Desipramine adverse effects

Alprazolam has no significant anticholinergic or cardiovascular effects, but in almost all studies reporting adverse effects, alprazolam-induced sedation was comparable with or greater than that of the tertiary amine TCA. In one comparison with desipramine, drowsiness led to motor vehicle accidents in 2 of 16 outpatients taking alprazolam and required discontinuation in another 3 (212, 213). 

As a results of these studies, clinicians have proposed that switching to reboxetine or bupropion might a useful strategy given that these antidepressants share the ability with desipramine and imipramine to block NE uptake. Nevertheless, only one small open label study has been done to test this possibility ( 365). If bupropion is to be used in patients switched from an ineffective trial of fluoxetine, the dose should be kept low for several weeks to allow for the clearance of fluoxetine and norfluoxetine. Case reports indicate that fluoxetine can elevate levels of the active metabolites of bupropion, which, in turn, could mediate an increase risk of adverse effects (366). 

As with most data for reboxetine, this information primarily comes from summary papers rather than primary sources (473, 474). With this caveat, the adverse-effect profile of reboxetine is consistent with its pharmacology as an NSRI. Thus, it is similar to that of desipramine and maprotiline but without the risk of serious CNS (i.e., seizures, delirium) or cardiac (i.e., conduction disturbances) toxicity. The most common adverse effects of reboxetine are dry mouth, constipation, urinary hesitancy, increased sweating, insomnia, tachycardia, and vertigo. Whereas the first three adverse effects are commonly called anticholinergic, they are well known to occur with sympathomimetic drugs as well. In other words, these effects can be either the result of decreased cholinergic tone or increased sympathetic tone, although they tend to be more severe with the former than the latter. In contrast to TCAs, reboxetine does not directly interfere with intracardiac conduction. The tachycardia produced by reboxetine, however, can be associated with occasional atrial or ventricular ectopic beats in elderly patients. 

A number of studies indicate that some but not all antidepressants are effective in ADHD. Spencer and colleagues (66) found 29 studies (involving 1,016 patients) that supported the efficacy of TCAs in the treatment of ADHD. Desipramine is the TCA with the most efficacy data. Desipramine, based on a meta-analysis of five randomized trials involving 170 ADHD patients had efficacy (i.e., effect size) comparable with that of methylphenidate ( 90, 91). However, desipramine produced a higher rate of adverse effects compared with psychostimulants. Moreover, several sudden, unexpected deaths have been reported in children on desipramine ( 92,... 

The adverse effects of TCAs are also similar to those reported in adults (see Chapter 7). The secondary amine TCAs (e.g., desipramine, nortriptyline) are generally as well tolerated as newer antidepressants. Increased blood pressure may be more likely to occur in children than in adults but hypertension per se is rare ( 135). The most common cardiovascular effect is mild tachycardia. Despite their generally favorable adverse effect profile, secondary amine TCAs can cause serious toxicity in children and adolescents just as in adults when a taken in an overdose or when a high TCA plasma level occurs as a result of slow metabolism ( 136). For that reason, most clinicians reserve TCAs for the child or adolescent who has at least a moderate depressive disorder unresponsive to a trial of one or more newer antidepressants. In such instances, TDM should be done at least once to ensure plasma concentrations greater than 450 ng/mL do not develop ( 137). Such levels are associated with an increased risk of the following ... 

The primary adverse effects of TCAs have been described in the previous text. Anticholinergic effects are perhaps the most common. These effects result in dry mouth, constipation, urinary retention, blurred vision, and confusion. They are more common with tertiary amine TCAs such as amitriptyline and imipramine than with the secondary amine TCAs desipramine and nortriptyline. The potent a-blocking property of TCAs often results in orthostatic hypotension. Hi... 

T effects OF amiodarone, astemizole, atorvastadn, barbiturates, bepridil, bupropion, cerivastatin, cisapride, clorazepate, clozapine, clarithromycin, desipramine, diazepam, encainide, ergot alkaloids, estazolam, flecainide, flurazepam, indinavir, ketoconazole, lovastatin, meperidine, midazolam, nelfinavir, phenytoin, pimozide, piroxicam, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, simvastatin, SSRIs, TCAs, terfenadine, triazolam, troleandomycin, zolpidem X effects W/ barbiturates, carbamazepine, phenytoin, rifabutin, rifampin, St. John s wort, tobacco X effects OF didanosine, hypnotics, methadone, OCPs, sedatives, theophylline, warfarin EMS T Effects of amiodarone, diazepam, midazolam and BBs, may need X- doses concurrent use of Viagra-type drugs can lead to hypotension X- effects of warfarin concurrent EtOH use can T adverse effects T glucose ODs May cause an extension of adverse SEs symptomatic and supportive Rivasrigmine (Exelon) [Cholinesterase Inhibitor/Anri ... 

Lofepramine has apparently not been compared with desipramine, to which it is mainly metabolized. The claim that lofepramine has fewer adverse effects than traditional tricyclic compounds must be viewed with skepticism (SEDA-11, 14). However, lofepramine is safer than conventional tricyclic antidepressants in overdose. 

In healthy elderly patients, cautious use of a secondary amine TCA (desipramine or nortriptyline) may be appropriate because of their defined therapeutic plasma concentration ranges, well-established efficacy, and well-known adverse-effect profiles. 

There are few reports on the excretion of antidepressant drugs in breast milk, even though postpartum depression is relatively common. In a 32-year-old woman who took imi-pramine 200 mg/day from 1 month postpartum imipramine and desipramine were detectable in breast milk (135). There have also been reports that amitriptyline (136), desipramine (137), and nortriptyline (138,139) were detectable in the milk of nursing mothers and in the plasma of the mothers and infants. Neither parent compound nor metabolite were detected in infants serum, except for two infants who had low concentrations of 10-hydroxynortriptyline. There were no adverse effects in any of the infants. The use of antidepressants during lactation has been reviewed, including 15 studies in which serum concentrations of antidepressants were obtained from nursing infants (140). 

This can increase TCA serum levels (clomipramine and nortriptyline). Desipramine levels were not found to be impaired, although an additive adverse effect profile is evident (nausea, tremor, and tachycardia). 

Their in vitro potenoy for selectively inhibiting the 5-HT transporter more or less mirrors their clinical efficacy as SSRIs (11) paroxetine> sertraline> clomipramine> fluoxetine> citralopram> fluvoxamine> imipramine> amitriptyline> roboxetine> venlafaxine = milnacipran> desipramine. Clinically, however, all the SSRIs are equally effective over time, suggesting that these variations in potency do not affect efficacy or adverse effects. The SSRIs have less affinity for ai, 02, Hi, and musoarinic receptors, which may explain the adverse-effect profile differences between TCAs and SSRIs. 

The SSRIs are reported to have fewer side effects than the TCAs, which have strong anticholinergic and cardiotoxic properties (50). Among the SSRIs, there are few differences in adverse effects. The adverse effects observed for the SSRIs include nausea, diarrhea, anxiety, agitation, insomnia, and sexual dysfunction. Fewer patients have discontinued SSRIs than TCAs (amitriptyline and imipramine, and not nortriptyline, desipramine, doxepin, and clomipramine). 

The mean serum levels of desipramine 2.5 mg/kg daily were approximately doubled in 5 men who took methadone 500 micrograms/kg daily for 2 weeks. Previous observations in patients given both drugs had shown that desipramine levels were higher than expected and adverse effects developed at relatively lowdoses. Further evidence of an increase in plasma desipramine levels due to methadone is described in another study. ... 

In a double-blind study 3 patients given a phenothiazine and benzatropine for the parkinsonian adverse effects, developed an intermittent toxic confusional state (marked disturbance of short-term memory, impaired attention, disorientation, anxiety, visual and auditory hallucinations) with peripheral antimusearinies signs. Similar reactions occurred in 3 elderly patients given imipramine or desipramine, with trihexyphenidyl, and in another man given chlorpromazine, benzatropine and doxepin. ... 

Methylphenidate can increase the levels and rate of response to tricyclic antidepressants. This has led to both increased beneficial and adverse effects. No significant pharmacokinetic interaction has been reported between desipramine and dexamfetamine or methylphenidate. An isolated report describes a blood dyscrasia in a child given methylphenidate and imipramine. 

Bupropion may increase the levels of tricyclic antidepressants that are metabolised by CYP2D6, including desipramine, imipramine, and nortriptyline. Adverse effects including confusion, lethargy and unsteadiness have been reported with nortriptyline and bupropion. A seizure occurred in a patient given trimipramine and bupropion. 

The interactions with cimetidine are well established, well documented and of clinical importance. The incidence is uncertain hut most patients could be affected. Those taking amitriptyline, desipramine, doxepin, imi-pramine or nortriptyline who are given cimetidine should be warned that adverse effects such as mouth dryness, urine retention, blurred vision, constipation, tachycardia, postural hypotension may be more likely to occur. Other tricyclic antidepressants would be expected to be similarly affected. If symptoms are troublesome reduce the dosage of the antidepressant (33 to 50% has been suggested) or replace the cimetidine with ranitidine, which does not appear to interact. Other H2-ieceptor antagonists that do not cause enzyme inhibition (e.g. famotidine and nizatidine) would also not be expected to interact. 

The clinical importance of these interactions awaits assessment, but be alert for evidence of increased tricyclic antidepressant effects and possibly toxicity if quinidine is added. One report suggested steady-state increases of 30% with imipramine and more than 500% with desipramine in extensive metabolisers. More study is needed. There seems to be no information about the effect of quinidine on other tricyclics. Information about the effect of quinine on tricyclics is very limited, but the effects are smaller than those of quinidine and therefore less likely to result in clinically significant adverse effects. Note that quinidine, possibly quinine, and the tricyclics (notably in overdose) may prolong the QT interval, see also Drugs that prolong the QT interval + Other drugs that prolong the QT interval , p.257. 

Venlafaxine can cause a marked increase in the antimuscaiinic adverse effects of clomipramine, desipramine and nortriptyline. There are isolated reports of seizures in a patient taking venlafaxine and trimipramine and the serotonin syndrome has been seen in patients taking venlafaxine with, or shortly before, the use of tricyclics. 

Four patients given daily doses of desipramine 300 mg, imipramine 150 mg or nortriptyUne 100 mg had two to fourfold increases in plasma tricyclic antidepressant levels within 1 to 2 weeks of starting fluoxetine 10 to 60 mg daily. Two of them developed antimusearinie adverse effects (constipation, urinary hesitancy). ... 

A study in 17 healthy subjects who were extensive metabolisers and taking desipramine 50 mg daily found that when they were also given paroxetine 20 mg daily for 10 days the maximum plasma levels of the desipramine rose by 358%, the trough plasma levels rose by 511% and the AUC rose by 421%. An approximately tenfold increase in the maximum plasma levels and the AUC of the paroxetine also occurred. Another stuty found a fivefold decrease in desipramine clearance in extensive metabolisers given paroxetine 20 mg daily. Paroxetine has also been shown to increase the levels of clomipramine, desipramine, imipramine, and trimipramine. This resulted in a variety of adverse effects including dizziness, confusion, sedation and memory impairment. ... 

A man with major depression responded well to desipramine 175 mg daily with serum desipramine levels in the range of 500 to 1000 nanomol/L. When he was treated for paroxysmal atrial fibrillation with digoxin 250 micrograms daily and propafenone 150 mg twice daily and 300 mg at night he developed markedly elevated serum desipramine levels (2092 nanomol/L) and toxicity (dry mouth, sedation, shakiness) while taking desipramine 150 mg daily. The adverse effects resolved when the desipramine was stopped for 5 days, but when it was restarted at 75 mg daily his serum desipramine levels were still raised (1130 nanomol/L). 

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. 

Reboxetine is a nontricyclic SNRI in which the propylamine side chain of the TCAs is constrained into a morpholine ring (Fig. 21.8). It is a potent and selective ligand for the NET, with a mechanism of action is similar to that of desipramine. Reboxetine is used for the treatment of major depressive disorders. It is a chiral compound that is marketed as a racemic mixture of R,R- and S,S-reboxetine. The antidepressant activity for reboxetine appears to reside with the S,S-(+)-enantiomer, which has approximately twofold the inhibition potency of the R,R-enantiomer (42). It is well tolerated, with different adverse-event profiles, and it appears to be at least as effective as the SSRIs in the treatment of depressive illness. Currently, it is available only in Europe and is under U.S. FDA review. It preferentially inhibits the reuptake of NE (5-FIT NE ratio, 8). Reboxetine is not metabolized by the polymorphic isoforms, CYP2D6 or CYP2C19, and may offer a valuable alternative to the secondary amine TCAs in the treatment of major depression. Reboxetine is likely to become a promising alternative for patients who have failed treatment with or do not tolerate serotonergic antidepressants. Reboxetine has been shown to be effective and well tolerated in the treatment of panic... 

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