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Comparing Selective Serotonin Reuptake Inhibitors (SSRIs) to Tricyclic Antidepressants (TCAs)

Selective Serotonin Reuptake Inhibitors versus Tricyclic Antidepressants
History of development
Mechanism of action
Efficacy
Side effects
Tolerability
Dropout rates
Safety in overdose
Simplicity
Conclusions

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

SSRIs versus Tricyclic Antidepressants

Antidepressants are the third most-prescribed drugs in the United States. Antidepressants, the drugs that relieve the symptoms of depression, were first developed in the 1950s and have been extensively used since then. There are many different types of antidepressants available today. The two most valuable classes are Selective Serotonin Reuptake Inhibitors (SSRIs) and Tricyclic Antidepressants (TCAs).

Tricyclic antidepressants are a class of antidepressant drugs first used in the 1950s. They are named after the drugs' molecular structure, which contains three rings of atoms. Tricyclic antidepressants are one of the oldest classes of antidepressants and are still widely used. Before the introduction of Selective Serotonin Reuptake Inhibitors, TCAs were the first-line treatment choice for depression and anxiety disorders.

Selective Serotonin Reuptake Inhibitors have replaced TCAs as the drugs of choice in the treatment of depressive disorders, mainly because of their improved tolerability and safety.

History of development

Prior to the SSRIs, most of psychotropic medications were the result of chance observation. Tricyclic antidepressants were discovered by chance. The TCAs were the result of an unsuccessful attempt to improve on the antipsychotic effectiveness of phenothiazines (medication used in the treatment of schizophrenia). Molecular modifications of phenothiazines led to synthesis of imipramine, the first clinically useful tricyclic antidepressant.

Older chance-discovery drugs have many clinical effects either because they affect a site of action with broad implications for organ function or because they affect multiple sites of action. Chance-discovery drugs typically will produce a number of undesired, as well as desired, effects and will have a narrower therapeutic index in comparison with a drug that was rationally developed to affect only the site of action necessary to produce the desired response.

The SSRIs were developed in response to the need for better tolerated, safer antidepressants than the TCAs, but no less effective for the symptoms of depression. The first SSRI, fluoxetine (Prozac) was released in 1987. Each of the SSRIs was the product of a development strategy in which the goal was to produce a drug capable of inhibiting the reuptake of serotonin, but without affecting the various other neuroreceptors (ie, histamine, acetylcholine, and alpha1-adrenergic receptors).

The development of the SSRIs, with their selective mode of action, has resulted in a class of antidepressant drugs possessing an improved side-effect profile, while retaining good clinical efficacy.

The fact that SSRIs were designed to avoid affecting other neuroreceptors explains many of the pharmacological differences between the SSRIs and the TCAs and explains the similarities among the SSRIs.

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.

Tricyclic antidepressants work by raising the levels of neurotransmitters serotonin and norepinephrine in the brain by slowing the rate of reuptake (reabsorption) by nerve cells. TCAs act as strong inhibitors in the reuptake of both norepinephrine and serotonin. Unfortunately, the TCAs also block histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this lack of selectivity is what accounts for the unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness.

Unlike TCAs antidepressants, 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. Because of this selectivity, there are fewer side effects associated with SSRIs than with TCAs and their side effects are due to actions at other serotonin receptors in the central nervous system and the gut wall.

Unlike TCAs, SSRIs have variances in molecular structures. Tricyclic antidepressants (amitriptyline, amoxapine, clomipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, and trimipramine) are structurally similar. Selective serotonin reuptake inhibitors (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) are structurally diverse but share a common mechanism of action.

Efficacy

Both TCAs and SSRIs are effective for the treatment of depression. There is no clinically significant difference in the effectiveness between SSRIs and TCAs. Generally, about two thirds of people with depression who take any one type of antidepressant will find that it improves the way they feel.

Overall efficacy between the two classes is comparable. The conclusion that TCAs and SSRIs have comparable antidepressant efficacy is based on the fact that they both produce overall response rates of about 60%. Both the SSRIs and the TCAs produce a 20% higher response rate than placebo 10, 11.

Tricyclic antidepressants and selective serotonin reuptake inhibitors are equally effective in the treatment of moderate depressive disorders 14. No significant differences exist in efficacy between selective serotonin reuptake inhibitors and tricyclics in patients in primary care 36.

SSRIs and TCAs are equally effective in the treatment of panic disorder 19.

Although the SSRIs have become the most commonly prescribed drugs for depression, there are clinical situations in which TCAs may be more appropriate:

Depressed in-patients. SSRIs are not proven to be as effective as TCAs in in-patients and against amitriptyline 11. Several studies have shown that some TCAs may be more effective than SSRIs in depressed in-patients, with the strongest evidence for amitriptyline 3, 40. It may be explained that TCAs have a dual action in inhibiting both 5-HT and noradrenaline reuptake.
Severe depression. There is evidence that the TCAs are more efficacious for severe depression. They have an important place as the first-line treatment for patients with severe (melancholic/endogenous) depression 34.

Remission rate. Remission rate for TCAs (44.1%) is higher than for SSRIs (37.7%) 12.

Side effects

SSRIs affect fewer sites of action than TCAs, and as a result cause fewer types of adverse effects. The SSRIs have a better overall tolerability profile than the TCAs in both acute and long-term treatment 33. SSRIs induce significantly less anticholinergic, antihistaminergic and cardiotoxic side-effects than TCAs 5.

Cardiovascular effects. Tricyclic antidepressants have significantly higher rate of serious cardiovascular side effects 18. Selective serotonin reuptake inhibitors as a class are less likely to affect cardiovascular parameters.

Through a combination of anticholinergic activity, direct myocardial depressant activity and an effect on the adrenergic neuron, TCAs can cause a combination of arrhythmias (disturbances in cardiac rhythm or conduction), blood pressure abnormalities (orthostatic hypotension) and congestive heart failure 31. The major side effects in therapeutic dosage include heart rate increase, postural hypotension and slight prolongation of the intraventricular conduction time and QT interval. 39

Recent nationwide population-based study revealed that the use of tricyclic antidepressants is associated with a higher rate of stoke, compared to use of SSRIs 43.

SSRIs also appear to affect the cardiovascular system 13, 32.

Anticholinergic effects (dry mouth, blurred vision, drowsiness, constipation, and difficulty in urination). Dry mouth is a most common TCAs' side effect 37. Tricyclic antidepressants produce a greater incidence of dry mouth, drowsiness, constipation and fatigue than SSRIs 4, 38.

Weight gain and increased appetite. Both SSRIs and TCAs can cause unwanted weight gain. However, there is some evidence that tricyclic antidepressants may be more likely to cause weight gain and increased appetite than the selective serotonin reuptake inhibitors 41, 42.

Sexual effects. Sexual dysfunction such as decreased sexual desire, erectile difficulties and delayed ejaculation has been reported with all classes of antidepressants. Sexual dysfunction is one of the most frequent and persistent SSRI adverse effect. These drugs are more likely to cause sexual dysfunction than the TCAs 4, 23.

Central Nervous System effects (headache, dizziness, agitation, insomnia and tremor). In contrast to the tricyclic antidepressants, SSRIs are more likely to cause headache, agitation, insomnia and tremor 42.

Nausea. Nausea occurs more frequently with SSRIs. It is the most common adverse event reported during treatment with SSRIs 37, 38.

Gastro-intestinal effects. Compared to TCAs, SSRIs have higher incidence of gastro-intestinal side effects 23, 42.

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.

Interactions

Alcohol. TCAs are associated with the dangers of drinking alcohol while taking antidepressant. TCAs cause serious potentiation of the central nervous system (CNS) depressant effects of alcohol and other CNS depressants such as benzodiazepines. Such potentiation occurs when TCAs and alcohol are taken together due to the antihistaminic effects of TCAs. Since SSRIs have been designed to avoid blocking the histamine receptor, they do not pharmacodynamically potentiate the effect of alcohol or other CNS depressants.

Drug-drug interactions. Since TCAs block alpha1-adrenergic receptors they can reverse the antihypertensive effect of guanethidine and clonidine. Orthostatic hypotension may be increased with diuretics and hydralazine. Myocardial depression may occur with lidocaine, phenytoin or propranolol. Dangerous additive effects may result from concomitant use of a tricyclic antidepressant and either quinidine or procainamide 30.

The selective pharmacology of the SSRIs results in a lower potential for pharmacodynamic drug interactions relative to other antidepressants. SSRIs are designed to avoid blocking the alpha1-adrenergic receptor, so they do not potentiate the effects of concomitantly prescribed antihypertensive medications, in contrast to TCAs.

Serotonin syndrome. SSRIs have been implicated in the development of the serotonin syndrome 35. The serotonin syndrome, a potentially life-threatening condition, is an adverse drug interaction characterized by the triad of altered mental status, autonomic dysfunction, and neuromuscular abnormalities.

SSRIs are more likely to cause serotonin toxicity than TCAs.

Tolerability

SSRIs have significant and clinically important advantage over TCAs with respect to tolerability. Selective serotonin reuptake inhibitors are better tolerated than tricyclic antidepressants 1, 11, 36. Recent meta-analysis found that SSRIs are noticeably better tolerated compared with TCAs in young patients44.

One of the major advances of the SSRIs antidepressants is their lack of anticholinergic, cardiovascular and other adverse effects, which were a major limitation of the TCAs 8. Unlike the TCAs, they do not cause anticholinergic, hypotensive or sedating reactions, and are not associated with impaired cognitive function 33. Also, SSRIs do not have significant effects on cardiac conduction. This contributes to the better tolerability of these antidepressants and results in fewer side effect attributed discontinuations than is usual with the TCAs.

TCA's well known anticholinergic effects are often cited by patients as the reason for withdrawing from treatment. The difficulty experienced in tolerating the unwanted side effects also prejudices the use of therapeutic doses. Even if treatment is initiated at low doses and increased slowly, it is sometimes difficult to reach the full therapeutic dose.

Drop-outs

SSRIs have an advantage over tricyclics in terms of lower rates of treatment discontinuation, particularly when the discontinuation is attributed to side effects 11, 36.

Also, older tricyclics (imipramine and amitriptyline) are associated with higher discontinuation rates than more recent compounds 2.

Toxicity and safety

The clinical use of tricyclic antidepressants is often complicated by toxicity and safety problems due to their effects on multiple mechanisms of action, many of which are unnecessary for therapeutic effect. SSRIs represent a major advance over tricyclics, because of their lower toxicity.

Tricyclic antidepressants are among the commonest causes of both non-fatal and fatal drug poisoning in the world. TCAs produce a wide variety of toxic effects. The most severe toxicity occurs in the cardiovascular system, the peripheral nervous system (PNS), and the central nervous system. The SSRIs are dramatically safer in overdose than the TCAs, and exhibit lower toxicity and lethality 28, 33.

Since all SSRIs have been designed to avoid affecting fast sodium channels in contrast to TCAs, they all have a wide therapeutic index (ie, the gap between the effective dose and a potentially toxic dose). 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. All of these adverse effects do occur with overdose of TCAs as little as 5 times their therapeutic doses.

An overdose of a tricyclic is serious and potentially lethal, it requires immediate medical attention. 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, hypotension, pulmonary edema 26, 28. In a potentially fatal situation can develop respiratory arrest, convulsions, ventricular arrhythmias, coma and death 29. The cardiotoxic effect of TCA overdose is the most serious complication. The greatest number of adverse cardiac symptoms and electrocardiographic changes are likely to occur within the first 24 hours after overdose 27.

Simplicity

Simplicity refers to how easy it is for the physician to prescribe the optimal dose and for the patient to take it. One advantage shared by both TCAs and SSRIs is that they can generally be taken once a day and be effective. However, optimal dosing with TCAs is often more problematic than with SSRIs.

Traditionally, treatment with TCAs is begun at what is usually a subtherapeutic dose and gradually titrated upward to an effective antidepressant dose. This approach is taken so that the patient can develop some tolerance to the adverse effects caused by these drugs due to their ability to block specific neuroreceptors. In contrast, SSRIs can usually be started at the effective dose from the beginning. There is generally no need to titrate the dose of the SSRIs upward in most patients.

With TCAs, the physician can use therapeutic drug monitoring (TDM) to ensure that the patient is achieving plasma drug concentration within a range associated with the optimal antidepressant response with the minimum risk of adverse effects in most patients. The avoidance of potentially toxic concentrations is the primary reason for using TDM with TCAs.

Costs

The main advantage of tricyclics over SSRIs is that the tricyclics have generic versions which are far less expensive. However, because of the many side effects associated with tricyclics, doctors often begin with SSRIs.

Studies have shown that overall treatment costs with SSRIs are no greater than those for TCAs. This is despite the tricyclic antidepressants are less expensive per tablet than the SSRIs 15, 16. The total cost of therapy with TCAs may be substantially increased by noncompliance. If patients discontinue treatment, overall cost increases as a result of prolongation of the illness and the cost of additional treatment.

Conclusions

Main similarities and differences, which explain why SSRIs are more commonly prescribed than TCAs in the treatment for depression:

SSRIs and TCAs have similar efficacy for the treatment of depression
SSRIs have fewer anticholinergic and cardiovascular side effects
TCA have fewer sexual and gastrointestinal side effects
SSRIs are better tolerated by patients
TCAs are associated with more frequent treatment discontinuations (i.e. more people dropping out tricyclics than SSRIs)
SSRIs are safer in overdose than TCAs

Comparing Selective Serotonin Reuptake Inhibitors (SSRIs) to Tricyclic Antidepressants (TCAs)

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