indications: irritability, anxiety, aggression, obsessive-compulsive symptoms
pros: relatively little risk of activation, mildly sedating; generic available
cons: multiple dosing necessary; no liquid, chewable, or pediatric-size dose available; rare reports of liver toxicity
use: nefazodone is essentially a new, improved version of trazodone, to which it is closely related chemically; it is significantly better tolerated than trazodone because it causes less sedation and orthostatic hypotension. The mechanism of action of nefazodone is basically identical to that of trazodone: it inhibits re-uptake of serotonin and norepinephrine, while blocking a subclass of serotonin receptor (5HT2, the "bad" serotonin receptor). These differences mean that nefazodone is not as useful for sedation--for treatment of insomnia or acute treatment of agitation. However, nefazodone is more useful as an antidepressant, and as a treatment for anxiety disorders because therapeutic doses are far more easily tolerated.
Nefazodone offers a major advantage as a treatment for many of the typical symptoms of Fragile X: it is much less likely to cause the kind of excessive activation which is so often a problem in the treatment of children with other antidepressants. Its 5HT2 antagonist properties also likely yield enhanced antiaggressive effects compared to SSRIs, while its noradrenergic properties probably confer greater effectiveness in treating attention deficit. One minor disadvantage of this medication is that it must be given twice a day due to its short half-life. However, this can be an ideal choice for patients who have particular problems sleeping, since most of the total daily dose can be given at bedtime for a gently sedating effect.
common side effects
sedation: usually mild and transient; temporary dosage reduction often helpful
orthostatic hypotension: benign; can be minimized by initially dividing dose further, i.e. 25 mg four times a day rather than 50 mg twice a day
nausea: take with food; Pepto-Bismol is safe to use
uncommon side effects
priapism: not actually reported with this drug, but a theoretical concern since it is closely related to trazodone; discontinue medication immediately
headache: any OTC (over the counter) remedy is fine
children: start with 50 mg at bed time and increase as tolerated in 50 mg increments, using divided doses; usual effective dose is 100-200 mg/day; 300 mg/day is usually well tolerated in older kids
adults and teens: start with 50 mg two to three times a day, increasing as tolerated over the first week to 200-300 mg per day; maximum recommended dose is 500-600 mg per day
Update 2008: Nefazodone has gone through a number of ups and downs since its introduction. Initially, it gained great popularity as an alternative to SSRIs, but its market share was gradually diluted with later entries into the antidepressant field, like Celexa and Remeron. As its patent was nearing its end, reports surfaced of rare episodes of hepatotoxicity (liver damage) in some patients. These severe adverse effects were quite rare, and the FDA did not consider the risk sufficient to justify withdrawal from the market, but it did issue a “black box” warning, which spelled commercial death for Serzone. The original manufacturer stopped selling Serzone, but generic nefazodone is still available.
Nefazodone is actually a very safe drug, despite the dire warnings. The risk of hepatotoxicity is estimated at about 1 in 250,000 per year of treament (so, if you were on it for 10 years, you’d have a 1 in 25,000 risk of liver damage.) This is quite a bit less than similar risks from valproate or other common drugs, most of which don’t even carry this kind of warning. Nevertheless, this has scared virtually all pediatricians and child psychitrists away from this medication, and nefazodone has been used relatively little in pediatric populations. In the end, the popularity of the SSRIs swamped nefazodone.
This is a shame, in many ways. Nefazodone is significantly less likely than most other antidepressants to induce mania in people with Bipolar Disorder, and it is also much less likely to cause excessive activation in pediatric patients. It has a mild calming and sedating effect, which greatly aids sleep. It has few GI side effects, and is generally easy to take.
For fragile X patients (of any age), nefazodone has many advantages. Like the SSRIs, it blocks reuptake of serotonin, which gives it antidepressant, anxiolytic, and antiobsessional effects. It also blocks reuptake of norepinephrine, which further boosts mood and can help with attention. It blocks 5HT2 receptors, helping to stabilize mood and decrease aggression, and even conferring some antipsychotic effects. Finally, its antagonism of alpha 1 norepinephrine receptors may be especially helpful in facilitating sleep and decreasing hyperactivity in fragile X. While it’s far from a “clean drug” with just one mechanism of action, its multiple effects overlap very nicely with the symptoms seen in fragile X and other autism spectrum disorders. For these reasons, nefazodone is one of the most potentially useful drugs for the treatment of fragile X, even if it is one of the most under-utilized in actual practice.