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Comparing Selective Serotonin Reuptake Inhibitors (SSRIs) to Tricyclic Antidepressants (TCAs)
Safety and Tolerability of TCAs versus SSRIs - possible title for article for sending
Selective Serotonin Reuptake Inhibitors versus Tricyclic Antidepressants Antidepressants are the third most-prescribed drugs in the United States. Antidepressants are drugs that relieve the symptoms of depression. They were first developed in the 1950s and have been used regularly since then. There are many different families of antidepressants available today. The two most common groups 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 used extensively. Before the introduction of Selective Serotonin Reuptake Inhibitors TCAs were the standard treatment for depression. 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 if taken in overdose. Main similarities and differences, which explain why SSRIs are more commonly prescribed than TCAs in the treatment for depression:
Prior to the SSRIs, all 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. The other class of antidepressants, the monoamine oxidase inhibitors (MAOIs), came from a failed attempt to develop effective antitubercular medications. The first studies of benzodiazepines were unsuccessful attempts to treat patients with schizophrenia. The nature of older chance-discovery drugs is that they have many clinical effects either because they affect a site of action with broad implications for organ function or because they affect multiple site of actions. 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. It was hoped that the SSRIs, which act selectively on the serotonergic system and avoid activity on receptor systems that appear unrelated to antidepressant effect, would not be associated with the unwelcome side effects characteristic of the TCAs. This selectivity of pharmacological action was also expected to result in safer drugs particularly in cardiotoxicity and overdose toxicity. Each of the SSRIs was the product of a similar 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 a-adrenergic receptors), affected by the TCAs. The fact that SSRIs were designed to avoid affecting these other neuroreceptors explains many of the pharmacological differences between the SSRIs and the TCAs and explains the similarities among the SSRIs. 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. Tricylic antidepressants work by raising the levels of neurotransmitters serotonin and norepinephrine in the brain by slowing the rate of reuptake, or 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 less 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 or other antidepressants, SSRIs exhibit 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. There is no clinically significant difference in effectiveness between SSRIs and TCAs. SSRIs are as effective as TCAs in the treatment of major depression. Generally, about two thirds of people with depression who take any one type of antidepressant will find that it improves the way they feel. The conclusion that TCAs and SSRIs have comparable antidepressant efficacy is based on the fact that 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. Important difference between SSRIs and TCAs is a better overall tolerability profile in terms of a lower incidence of both nuisance and serious adverse effects. SSRIs affect fewer sites of action and hence cause fewer types of adverse effects. Many side effects associated with TCAs are related to anti-muscarinic properties. TCAs most commonly cause anticholinergic adverse 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, occasionally precipitating conditions requiring immediate medical attention such as acute glaucoma, paralytic ileus of the bowel or acute urinary retention. 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 have marked effects on cardiac function and 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. Although the SSRIs are associated with a long list of adverse effects, in most patients they tend to be better tolerated than the adverse effects of the TCAs. In most patients side effects of SSRIs are mild and transient, rarely requiring discontinuation of therapy. 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. Compared to TCAs, SSRIs have more gastro-intestinal side effects. SSRIs most commonly cause:
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. TCAs are poorly tolerated by patients, which contributes considerably to the therapeutic failure of these antidepressants due to poor compliance. Their 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. Unlike the TCAs, the SSRIs do not possess significant sedative, anticholinergic, or hypotensive effects and do not have significant effects on cardiac conduction. This contributes to the tolerability of these antidepressants and results in fewer side effect attributed discontinuations than is usual with the TCAs. SSRIs have a relatively modest advantage over tricyclic agents in terms of lower dropout rates, particularly when discontinuation of drug therapy is attributed to the occurrence of adverse side effects. The SSRIs are dramatically safer in acute overdose than the TCAs. An overdose of a tricyclic medication is serious and potentially lethal, it requires immediate medical attention. Overdosing on tricyclic antidepressants can lead to involvement of many organ systems but primarily affects the heart and the brain. 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 than that with TCAs. 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. 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 SSRIs are generally more expensive than TCAs, but large price differences exist among TCAs. SSRIs are equally as efficient as the tricyclics in the treatment of mild to moderate depression. However, the TCAs still have an important place as the first-line treatment for patients with severe (melancholic/endogenous) depression. The major clinical advantage of the SSRIs lies in their improved side effect profile and better tolerance, which is reflected in the better compliance seen even in the controlled studies. They appear to be safer than the TCAs on cardiotoxic measures and are associated with fewer deaths from overdosage. Increasingly clinicians are recognizing the importance of using these safer well-tolerated antidepressants as first line treatment. Comparison of compliance between SSRIs and tricyclic antidepressants: a meta-analysis. PubMed. U.S. National Library of Medicine . |
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