Toxicity SNRIs

The clinician should bear in mind the toxic potential for the various antidepressant medications when patients already have or develop suicidality. The TCAs and MAOIs have narrow therapeutic indices, whereas the SSRIs, SNRIs, nefa-zodone, and mirtazapine have wide therapeutic indices.22... 

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. 

Similar observations can be made with regard to the antidepressants introduced in the last 15 years or so. Both SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) represent some quantitative progress from the earlier antidepressants in that they are less toxic, cause fewer medically significant adverse events and support treatment compliance. As is the case for antipsychotics and schizophrenia, the development of these newer antidepressants was not based on fundamentally new insights into the pathophysiology of affective disorders. 

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. 

Imipramine Mixed and variable blockade of NET and SERT Like SNRIs plus significant blockade of autonomic nervous system and histamine receptors Major depression not responsive to other drugs chronic pain disorders incontinence obsessive-compulsive disorder (clomipramine) Long half-lives CYP substrates active metabolites Toxicity Anticholinergic, G.-blocking effects, sedation, weight gain, arrhythmias, and seizures in overdose Interactions CYP inducers and inhibitors... 

SNRIs MAOIs Risk of severe hypertensive reactions and of serotonin syndrome - For signs and symptoms of serotonin toxicity, see Clinical Features of Some Adverse Drug Interactions, Serotonin toxicity and serotonin syndrome Duloxetine and venlafaxine inhibits the reuptake of both serotonin and norepinephrine. Due to impaired metabolism of these amines, there is an accumulation of serotonin and norepinephrine in the brain and at peripheral sites Do not co-administer duloxetine and venlafaxine prior to 14 days after discontinuing an MAOI, and do not co-administer an MAOI for 5 days after discontinuing duloxetine, 1 week after venlafaxine... 

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... 

Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding reported symptoms are consistent with either a direct toxic effect... 

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