Imipramine adverse effects

Imipramine treatment resulted in a higher rate of remission of anxiety symptoms than trazodone, diazepam, or placebo (e.g., 73% versus 69% versus 66% versus 47%) in an 8-week controlled trial of DSM-III-diagnosed GAD patients. Antidepressants were more effective than diazepam or placebo in reducing psychic symptoms of anxiety. The use of TCAs generally is limited by bothersome adverse effects (e.g., sedation, orthostatic hypotension, anticholinergic effects, and weight gain). 

One common denominator of all antipsychotics is the biockade of centrai dopamine (DA) receptors. As a result, extrapyramidal reactions, particularly parkinsonian symptoms, are a major adverse effect of many of these drugs, as well as an important clue to their mechanism of action. True Parkinson s disease is caused by a DA deficiency in the nigrostriatal system. Further, crystallographic data have demonstrated that CPZ s molecular configuration is similar to that of DA, which could explain its ability to block this neurotransmitter s receptors. Drugs with similar structures that do not block DA receptors (e.g., promethazine, imipramine) do not have antipsychotic activity. Another example is the isomer of flupenthixol, which blocks DA receptors is an effective antipsychotic, but the isomer that does not is ineffective (7). The other family of dopamine receptors, D and Dg, have not yet been implicated in psychosis. 

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). 

Early reports on imipramine noted that some patients developed first-degree heart block, as well as other bundle branch patterns, but it took almost 15 years to clarify that these conduction delays were the only adverse effects at therapeutic plasma concentrations. It is now well documented that increased PR, QRS, or QT intervals occur with all standard TCAs, at or slightly above their therapeutic plasma levels. 

In terms of comparative adverse effects, imipramine produces more dry mouth than reboxetine probably because imipramine blocks muscarinic cholinergic receptors as well as inhibiting NE uptake (47,5). Imipramine also produces more tremulousness and hypotension than reboxetine. Consistent with their pharmacology, fluoxetine produces more serotonin-mediated adverse effects than does reboxetine (i.e., nausea, loose stools, and somnolence), whereas reboxetine causes more sympathomimetic adverse effects (476). To date, reboxetine has not been reported to cause an increased incidence of laboratory abnormalities. 

Two studies have indicated that the tricyclic antidepressant (TCA) imipramine may be as effective as BZDs in the treatment of GAD ( 58, 59). No studies longer than 8 weeks duration have been conducted, however, and imipramine s onset of anxiolytic action may be even slower than that of buspirone. Aithough adverse effects also may limit usefulness, its lack of dependence liability may make it an appropriate alternative in chronically anxious patients who also suffer from panic and depression. 

Wells BG, Evans RL, Ereshefsky L, et al. Clinical outcome and adverse effect profile associated with concurrent administration of alprazolam and imipramine. J Clin Psychiatry 1988 49 394-399. 

In 1962, Klein and Fink (88) reported that imipramine blocked panic attacks but had only a minor effect on phobic avoidance or anticipatory anxiety. This clinical observation has been validated by approximately 15 double-blind studies, and TCAs have since been studied for their antipanic efficacy. Although many TCAs are effective antipanic agents, they differ in safety and efficacy, a fact that mandates fitting the drug to the individual patient based on the known advantages and potential adverse effects of each TCA (Table 13-4). 

All SSRIs have an antipanic effect. Their advantages are limited adverse effects and lack of toxicity. Because of more acceptable adverse effect profiles, the SSRIs are usually the drugs of choice. Several studies consistently indicate that SSRIs such as fluoxetine, sertraline, paroxetine, fluvoxamine, as well as agents such as clomipramine and trazodone, all possess antipanic efficacy, although the last may be less effective than imipramine ( 24, 105, 106, 107, 108 and 109). 

SNRIs are chemically unrelated to each other. Venlafaxine was discovered in the process of evaluating chemicals that inhibit binding of imipramine. Venlafaxine s in vivo effects are similar to those of imipramine but with a more favorable adverse-effect profile. All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters, as do the TCAs. However, unlike the TCAs, the SNRIs do not have much affinity for other receptors. Venlafaxine and desvenlafaxine are bicyclic compounds, whereas duloxetine is a three-ring structure unrelated to the TCAs. Milnacipran contains a cyclopropane ring and is provided as a racemic mixture. 

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... 

Oral contraceptives reduce the clearance of imipramine, probably by reducing hepatic oxidation, and thus increase its half-life. Hydroxylation of amitriptyline is inhibited by contraceptive steroids. The clinical significance is uncertain, but there is at least anecdotal evidence of an increase in antidepressant adverse effects (360). Caution should be exercised when tricyclic antidepressants are used long term in women taking oral contraceptives. 

Adverse effects of various antidepressants are summarized in Table 30-5. Most common unwanted effects are minor, but they may seriously affect patient compliance the more seriously depressed the patient is, the more likely it is that unwanted effects will be tolerated. Most normal persons find that even moderate doses of many antidepressants cause disagreeable symptoms, especially the classic tertiary amine tricyclics amitriptyline, imipramine, clomipramine, and doxepin. With the SSRIs, transient nausea is the most frequent complaint, and decreased libido and sexual dysfunction create the greatest concerns during maintenance treatment. 

Treatment guidelines for depression and anxiety increasingly emphasize the value of longer-term maintenance treatment with antidepressants in order to prevent recurrence of illness. It is therefore important to assess the adverse effects burden of longer-term medication. The change in adverse effects profile over 1 year of treatment has been studied in a double-blind, placebo-controlled study of maintenance treatment with imipramine (average daily dose 160 mg) in 53 patients with panic disorder (15). Adverse effects of imipramine, such as sweating, dry mouth, and increased heart rate, persisted over the year... 

Clomipramine is the imipramine analogue of chlorproma-zine. However, while the difference between chlorproma-zine and promazine is large, adding a chloride atom to imipramine hardly affects its actions. Most trials have failed to show any superiority of the chlorinated compound over imipramine. The adverse effects profile is similar (1), but drowsiness, confusion, and feeling awful are commonly reported (2). 

Dibenzepin is a 6,7,6 tricyclic compound of the dibenzodiazepine type. A comparison with imipramine was said to show equal efficacy adverse effects were comparable in type and degree (1). 

Imipraminoxide is an imipramine metabolite. In a comparison with the parent drug, efficacy was identical adverse effects were of the same type but possibly less frequent (1). 

A randomized comparison of brofaromine with imi-pramine in inpatients with major depression showed that brofaromine was as effective as imipramine in the treatment of major depression but had a different adverse effects profile (1). Brofaromine was more likely to cause sleep disturbances but lacked the anticholinergic and certain cardiovascular adverse effects of imipramine. 

The adverse effects of moclobemide have been well reported in several studies, mainly comparisons of moclobemide with standard antidepressants. The consensus has been that moclobemide produces fewer anticholinergic effects and less orthostatic hypotension and dizziness than clomipramine or imipramine. The main problems... 

There have been several comparisons of maprotiline with other antidepressants. There was no significant difference in adverse effects compared with doxepin (5), amitriptyline (6), or imipramine (7). 

Viloxazine, a bicyclic compound, is related structurally (but not pharmacologically) to the beta-adrenoceptor antagonists. In animal tests, its profile shows properties of both the imipramine-like compounds (reversal of reser-pine-induced hypothermia) and amphetamine (stimulation of the electroencephalogram). A review of animal and clinical data confirmed the impression that viloxazine has efficacy comparable to that of imipramine but with a different adverse effects profile (1). There is a reduced frequency of anticholinergic and sedative effects and a tendency to lose rather than to gain weight. However,... 

AMOXAPINE, CLOMIPRAMINE, DOXEPIN, IMIPRAMINE, NORTRIPTYLINE, TRIMIPRAMINE PROTEASE INHIBITORS Possibly t adverse effects of amoxapine with atazanavir and ritonavir Inhibition of CYP3A4-mediated metabolism of amoxapine, clomipramine and doxepin inhibition of CYP3A4-, CYP2D6-and CYP2C9-mediated metabolism of imipramine inhibition of CYP2D6-mediated metabolism of nortriptyline and trimipramine Monitor closely... 

It is essential to remember that there is great heterogeneity in adverse effect profiles between TCAs. Imipramine and lofepramine cause relatively little sedation and lofepramine is associated with milder antimuscarinic effects (but is contraindicated in patients with severe liver disease). 

Note. When SSRIs are compared with TCAs for patients who discontinue therapy (a surrogate endpoint for tolerability), most meta-analyses show a slight benefit in favour of SSRIs. Comparisons which exclude TCAs with the most prominent anti-muscarinic effects (amitriptyline and imipramine) show either marginal benefits in favour of SSRIs or no difference between the groups. It is noteworthy that despite their pronounced adverse effects, amitriptyline and imipramine tend to be selected as standard TCAs against which SSRIs are compared. Lofepramine, the second most prescribed TCA in the UK and the one TCA which causes little sedation, has few antimuscarinic effects and is as safe as SSRIs in overdose is it under-represented in meta-analyses... 

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