Tricyclic antidepressants tolerance

The tricyclic antidepressant clomipramine also has been studied for PMDD. In placebo-controlled trials, both continuous daily dosing and luteal phase administration proved effective.17 Compared with the SSRIs, however, clomipramine has a less desirable side-effect profile with low tolerability. 

In many clinical trials a positive control of a clinically established drug is often used for comparison purposes for example, a novel selective serotonin reuptake inhibitor (SSRI), may be compared with a more established tricyclic antidepressant, such as imipramine. The aim is to see whether the new SSRI is more efficacious or has fewer adverse side effects than the more established tricyclic (Chapter 12). In many such comparisons the new and older treatments are equally efficacious at relieving depression, but the newer drugs display fewer side effects this means that they are better tolerated by patients, so that they are more willing to continue taking the tablets. The high rates of compliance also mean that, in overall terms, newer drugs with fewer side effects tend to be more efficacious. 

Tricyclic antidepressants (TCAs) are effective for all depressive subtypes, but their use has diminished because of the availability of equally effective therapies that are safer on overdose and better tolerated. In addition to inhibiting the reuptake of NE and 5-HT, they also block adrenergic, cholinergic, and histaminergic receptors. 

Ziprasidone is well tolerated. Its common side effects are drowsiness, nausea, and constipation. Though there were initial concerns about untoward cardiological side effects similar to those produced by thioridazine and the tricyclic antidepressants, ziprasidone appears to be safe though it should probably not be used in patients with preexisting heart disease. 

The so-called atypical antidepressants such as venlafaxine and bupropion can be tried, but their safety and efficacy in treating patients with dementia have not been well studied. The older tricyclic antidepressants and monoamine oxidase inhibitors are not tolerated well by demented patients and should be avoided. Two possible exceptions are nortriptyline (Pamelor) and desipramine (Norpramin), but even these should be tried only after the newer antidepressants have proved ineffective. 

Antidepressants. Depression after TBl is routinely treated with antidepressant medicines. Although all antidepressants are potentially helpful, antidepressants prone to burdensome side effects, particularly sedative and anticholinergic side effects, should generally be avoided, as they are likely to be tolerated poorly by these patients. In addition, antidepressants that may increase the risk for seizure, such as many of the older tricyclic antidepressants (TCAs) and bupropion (Well-butrin), should be avoided because post-TBl patients as a rule are already more vulnerable to seizures. 

The word "tolerability" is perhaps a little clumsy but it describes accurately what is assessed, namely how well the drug is tolerated by those to whom it is administered. This last qualification is necessary because there are many instances in which a drug is better tolerated or less well tolerated by young healthy volunteers than by patients. For example, anxiolytics and tricyclic antidepressants are usually far better tolerated by patients with depression than by healthy volunteers. However, healthy volunteer studies generally provide useful information about tolerability even if it may under- or overestimate tolerability in patients. Many adverse reactions wiU be directly related to the known pharmacological activity of the drug and are therefore predictable. 

Use caution in patients with a recent history of Ml or unstable heart disease. Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants and was generally well tolerated in depressed patients with stable CHF. Bupropion was associated P.784... 

Our understanding of the mechanism of antidepressant action has evolved over time. In the late 1950s, the first molecules introduced for the treatment of MDD were the so-called tricyclic antidepressants (TCAs), represented by imipramine (7). Subsequent experience with TCAs supported the role of both 5-HT and NE, although these drug molecules act on other neuronal systems as well. Despite their elfectiveness, the use of TCAs was limited due to poor tolerability and safety concerns, in particular, severe toxicity when taken in overdose. 

In trials of hospitalized patients tricyclic antidepressants have generally been more efficacious than selective serotonin reuptake inhibitors (SSRIs). Otherwise there are no overall differences between the drugs in terms of tolerability or efficacy in primary care settings. After reviewing 15 trials it was concluded that drags are effective in the treatment of dysthymia with no differences between and within class of drugs. Tricyclic antidepressants are more likely to cause adverse events and dropouts. As dysthymia is a chronic condition, there remains little information on quality of life and medium or longterm outcome. 

With the introduction of the SSRIs, the safety and tolerability of antidepressants improved remarkably. As a class, these medications have little or no affinity for cholinergic, (3-adrenergic or histamine receptors and do not interfere with cardiac conduction. They are well tolerated by patients with heart disease and by the elderly, who are especially sensitive to the anticholinergic and orthostatic effects of the tricyclic antidepressant agents (TCAs) and monoamine oxidase inhibitors (MAOIs). 

In general, the SSRIs have a more tolerable side effect profile than the tricyclic antidepressants with their anticholinergic effects. Review of the rate that subjects in the controlled studies discontinued a SSRI because of adverse effects provides some perspective on how well tolerated the medications are, although the specifics may vary according to dosage and design (e.g., forced titration) and are not directly comparable. The rate of discontinuation was reported to be 12% (4/48) for fluoxetine (Emslie et ah, 1997), 9.7% for paroxetine (Keller et ah, 2001), 13% (12/92) for sertraline (March et ah, 1998), and 33% (19/57) (Riddle et ah, 2001) and 7.9% (5/63) for fluvoxamine (Walkup et ah, 2001). 

Antidepressants are as effective as benzodiazepines in the treatment of panic disorder. Moreover, antidepressants do not have the same risks of tolerance and dependency that are associated with benzodiazepine treatment. However, antidepressants take longer to work, so that significant improvement might not be observed until after a month of treatment. Although tricyclic antidepressants have been approved for the treatment of panic disorder, the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in its treatment has led them to become the favored treatment among antidepressant drugs. 

The selective serotonin reuptake inhibitors (SSRIs) are established and accepted antidepressants. Their easy tolerability and simplicity of use have led to their widespread use it has been estimated that at least 50 million people who would not otherwise have received treatment for their depression have received these drugs. It appears that the proportion of patients treated with tricyclic antidepressants (TCAs] has remained relatively stable and the contribution of the SSRIs has been to increase substantially the size of the patient pool receiving treatment for depression. It is fair to say that the advent of the SSRIs has facilitated more ready discussion of depression and has reduced to some extent the stigma of mental illness. The development of the SSRIs has made it more acceptable for patients to come forward for treatment, although... 

In this chapter, we review the pharmacology of several selective serotonin reuptake inhibitors [SSRIs] and other drugs that act on the serotonergic system. That these developments have enhanced safety and tolerability is now beyond dispute, but it is also clear that these agents are no more effective than the old-style tricyclic antidepressants [TCAs]. [For a comprehensive discussion of serotonergic medication, see Montgomery, Chapter 12, in this volume.] Here, several compounds are discussed in detail. 

Long-term efficacy and tolerability is of considerable clinical importance for any medication proposed for the treatment of panic disorder. Tricyclic antidepressants, in particular, are associated with side effects such a weight gain and anticholinergic effects, which may make them difficult for patients to tolerate long-term. 

Mexilitine has analgesic properties in several neuropathic pain syndromes and is an alternative agent for treatment of patients who fail to respond to tricyclic antidepressants or who cannot tolerate them... 

FIGURE 6-39. Mechanism of action of serotonin selective reuptake inhibitors (SSRIs)—part 5. Finally, once the SSRIs have blocked the reuptake pump (Fig. 6-36), increased somatodendritic serotonin (Fig. 6-36), desensitized somatodendritic serotonin 1A autoreceptors (Fig. 6—37), turned on neuronal impulse flow (Fig. 6-38), and increased release of serotonin from axon terminals (Fig. 6— 38), the final step shown here may be the desensitization of postsynaptic serotonin receptors. This has also been shown in previous figures demonstrating the actions of monoamine oxidase (MAO) inhibitors (Fig. 6-4) and the actions of tricyclic antidepressants (Fig. 6—6). This desensitization may mediate the reduction of side effects of SSRIs as tolerance develops. 

MacGillivray S, Arroll B, Hatcher S, et al. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care systematic review and metaanalysis. BMJ. 2003 326 1014. 

Peretti S, Judge R, Hindmarch I. Safety and tolerability considerations tricyclic antidepressants vs. selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl. 2000 403 17-25. 

The efficacy of imipramine has been repeatedly demonstrated in controlled trials about 85% of children treated within a week of the start of medication, but tolerance frequently develops after a number of weeks and relapse is high after discontinuation of the treatment. Relatively low doses of imipramine only are needed, but the typical side effects of tricyclic antidepressants limit the prolonged use of the drug. The mechanism of action of imipramine in the treatment of nocturnal enuresis is unclear but one possible action is through a direct anticholinergic action on the bladder wall. 

Antidepressants were first introduced into the market in the 1950s with the serendipitous discovery of the antidepressant effect of two drugs initially evaluated for other medical uses Iproniazide, a monoamine oxidase inhibitor (MAOI), and Imipramine, a tricyclic antidepressant (TCA). Since then, a whole new generation of chemically and pharmacologically unrelated compounds have been introduced, which appear to be safer and better tolerated due to a more specific mechanism of action. These include selective serotonin reuptake inhibitors (SSRIs), serotonin and... 

Correct choice = A. The choice of tricyclic antid-pressants depends on the tolerance of side effects and the desired duration of action. Orthostatic hypotension (not hypertension) is a side effect of the tricyclic drugs. The tricyclic antidepressants nonspecificaily block the uptake of norepinephrine and serotonin the onset of action requires 2 weeks or longer. These drugs are usually given orally. 

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