Tricyclic antidepressants TCAs

The main focus of pharmacoeconomic studies of antidepressants has inevitably fallen on comparisons between tricyclic antidepressants (TCAs) and the more expensive selective serotonin reuptake inhibitors (SSRIs). Few data are available for comparisons within the SSRIs or for newer antidepressants. 

The tricyclic antidepressants (TCAs) derive their name from their three-ringed molecular structure (Fig. 20.3) and emerged, in 1958, from a search for better neuroleptics than chlopromazine among the phenothiazines. The prototype, imipramine, turned out to be ineffective in treating the positive symptoms experienced by schizophrenics but it did relieve their depression (negative symptoms). In fact, imipramine is still the standard agent against which novel antidepressants are compared in clinical trials. 

Tricyclic antidepressants (TCAs) such as amitriptyline and doxepin have been used with some success in the treatment of IBS-related pain (Table 18-5). They modulate pain principally through their effect on neurotransmitter reuptake, especially norepinephrine and serotonin. Their helpfulness in functional gastrointestinal disorders seems independent of mood-altering effects normally associated with these agents. Low-dose TCAs (e.g., amitriptyline, desipramine, or doxepin 10 to 25 mg daily) may help patients with IBS who predominantly experience diarrhea or pain. 

The tricyclic antidepressants (TCAs), such as imipramine, can alleviate symptoms of ADHD. Like bupropion, TCAs likely will improve symptoms associated with comorbid anxiety and depression. The mechanism of action of TCAs is in blocking norepinephrine transporters, thus increasing norepinephrine concentrations in the synapse the increase in norepinephrine is believed to alleviate the symptoms of ADHD. TCAs have been demonstrated to be an effective non-stimulant option for ADHD but less effective than stimulants. However, their use in ADHD has declined owing to case reports of sudden death and anticholinergic side effects6,13 (Table 39-3). Further, TCAs may lower seizure threshold and increase the risk of car-diotoxicity, (e.g., arrythmias). Patients starting on TCAs should have a baseline and routine electrocardiograms. 

Interaction with drug metabolism liquorices, which are the most commonly used herbs in TCM can increase metabolites (e.g., nortriptyline, desipramine, and norclomipramine) of tricyclic antidepressants (TCAs) and may produce more side effects (such as dry mouth, constipation, palpitation, etc.) (Xu, 2004 Zhu Huang, 2004). 

Non-compliance issues appear more prevalent in some non-Western cultures. One study in South Africa revealed non-compliance rates to oral neuroleptics in two-thirds of Black patients and one-half of colored patients compared to only one-quarter of Caucasians (Gillis.Trollip, Jakoet etal., 1987). Cultural and communication factors were considered to be significant barriers apart from those related to cost and social factors. Kinzie et al. (1987) reported that despite prescribing adequate doses of tricyclic antidepressants (TCAs) to depressed Asian refugees,... 

Compared to antipsychotics, there are even fewer studies on the prescribing patterns of antidepressants done in Asian countries. Pi etal. (1985) conducted a survey of psychotropic prescribing practices reported by psychiatrists in 29 medical schools in 9 Asian countries. Daily dose range of tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and nortriptyline in Asian countries was comparable to the practice in USA. This is despite differences found between Asian and non-Asian populations in the pharmacokinetics of TCAs (Pi et al, 1993). A questionnaire on the practical prescribing approaches in mood disorders administered to 298 Japanese psychiatrists was reported by Oshima et al. (1999). As first-line treatment, the majority of respondents chose newer TCAs or non-TCAs for moderate depression and older TCAs for severe depression. Combination of antidepressants and anxiolytics was preferred in moderate depression, while an antidepressant and antipsychotic combination was common in severe psychotic depression. Surprisingly, sulpiride was the most favored drug for dysthymia. In a naturalistic, prospective follow-up of 95 patients with major depression in Japan, the proportion of patients receiving 125 mg/day or less of imipramine was 69% at one month and 67% at six months (Furukawa et al., 2000). 

Virtually all types of drug that have been shown to be effective in major depression exert profound effects on the functioning of the serotoninergic or noradrenergic systems, or both. Although some treatments have been shown to decrease the sensitivity of certain postsynaptic 5-HT and NE receptors, it is generally believed that it is an enhancement of neurotransmission in these systems that is responsible for the improvement of the core symptoms of depression. For instance, long-term administration of tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs) decreases the density of (3-adrenoceptors and cortical 5-HT2 receptors (Blier and Abbott 2003). 

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

Amitriptyline appears to be the tricyclic antidepressant (TCA) of choice, but imipramine, doxepin, nortriptyline, and protriptyline have also been used. 

Common side effects of the SSRIs are somnolence, nausea, ejaculation disorders, decreased libido, dry mouth, insomnia, and fatigue. Tricyclic antidepressants (TCAs) commonly cause sedation, orthostatic hypotension, anticholinergic effects, and weight gain. TCAs are very toxic on overdose. 

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. 

Pharmacokinetic Drug Interactions Involving Tricyclic Antidepressants (TCAs)... 

Tricyclic antidepressants (TCAs) Epilepsy Lower seizure threshold (more so if toxic levels of TC A)... 

GG is used extensively for analysis of antidepressants (Orsulak et al, 1989), but HPLC assays and enzyme immunoassays have become more popular in recent years. However, GC has advantages such as economy and ready availability. LCD and NPD generally are the detectors of choice (Coutts and Baker, 1982). NPD is relatively efficient for the analysis of tricyclic antidepressants (TCAs) as derivatization is not necessary, although the secondary, demethylated amines are sometimes derivatized to improve resolution and peak shape (Coutts and Baker, 1982). Acetylation, under aqueous or anhydrous conditions, followed by GC-NPD, has been used extensively for analysis of TCAs and the tetracyclic antidepressant maprotiline in plasma samples (Drebit et al., 1988). O Table 1-1 summarizes GC assays for some commonly prescribed antidepressants and their metabolites. 

The traditional scheme is complicated by the fact that some antidepressants exhibit characteristics of more than one class. For example, clomipramine, a tricyclic antidepressant (TCA) with side effects and toxicity similar to other TCAs, works more like the selective serotonin reuptake inhibitors (SSRls). Similarly, venlafaxine and duloxetine, which are usually grouped with the atypical antidepressants, have a side effect and safety profile comparable to the SSRls. Although a classihcation system based on mechanism of action offers some advantage (see Table 3.7), even this scheme is limited by the fact that antidepressants that work in the same way may have widely divergent side effect and safety profiles. In the following discussion, the traditional classification system is adopted. Although fraught with problems and inconsistencies. 

Tricyclic Antidepressants (TCAs). Like iproniazid, the first TCA was also developed in the 1950s for another purpose. Imipramine (Tofranil) is structurally similar to the early antipsychotics and was hoped to provide an alternative to chlor-promazine (Thorazine). It proved to be a poor antipsychotic but was surprisingly found to be an effective antidepressant. The tricyclics are so named because a three-ringed structure forms the hub of the molecule. 

Tricyclic Antidepressants (TCAs). The TCAs were also introduced in the 1950s, and some were discovered to be effective anxiolytics in the 1960s. For example, early studies pioneered by Donald Klein and his colleagues indicated that imipra-mine (Tofranil) effectively relieved panic attacks. Like the MAOIs, the TCAs are not addictive but also require over 3 weeks to begin to achieve significant therapeutic benefit for anxiety. 

Tricyclic Antidepressants (TCAs). The TCAs, particularly imipramine (Tofranil), were also discovered soon after their introduction to be effective in the treatment of panic attacks. Imipramine, the best-studied TCA in the treatment of panic disorder, is most often helpful at daily doses of 150-250 mg, though it must be started at 10-25 mg, usually at bedtime, and gradually increased over 2-4 weeks. Although they are not as well studied, many clinicians prefer to use the secondary amine TCAs, desipramine (Norpramin) and nortriptyline (Pamelor), because they have milder side effects than imipramine. Clomipramine (Anafranil), though probably the TCA with the greatest side effect burden, is often said to be most effective in patients with refractory disease. 

Tricyclic Antidepressants (TCAs). Because of their effectiveness not only for depression but for anxiety disorders such as panic disorder as well, TCAs were the first medications formally tested in the treatment of PTSD. Three TCAs, amitriptyline, imipramine, and desipramine, have been studied in small trials, producing modest benefit for reexperiencing and hyperarousal symptoms, without any relief of avoidance/numbing symptoms. Given this limited benefit in conjunction with the side effect burden and potential for toxicity in a suicide prone population, TCAs are infrequently used in the treatment of PTSD. Please refer to Chapter 3 for more information regarding TCAs. 

Antidepressants. There are numerous reasons to expect that antidepressants may be helpful in the treatment of AN. First, depressed mood and other symptoms of depression such as anhedonia, decreased energy, poor concentration, and psychomotor retardation are common in cases of starvation from any cause. Second, AN patients and their family members have high rates of comorbid MDD and OCD, illnesses best treated with antidepressant medications. Finally, weight gain is a well-documented side effect of many antidepressants including the tricyclic antidepressants (TCAs) and mirtazapine. 

Antidepressants. A wide variety of antidepressants have been used to treat ADHD. These include the older tricyclic antidepressants (TCAs) and monoamine... 

Tricyclic Antidepressants (TCAs). The TCAs have been nsed to treat ADHD for 30 or more years. Most often used are imipramine (Tofranil) and desipramine (Norpramin), mainly becanse they are the TCAs that most specihcally increase norepinephrine activity. Remember, boosting norepinephrine activity in the brain shonld improve attention. Other TCAs, namely, amitriptyline (Elavil, Endep) and nortriptyline (Pamelor), have been used, though they also increase norepinephrine activity. TCAs do offer a modest benefit for both the inattention and the hyperactivity of ADHD. In addition, they are often effective at doses mnch lower than those required to treat depression. However, their effectiveness nsnally falls short of the stimulant medications. In addition, TCAs have considerable side effects including dry mouth, constipation, drowsiness, weight gain, and adverse cardiac effects. 

Tricyclic Antidepressants (TCAs). TCAs were introduced in the 1950s and over the years have become the mainstay of treatment for cataplexy and the other REM-related symptoms. The doses used are usually less than the doses required in the treatment of depression. Imipramine (Tofranil) is the most widely used TCA for narcolepsy and is usually effective at doses from 10 to 75 mg given once a day. Some doctors prefer the TCA protriptyline (Vivactil) because it has mild stimulant effects, but it has not been as widely used or as thoroughly studied in narcolepsy. The common side effects of TCAs are drowsiness, dry mouth, and constipation, but these are usually not a problem at the lower doses used for narcolepsy. Patients should receive a baseline electrocardiograph (EKG) before starting a TCA and should have blood levels of the medication checked periodically. 

Tricyclic Antidepressants (TCAs). The tricyclic antidepressants are believed to act mainly by increasing norepinephrine and/or serotonin reuptake inhibition. The few studies that have evaluated their use in the treatment of BPD were not promising. Given those disappointing results in conjunction with the prominent side effects and danger in overdose, TCAs are not generally recommended for the treatment of BPD. 

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. 

Medications that enhance norepinephrine activity can do so in one of several ways. First, they can block the reuptake of norepinephrine back into the nerve cell once it has been released. This keeps the norepinephrine in the synapse longer and therefore makes it more active. The tricyclic antidepressants (TCAs), duloxetine (Cymbalta), and venlafaxine (Effexor) act in this manner, as does paroxetine (Paxil) at higher doses. Atomoxetine (Strattera), a treatment for ADHD, also works in this way. 

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