Venlafaxine risks

MAOIs DULOXETINE, VENLAFAXINE 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 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 MAOI for 5 days after discontinuing duloxetine, 1 week after venlafaxine... 

AMPHETAMINES VENLAFAXINE Risk of severe and life-threatening hypertension and arrhythmias Additive effects on cardiovascular system due to enhanced noradrenergic activity Avoid concurrent use... 

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... 

A number of non-hormonal therapies have been studied for symptomatic management of vasomotor symptoms, including antidepressants [e.g., selective serotonin reuptake inhibitors (SSRIs) and venlafaxine], herbal products (e.g., soy, black cohosh, and dong quai), and a group of miscellaneous agents (e.g., gabapentin, clonidine, and megestrol). The choice of therapy depends on the patient s concomitant disease states, such as depression and hypertension, and the risk for potential adverse effects. 

In addition, whenever an antidepressant that blocks serotonin reuptake is discontinued, an unpleasant but harmless discontinuation syndrome manifested by abdominal discomfort, instability, anxiety, and occasionally painful shock-like sensations in the extremities can arise. The risk appears to be greatest with venlafaxine and paroxetine. Consequently, switching from one of these medications to another that does not block serotonin reuptake requires a gradual taper of the first medication over days to weeks. 

Diclofenac is available as dispersible tablets, tablets, gel, suppositories and for intravenous or intramuscular injection. The maximum dose of diclofenac administered via any route is 150 mg. As v/ith other non-steroidal anti-inflammatory drugs, concomitant use in patients receiving venlafaxine increases the risk of bleeding. 

Suicidality in children and adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of venlafaxine or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. 

Discontinuation - When discontinuing venlafaxine after more than 1 week of therapy, it is generally recommended that the dose be tapered to minimize the risk of discontinuation symptoms. Patients should have their dose tapered gradually over a 2-week period. 

Side effects, mainly due to serotonin reuptake inhibition include G1 upset, nervousness, and sexual dysfunction. SSRls are associated with an increased risk of falls. Hyponatraemia due to SIADH is an uncommon, but important side effect in elderly patients. Selective serotonin and norepinephrine reuptake inhibitors (S SNRls) such as venlafaxine and duloxetine are also useful in older patients. Other heterocyclic antidepressants of importance in older patients because of relative safety include bupro-prion and mirtazepine. They are reserved for patients with resistance to or intolerance of SSRls. Currently, trazodone is used mostly for sleep disturbance in depression in doses of 50-100 mg at bedtime. The monoamine oxidase inhibitors phenelzine. 

They have a delayed onset of effect just like the tricyclics. Examples are fluoxetine, paroxetine, flu-voxamine, zimelidine, venlafaxine, citalopram and sertraline. Zimelidine was withdrawn worldwide in 1983 due to risk of Guillain-Barre syndrome. 

Adverse reactions include nausea, nervousness, headache, insomnia, anxiety. Sexual dysfunction with loss of libido is a common complaint. Insomnia can be a problem. Urticaria and rashes have been described. Venlafaxine may significantly increase the risk of suicide and is therefore not recommended as a first line treatment of depression. The view that also fluoxetine and other SSRIs can lead to suicide is under debate for quite some time now. In most countries SSRIs are not approved for use in pediatric populations. In the UK and in the USA only fluoxetine can be prescribed for children. 

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... 

The coadministration of venlafaxine and MAOls is contraindicated because of the risk of serotonin syndrome. Venlafaxine is a relatively weak inhibitor of the CYP450-2D6 system, therefore it has few drug interactions (Ball et al. 1997). 

A more common approach in difficult to treat cases would be the combination of clomipramine with a SSRI several reports lend support to this practice (Simeon and Thatte, 1990 Figueroa et al., 1998). In this situation, careful attention to the potential pharmacokinetic interactions discussed above are recommended. Sertraline and citalopram are least likely to elevate tricyclic levels due to less potential GYP interactions. By expert consensus, second- (venlafaxine) and third-line (nefazadone and gabapentin) agents may be used when clinical response is inadequate despite a lack of controlled data. Venlafaxine may be substituted for a more typical SSRI while nefazadone or gabapentin may be added to either clomipramine or a SSRI. The combination of venlafaxine with other SSRIs is not generally recommended as it may increase the risk of a serotonin syndrome. The addition of nefazadone to SSRIs presents a lesser risk. 

TCAs in more serious forms of depression such as melancholic or psychotic depression. Some studies have suggested that the SSRls do not work as well as the TCAs in melancholic depression (Roose et al. 1994]. Likewise, one study has suggested that venlafaxine, a drug with a mechanism of action similar to that of the TCAs, was superior to fluoxetine in the treatment of inpatients with melancholic depression (Clerc et al. 1994]. Still, other metaanalyses have failed to find a difference in the efficacy of SSRls versus TCAs in serious forms of depression [Nierenberg 1994]. Nonetheless, given that most studies have employed TCAs, and some debate exists about the utility of SSRls in severe subtypes, it may be prudent to start with a TCA in most patients until the debate is further resolved. For patients who present a significant suicide risk or who have not been able to tolerate TCAs, the SSRls in combination with a standard antipsychotic appears an effective option. 

Venlafaxine does not appear to inhibit cytochrome P450 enzymes significantly, and it is the antidepressant least likely to contribute to protein-binding interactions. Because of the risk of serotonin syndrome, venlafaxine should not be combined with MAOIs. 

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). 

As with venlafaxine, a double-blind continuation study has been done with nefazodone (see Jable 7-21). Patients who responded to nefazodone, imipramine, or placebo in the acute phase were offered the option of remaining on double-blind treatment for 1 year ( 272). Those patients who chose to participate were then followed up monthly to assess whether efficacy persisted. The relapse rate was 22% on placebo versus 10% on nefazodone and 7% on imipramine. The absolute difference in relapse rates between nefazodone and placebo was similar to that of venlafaxine versus placebo (i.e., 12% to 14%). Thus, maintenance treatment with nefazodone, as with venlafaxine and the SSRIs, reduced the risk of relapse when compared with placebo even when the comparison group had initially responded to placebo and remained on placebo for the maintenance period. 

Given their design differences, no direct comparison can be made between the relative relapse efficacy of SSRIs, venlafaxine, and nefazodone. The bottom line, however, is that both designs demonstrated that maintenance therapy for up to 1 year is important in reducing the risk of a depressive relapse after an initial response. 

A double-blind continuation study has been conducted with mirtazapine. As with venlafaxine and nefazodone, patients in this acute, double-blind, placebo- and active-controlled study with mirtazapine could remain on the double-blind treatment at the end of the initial 6-week efficacy trial and were then followed up for up to 1 year. There was a statistically significant lower risk of relapse (defined as HDRS > 16) on both mirtazapine (18%) and amitriptyline (28%) in comparison with placebo (53%), indicating that mirtazapine has maintenance efficacy (274). More recently, a 40-week, double-blind, placebo-controlled crossover study was performed with mirtazapine (275). Patients maintained on this drug had less than half the likelihood of relapsing than those patients switched to placebo (i.e., 19.7% versus 43.8%, p <0.01). 

The combination of an MAOl plus an SSRI, venlafaxine, or nefazodone should not be attempted because of the risk of a serotonin syndrome. 

Age, sex, renal or hepatic function, and baseline blood pressure were not clinically meaningful predictors of risk ( 143,147, 449, 450). It is not known whether unstable, elevated blood pressure is a serious risk factor because such patients were excluded from the venlafaxine studies. This exclusion criterion is standard for all such clinical trials and not unique to the venlafaxine studies. With this caveat in mind, patients in the clinical trials were grouped into quartiles by blood pressure. 

The adverse effects of SSRIs, venlafaxine, and nefazodone in children and adolescents are comparable with those in adults (see Chapter 7) and have been documented in both clinical trials and practice ( 35, 36, 119, 120 and 121 123). As in adults, isolated case reports have described behavioral activation in children and adolescents given SSRIs (133, 134). The significance of such reports in terms of a causal link to the drug is difficult because of their rare and anecdotal nature and because the patients are at increased risk for such behavioral disturbances relative to the general population as a result of their underlying psychiatric disorder. 

---