Venlafaxine toxicity

Administration of the CYP2D6 inhibitor quinidine, 200 mg/day for 2 days, to the extensive metabolizers reduced the oral clearance of venlafaxine to the level seen in poor metabolizers. Quinidine had no effect on venlafaxine clearance in subjects who were poor metabolizers before treatment. The authors suggested that poor metabolizers may be at particular risk of venlafaxine toxicity, as could subjects who take inhibitors of CYP2D6. 

The effects of buspirone are decreased when the drug is administered with fluoxetine Increased serum levels of buspirone occur if the drug is taken with erythromycin or itraconazole Should any of these combinations be required, the dosage of buspirone is decreased to 2.5 mg BID, and the patient is monitored closely. Venlafaxine blood levels increase with a risk of toxicity when administered witii MAOIs or cimetidine There is an increased risk of toxicity when trazodone is administered with the phenothiazines and decreased effectiveness of trazodone when it is administered with carbamazepine Increased serum digoxin levels have occurred when digoxin is administered with trazodone There is a risk for increased phenytoin levels when phenytoin is administered witii trazodone... 

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. 

Venlafaxine (Effexor, Effexor XR). Venlafaxine works by blocking the reuptake of both serotonin and norepinephrine. Because of this dual action, some believe that venlafaxine may be more effective than the SSRIs when treating severe depression. Its side effects and toxicity are similar to the SSRIs with abdominal discomfort, sexual dysfunction, and anxiety being commonly reported. At higher doses, it may mildly elevate blood pressure therefore, blood pressure should be checked periodically. When stopping venlafaxine, serotonin discontinuation symptoms may be especially problematic. Therefore, gradually tapering of the dose every 2-4 weeks is recommended. 

A controlled trial of duloxetine (Cymbalta)—like venlafaxine a dual serotonin-norepinephrine reuptake inhibitor—in the treatment of GAD is currently underway. Anecdotal data suggests that nefazodone (Serzone) and mirtazapine (Remeron) may be effective in the treatment of GAD, though no controlled data is available. In addition, recent concerns regarding nefazodone and liver toxicity have limited this medication s utility. Please refer to Chapter 3 for more information regarding these antidepressants. 

Regarding side-effect profiles, all three SSNRIs are generally well tolerated, most adverse events occurring early in treatment, with a mild to moderate severity and a tendency to decrease or disappear with continued treatment. Venlafaxine (1) seems to be the least weU-toIerated SNRI, combining a higher level of serotonergic adverse events (nausea, sexual dysfunction, withdrawal problems) with dose-dependent hypertension. In contrast, milnacipran (2) and duloxetine (3) appear better tolerated and essentially devoid of cardiovascular toxicity. 

There is a large evidence base for the antidepressant efficacy of venlafaxine, but fewer studies have been carried out in anxiety disorders. The best evidence is for GAD (Allgulander et al. 2001) and anxiety symptoms associated with depression (Silverstone and Ravindran 1999). Side-effects on initiation of therapy are similar to those of SSRIs, with nausea being the most common. Higher doses can cause raised blood pressure. A discontinuation syndrome similar to that seen with SSRIs has been reported. Toxicity causes cardiac conduction problems, seizures and coma, and venlafax-... 

Lessard E, Yessine MA, Hamelin BA, O Hara G, LeBlanc J, Turgeon J (1999) Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics 9 435-443 Lockhart DJ, Winzeler EA (2000) Genomics, gene expression and DNA arrays. Nature 405 827-836... 

C. Nortriptyline (Pamelor) is a TCA, and as a class these drugs require at least one steady-state blood level to safely and effectively use the medication. Paroxetine, venlafaxine, and bupropion have not had blood levels correlated to response, and their relatively low toxicity does not require therapeutic blood monitoring. Nardil is a MAOI, which can be... 

Place in therapy Similar to venlafaxine, with less risk of increased blood pressure alternative in major depression in poor responders to other agents at least as effective as tricyclics, but with lower toxicity more efficacious than SSRls... 

SNRIs have many of the serotonergic adverse effects associated with SSRIs. In addition, SNRIs may also have noradrenergic effects, including increased blood pressure and heart rate, and CNS activation, such as insomnia, anxiety, and agitation. The hemodynamic effects of SNRIs tend not to be problematic in most patients. A dose-related increase in blood pressure has been seen more commonly with the immediate-release form of venlafaxine than with other SNRIs. Likewise, there are more reports of cardiac toxicity with venlafaxine overdose than with either the other SNRIs or SSRIs. Duloxetine is rarely associated with hepatic toxicity in patients with a history of liver damage. All the SNRIs have been associated with a discontinuation syndrome resembling that seen with SSRI discontinuation. 

Duloxetine Moderately selective blockade of NET and SERT Acute increase in serotonergic and adrenergic synaptic activity otherwise like SSRIs Major depression, chronic pain disorders fibromyalgia, perimenopausal symptoms Toxicity Anticholinergic, sedation, hypertension (venlafaxine) Interactions Some CYP2D6 inhibition (duloxetine, desvenlafaxine)... 

Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM. 2003 96 369-374. 

Suicidal ideation of some kind almost invariably accompanies severe depression. Hence the relative toxicity of antidepressants in overdose can be important in determining treatment choice. It is accepted that SSRIs are less dangerous in overdose than tricyclic antidepressants, but there are fewer data on the toxicity of other antidepressants. The presentation and likely toxicity in overdose of several newer antidepressant drugs have been reviewed (9). Deaths in overdose have been most clearly associated with amfebutamone and venlafaxine. 

Amfebutamone overdose typically presents with neurological symptoms, including delirium, agitation, and seizures however, cardiac dysrhythmias, with QT interval prolongation and cardiac arrest, have occurred (10,11). Venlafaxine overdose is also associated with seizures and cardiac dysrhythmias (Numberg 56). Venlafaxine is a potent 5-HT re-uptake inhibitor, and signs of 5HT toxicity (agitation, myoclonus, hyperthermia) are common. 

In a prospective cohort study of over 450 patients who had attempted suicide by antidepressant ingestion the risk of seizures after venlafaxine overdose (14%) was significantly greater than that of SSRIs (1.3%) and similar to that seen with dosulepin (11%) (12). Rates of 5HT toxicity did not differ significantly between venlafaxine and SSRIs (29% versus 19%) but were greater than with tricyclic antidepressants (1.2%). Unlike SSRIs, venlafaxine was associated with significant prolongation of the QT interval tricyclic antidepressants had a similar effect. 

Overall the current data suggest that the safety advantage in overdose relative to tricyclic antidepressants enjoyed by SSRIs may extend to reboxetine and mirtazapine. Amfebutamone and venlafaxine are more toxic than SSRIs in overdose, but they are still likely to be safer than tricyclic antidepressants. 

In 225 patients who had taken overdoses of antidepressant drugs in suicide attempts, venlafaxine and citalopram were more likely to be associated with seizures than mir-tazapine and nefazodone and 5HT toxicity was more common after overdose of venlafaxine (94). These findings confirm the potential toxicity of venlafaxine in overdose and also suggest a pro-convulsant effect of large doses of citalopram. 

There have been previous reports of serotonin toxicity when venlafaxine was combined with therapeutic doses of conventional MAO inhibitors (SEDA 20, 21). The serotonin syndrome has been reported in four patients who were switched from the MAO inhibitor phenelzine to venlafaxine (83). In two of the subjects, the 14-day washout period recommended when switching from phenelzine to other antidepressant drugs had elapsed. 

These cases suggest that even after the recommended 2-week washout from MAO inhibitors, venlafaxine can provoke serotonin toxicity in some patients. In principle it should be possible to switch from one conventional MAO inhibitor to another without a washout period. However, there have been reports that patients who switched from phenelzine to tranylcypromine had hypertensive reactions, with disastrous consequences (84). Whenever possible, a 2-week washout period when switching MAO inhibitors or when introducing serotonin re-uptake inhibitors seems advisable. 

This suggests that even after the recommended 2-week washout from MAO inhibitors, venlafaxine can provoke serotonin toxicity in some patients. 

Deaths have been described after venlafaxine overdose, but in combination with other agents and alcohol. However, there have been two fatal cases of overdosage in which venlafaxine was the only agent detected postmortem (30). It therefore appears that venlafaxine can occasionally prove fatal in overdosage, probably through cardiac conduction abnormalities and seizures (30,31). It is possible that poor metabolizers may be especially liable to develop toxic effects. 

The analgesic drug tramadol can cause 5HT toxicity in association with SSRIs. Venlafaxine is also a potent reuptake inhibitor, and perhaps not surprisingly has been reported to cause features of the 5HT syndrome in a patient taking tramadol (49). 

Blythe D, Hackett LP. Cardiovascular and neurological toxicity of venlafaxine. Hum Exp Toxicol 1999 18(5) 309-13. 

Prior FH, Isbister GK, Dawson AH, Whyte IM. Serotonin toxicity with therapeutic doses of dexamphetamine and venlafaxine. Med J Aust 2002 176(5) 240-1. 

LeBlanc J, Turgeon J. Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics 1999 9(4) 435-43. 

BETA-BLOCKERS VENLAFAXINE T plasma concentrations and efficacy of metoprolol, propranolol and timolol Venlafaxine inhibits CYP2D6-mediated metabolism of metoprolol, propanolol and timolol Monitor PR and BP at least weekly watch for metoprolol toxicity (in particular, toss of its cardioselectivity) and propanolol toxicity... 

LITHIUM OTHER-VENLAFAXINE Possible risk of serotonin syndrome Additive effect Be aware of the possibility of serotonin syndrome. Also need to monitor lithium levels with appropriate dose adjustments during co-administration >- For signs and symptoms of serotonin toxicity, see Clinical Features of Some Adverse Drug Interactions, Serotonin toxicity and serotonin syndrome... 

SSRIs METOPROLOL t plasma concentrations of metoprolol SSRIs inhibit metabolism of metoprolol (paroxetine, fluoxetine, sertraline, fluvoxetine, and venlafaxine via CYP2D6 (es)citalopram uncertain at present) Monitor PR and BP closely watch for metoprolol toxicity, in particular loss of its cardioselectivity... 

SNRIs ANTIMALARIALS - ARTEMETHER/ LUMEFANTRINE t artemether/lumefantrine levels with risk of toxicity, including arrhythmias Venlafaxine inhibits CYP3A4, which is partly responsible for the metabolism of artemether Avoid co-administration with venlafaxine and caution with duloxetine... 

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