. The side effects of the tricyclic drugs are less frequent and far less serious than those of the MAO inhibitors.
The tricyclic compounds are also potent anticholinergic agents, which accounts for their most prominent and bothersome side effects—orthostatic hypotension, urinary bladder weakness, drowsiness, confusion, blurred vision, and dry mouth. They may also occasionally produce
CNS excitation—leading to insomnia, agitation, and restlessness—but usually these effects are readily controlled by small doses of benzodiazepines given concurrently or in the evenings.
As indicated earlier, the tricyclic drugs should not be given with a MAO inhibitor; serious reactions have occurred when small doses of imipramine were given to patients who had discontinued the MAO in the previous days or week. Both the MAO inhibitors and the tricyclic antidepressants are dangerous drugs when taken in excess.
Tricyclic compounds are a cause of accidental poisoning and suicide of depressed patients. It is common for the intoxicated patient to have taken several drugs, in which case chemical analyses of the blood and urine are particularly helpful in determining the drugs involved and in sorting out therapeutic and toxic concentrations. Mortality from overdose is mostly a result of cardiac rhythm disturbances, particularly tachyarrhythmias, and impaired conduction (atrioventricular block). Treatment consists of gastric aspiration and instillation of activated charcoal and the addition of physostigmine to reverse serious arrhythmias; the short duration of action of physostigmine requires that frequent doses be given. Dialysis is of no value because of the low plasma concentrations of the drug.
The selective serotonin reuptake inhibitors (SSRIs) constitute a newer class of antidepressants; paroxetine (Paxil), fluoxetine (Prozac), and sertraline (Zoloft) are common examples but they continue to be developed at a rapid pace. Of the several related drugs such as venlafaxine (Effexor), nefazodone (Serzone), mirtazapine (Remeron), citalopram (Celexa), trazodone (Desyrel), and bupropion (Wellbutrin), each has a novel structure that is not analogous to that of the other categories of antidepressants. They are believed to act similarly to the SSRI class by inhibiting the reuptake of serotonin and norepinephrine. This results in a potentiation of the actions of these neurotransmitters.