Venlafaxine overdose

SSRI/SNRI GAD OCD Panic disorder PTSD Social anxiety disorder Onset worsening side-effects on initiation few long-term effects Relatively safe in overdose (venlafaxine possibly less safe) Well-described more common with paroxetine uncommon with fiuoxetine... 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Nortriptyline (Pamelor). A recent study suggested that the tricyclic antidepressant nortriptyline, like bupropion, is effective in the treatment of smoking cessation. Nortriptyline does not have any significant effect on dopamine reuptake activity, but it does increase norepinephrine availability. Like bupropion, nortriptyline may therefore reduce the physical symptoms of nicotine withdrawal. Because nortriptyline carries the danger of lethality in overdose and has the unfavorable side effect profile of the tricyclics, we do not recommend its use for smoking cessation. However, it does raise the question as to whether other newer antidepressants that increase norepinephrine activity (e.g., venlafaxine, mirtazapine, duloxetine) may also prove to be effective treatments for nicotine withdrawal. 

Few data are available regarding venlafaxine in overdose, but the drug s pharmacological profile suggests that it is safer than TCAs. In most of the reported cases to date, symptoms were not present. 

TCAs derive their name from their chemical structure aU tricyclics have a three-ring nucleus. Currently, most clinicians are moving away from using TCAs as first-line drugs relative to the newer antidepressants, they tend to have more side effects, to require gradual titration to achieve an adequate antidepressant dose, and to be lethal in overdose. Some data suggest that TCAs may be more effective than SSRIs in the treatment of major depression with melancholic features (Danish University Antidepressant Group 1990 Perry 1996) however, many skilled clinicians and researchers continue to prefer the newer antidepressants, even for patients with melancholia, for the aforementioned reasons. Newer medications that affect both norepinephrine and serotonin (e.g., venlafaxine and mirtazapine) also may have superior efficacy in severely iU depressed patients or when remission is defined as the outcome (Thase et al. 2001). 

Venlafaxine, a phenylethylamine, sequentially inhibits first the neuronal uptake pump for serotonin and then NE ( 137). In contrast to tertiary amine TCAs, which can also inhibit serotonin and NE uptake pumps, venlafaxine has low binding for most other neuroreceptors and does not inhibit Na ion fast channels, making it relatively safe in overdoses compared with TCAs. 

Highly suicidal patients should be given agents posing less risk of lethality with overdose and less risk of interacting with other drugs taken in an overdose attempt (i.e., sertraline, citalopram, or venlafaxine). 

Those who fail to respond to an SSRI may respond to a TCA, and vice versa. Thus, these two broad-spectrum classes can be used in a sequential strategy to adequately treat the majority of cases. However, many physicians try another newer antidepressant (e.g, venlafaxine, bupropion, nefazodone) in such patients because of the safety and tolerability problems associated with TCAs. Of note, the tolerability profile of secondary amine TCAs such as desipramine is as favorable as any of the newer antidepressants and probably better than nefazodone. Nevertheless, the secondary amine TCAs have a therapeutic index as narrow as tertiary amine TCAs (e.g., amitriptyline, imipramine) in terms of lethality in overdoses resulting from cardiotoxicity. 

Nefazodone, like the SSRIs and venlafaxine, has negligible effect on Na ion fast channels and therefore does not slow intracardiac conduction. As a result, during clinical trials development, patients survived drug overdoses exceeding 11,200 mg without the need for any intervention beyond observation and routine nursing care (146, 451). One nonstudy patient who took 2,000 to 3,000 mg of nefazodone with methocarbamol and alcohol experienced a seizure (type not documented) but otherwise recovered uneventfully. 

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. 

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. 

None of the newer antidepressants have been shown to be more effective overall than the tricyclics with which they have been compared. Solid evidence to support a claim of more rapid onset of action has been difficult to obtain. Amoxapine and maprotiline seem to have as many sedative and autonomic actions as most tricyclics more recently introduced antidepressants such as bupropion and venlafaxine have fewer, although nefazodone and mirtazapine are very sedating. Amoxapine and maprotiline are at least as dangerous as the tricyclics when taken in overdoses the other newer agents seem to be safer. 

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. 

Preliminary data suggest that venlafaxine is safer in acute overdose than tricyclic antidepressants but more dangerous than SSRIs. Seizures have been reported in several cases of overdose (5-7). 

Venlafaxine has been associated with occasional reports of cardiac conduction disturbances at both therapeutic doses and in overdose (SEDA-24,19). 

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. 

A 44-year-old woman took an overdose of venlafaxine 3 g. An electrocardiogram showed sinus rhythm and incomplete right bundle branch block (32). She was monitored in an intensive care unit and 10 hours later a further electrocardiogram showed atrial fibrillation with a wide QRS complex. Both of these abnormalities resolved with sodium bicarbonate (100 ml of a 1 M solution). No further conduction disturbances were noted over the following days. 

The authors suggested that the effect of venlafaxine on cardiac conduction is mediated by its ability to block the fast inward sodium current in cardiac myocytes. This might promote membrane stabilizing effects in a similar way to tricyclic antidepressants. They recommended that the management of venlafaxine overdose should include cardiac monitoring. 

White CM, Gailey RA, Levin GM, Smith T. Seizure resulting from a venlafaxine overdose. Ann Pharmacother 1997 31(2) 178-80. 

Zhalkovsky B, Walker D, Bourgeois JA. Seizure activity and enzyme elevations after venlafaxine overdose. J Clin Psychopharmacol 1997 17(6) 490—1. 

Jaffe PD, Batziris HP, van der Hoeven P, DeSilva D, McIntyre IM. A study involving venlafaxine overdoses comparison of fatal and therapeutic concentrations in postmortem specimens. J Forensic Sci 1999 44(l) 193-6. 

An antidepressant should be selected to match individual patients requirements, such as the need or otherwise for a sedative effect or the avoidance of antimuscarinic effects (especially in the elderly). In the absence of special factors the choice rests on tolerability, safety in overdose and likelihood of an effective dose being reached. SSRIs, lofepramine, mirtazapine, nefazodone, reboxetine and venlafaxine are highlighted as best fulfilling these needs. 

Venlafaxine is generally regarded as being reasonably safe in overdose relative to conventional tricyclic antidepressants. 

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