Selective Serotonin Reuptake Inhibitors
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 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, 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), affected by the TCAs.

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 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, 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 medications for the treatment of depression. There is no clinically significant difference in 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.

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 are indicators 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.

Adverse 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 of major depression 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

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 / appetite increasing effects. 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. 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. The selective pharmacology of the SSRIs results in a lower potential for pharmacodynamic drug interactions relative to other antidepressants. However, the SSRIs have been implicated in the development of the serotonin syndrome - a potentially life-threatening complication of treatment with psychotropic drugs 35.

The serotonin syndrome 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.

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