Antidepressants: Comparison of SSRIs and TCAs

Tricyclic antidepressants are named after the drugs' molecular structure, which contains three rings of atoms. Before the introduction of SSRIs, TCAs were the standard treatment for depression. Selective serotonin reuptake inhibitors have replaced tricyclic antidepressants as the drugs of choice in the treatment of depressive disorders, mainly because of their improved tolerability and safety if taken in overdose.

Main similarities and differences:

• SSRIs and TCAs have similar efficacy for the treatment of depression
• SSRIs have fewer anticholinergic and cardiovascular side effects
• SSRIs are better tolerated by patientsSSRIs are safer in overdose than TCAs

Mechanism of action

The brain communicates with itself through the use of special chemicals called neurotransmitters such as serotonin, norepinephrine, and dopamine. There is correlation between the amount of these chemicals in the brain and a person's mood. Low levels of serotonin and norepinephrine have not been proven to cause depression but it widely believed that elevation of these chemicals is associated with improvement in mood in depressed people. Both SSRIs and TCAs work by prolonging the effects of neurotransmitters, but have different mechanism of action. TCAs work by raising the levels of neurotransmitters serotonin and norepinephrine in the brain by slowing the rate of reabsorption by nerve cells. Unfortunately, the TCAs also block histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this action leads to unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. Unlike TCAs, SSRIs are highly selective: they act as weak inhibitors in the reuptake of non-serotonergic neurotransmitters such as norepinephrine, but act as strong inhibitors in the reuptake of serotonin. This selectivity is what, perhaps, accounts to the fact that SSRIs are associated with lower rate side effects than with TCAs.

Efficacy

SSRIs are as effective as TCAs in the treatment of major depression. They both produce overall response rates of 60% to 65%. Both the SSRIs and the TCAs produce a 25% to 30% higher response rate than placebo. Although the SSRIs have become the most commonly prescribed drugs for depression, there are clinical situations in which TCAs may be more appropriate.

Side effects

SSRIs affect fewer sites of action and hence cause fewer types of side effects than TCAs. TCAs most commonly cause anticholinergic side effects, such as dry mouth, sedation, dizziness, blurred vision, constipation, and urinary retention. These effects can occasionally be quite serious or exacerbate underlying problems or tendencies in the affected organ system. Weight gain is a common complaint. The orthostatic hypotension (dizziness upon arising or otherwise rapidly changing posture) that can occur on TCAs may cause falls with resultant trauma. The TCAs can be cardiotoxic in therapeutic dosage as well as overdose. This limits their usefulness particularly in the elderly, who are at increased risk of undetected impaired cardiac function.

With many tricyclics, the most troublesome effect with ongoing use is sedation. They are often administered at bedtime so that this effect is bearable, but it may persist into the following day. Unlike the TCAs, the SSRIs do not possess significant sedative, anticholinergic, or hypotensive effects and do not have significant effects on cardiac conduction. Therefore, SSRIs are safer to use in elderly patients.

SSRIs most commonly cause:

• gastrointestinal adverse effects (nausea and diarrhoea)
• central nervous system effects (headache, dizziness, agitation, insomnia and tremor)
• sexual dysfunction

Compared to TCAs, SSRIs have fewer anticholinergic, sedative and cardiovascular adverse effects but have more gastro-intestinal side effects. With the exception of sexual dysfunction, SSRIs side effects generally are not severe enough to make the patient noncompliant and often subside as treatment continues.

Overdose

A major benefit of the SSRIs is the reduced toxicity in overdose compared with the TCAs. Overdosing on tricyclic antidepressants can lead to involvement of many organ systems but primarily affects the heart and the brain. An overdose of a TCAs requires immediate medical attention and is potentially lethal. Symptoms of an overdose usually develop within an hour of ingestion and may start with rapid heartbeat, dilated pupils, flushed face and agitation, and progress to confusion, loss of consciousness, seizures, irregular heart rate, cardiorespiratory collapse and death. Overdosage with SSRIs is much less hazardous and less likely to be life-threatening. They do not affect intracardiac conduction. Patients have survived overdoses of each of the SSRIs that were many times their usually effective antidepressant doses without serious toxicity: no arrhythmias, no disturbance of blood pressure, no seizures, no coma, no respiratory depression.