Medication Reference Guide

This reference guide provides a detailed evaluation of each medication commonly used in individuals with Fragile X syndrome.

Table of Contents

Antidepressants
Stimulants
Sympatholytics
Mood Stablilizers
Antipsychotics

About the Ratings for Medications

In an effort to simplify rapid comparison of a wide array of different medications, a basic rating mechanism is employed in the following pages. Roughly, these should be interpreted as follows:

Effectiveness
☺☺☺☺ an exceptionally effective treatment for the indications noted
☺☺☺ a very effective treatment for the indications noted
☺☺ a partially effective treatment, full resolution of target symptoms unlikely
☺ unlikely to be effective; may have partial effect in some cases

Safety
+ + + + non-toxic at any dose; no major medical or psychiatric side effects
+ + + non-toxic, but may have significant side effects in some cases
+ + potentially toxic and/or high incidence of significant side effects
+ very high incidence of serious adverse effects; not recommended

Cost
$$$$ very expensive, more than $5 per day for usual doses
$$$ expensive, in the $2-4 per day range
$$ moderately priced and easily affordable
$ practically free (in generic form only–brand name versions may cost much more)

Convenience
☯☯☯☯ medication taken once a day or less, convenient form of drug
☯☯☯ needs to be taken more than once a day or requires monitoring
☯☯ multiple daily doses required
☯ multiple daily dosing plus monitoring and/or highly controlled substance

 

About the Author

Mike Tranfaglia, MD, FRAXA Chief Scientific OfficerDr. Michael Tranfaglia is Medical Director and co-founder of FRAXA Research Foundation. Dr. Tranfaglia serves as a consulting psychiatrist for nursing homes and group homes in the greater Boston area. He received his B.A. in Biology from Harvard University in 1982 and his M.D. from the University of North Carolina at Chapel Hill in 1987. Dr. Tranfaglia and his wife, Katie Clapp, have a son, Andy, who has Fragile X.

Notice

This guide is not a medical textbook and cannot take the place of a qualified physician. It is intended to serve as background information to help parents, caretakers and others to communicate with their physicians regarding medications. The medications described in this guide are to be used only under the supervision of a qualified physician; almost all are available only by prescription.

Stimulants

methylphenidate (Ritalin)

Effectiveness:☺☺
Safety: + +
Cost: $$
Convenience: ☯☯
Indications and Use

Indications:
attention deficit, hyperactivity

Use

Methylphenidate is the most commonly prescribed psychostimulant in the United States. It is unclear just why this is, since it has few clinical advantages and numerous disadvantages compared to other available stimulants. Methylphenidate is a synthetic analog of amphetamine which causes somewhat less euphoria and less cardiovascular stimulation, and is generally thought to be less abusable, though it is still a schedule II controlled substance. It can be quite effective in enhancing attention, concentration, and general cognitive performance in Fragile X children (male or female), but its use is ordinarily restricted to lower doses by the emergence of dose-related anxiety and irritability (especially in males). Since its duration of action is very short–about 3 hours–it must be given at least twice a day, and periods of rebound are quite common as the drug is wearing off. At these times, attention deficit and/or hyperactivity can be worsened. A Sustained Release preparation is available to counteract this effect, but it comes in only one size (20 mg) and is still relatively short- acting (about 6 hours); some children do not find the therapeutic effect of the Sustained Release tablet equivalent to the regular tablet. Newer formulations like Concerta and Metadate overcome some of these problems by extending the duration of action; these are preferable to standard (short- acting) formulations, and there are now enough different versions to allow significant choice of dosages.

Pros & Cons

Pros:

works almost immediately, usually well tolerated; enhances attention and concentration

Cons

high incidence of psychiatric side effects; no liquid or chewable formulations available

Side effects

Common:
appetite suppression: give after meals to minimize this effect
behavioral rebound: more frequent doses or sustained release formulations should be used
insomnia: last dose of the day is too close to bed time–move to an earlier time
anxiety: dosage reduction (at least initially) is indicated
nausea: taking on a full stomach will greatly reduce this effect
headache: Tylenol is fine; temporary dosage reduction may help; usually transient

Uncommon:
motor tics: dosage reduction or discontinuation; can be treated with clonidine
palpitations: dosage reduction is indicated
rash: immediated discontinuation is required
psychosis (hallucinations or delusions): immediate discontinuation is required

Usual dosage

general: ordinarily, a total dose of 1.0 mg/kg/day is considered optimal for treating ADHD; a dose of 0.5-0.7 mg/kg/day is recommended for all individuals with Fragile X to minimize the risk of psychiatric side effects.
children: start with 2.5 mg (half tab) in morning, increasing as tolerated in 2.5 mg increments; doses over 30 mg/day are not recommended in Fragile X boys (36 mg Concerta may be well tolerated in some cases)
teens and adults: start with 5 mg morning and afternoon, increasing as tolerated up to 50-60 mg/day

Notes

The convenience of methylphenidate formulations has improved tremendously in the past few years; a number of different time-release formulations of methylphenidate are now available. One of the more successful is an advanced osmotic pump delivery system marketed as Concerta. This capsule actually contains a small bag full of methylphenidate liquid; when ingested, the stomach fluids cause an influx of water through the semi-permeable outer capsule, which squeezes the bag, pushing the drug out through a small hole at a controlled rate. Concerta is an expensive name-brand drug, but this delivery system is far better than the multiple daily doses of regular Ritalin which predictably yield a noticeable “roller-coaster effect.”

Please note that even the most advanced drug delivery system cannot overcome some of the adverse effects of the drug itself. Thus, fragile X patients treated with Concerta can still experience increased irritability, anxiety, and aggression. The risk of this adverse effect is still dose-dependent, and it is still inversely proportional to IQ.
One major limitation of time-release preparations is that they tend to be available in far fewer dosages, limiting the precision with which the dose can be adjusted. Fortunately, there have been many new “branded generic” time-release methylphenidate preparations released in the past few years, affording a wide range of options for individuals who respond well to methylphenidate, but need the dosage and timing of delivery adjusted. Newer time-release preparations include Focalin XR and Metadate CD; since these preparations all contain the same active drug, methylphenidate, there is little basic difference. However, individuals may respond much better to one preparation than another because of idiosyncratic factors such as drug absorption and metabolism, so some trial and error may be necessary to find the best medication.

Another interesting possibility is the Daytrana patch—methylphenidate delivered transdermally. Unlike the clonidine patch, Daytrana patches are made to be worn for one day only, and the timing of drug delivery can be tailored quite precisely by altering when the patch is applied and when it is removed. The patch delivers methylphenidate through the skin at a constant rate, which is proportional to the surface area of the patch, and it comes in several sizes designed to deliver from 10-30 mg per day. In many ways, this is an ideal way to administer a stimulant to children with fragile X, since the drug is delivered at a slow, steady, controlled rate over a prolonged time. There are no peak levels to cause greater side effects, and no interdose troughs to cause behavioral rebound.

For all fragile X individuals, the risk of side effects seems to depend on the level of functioning— higher functioning people with fragile X (at any given age) have fewer psychiatric side effects from stimulants. The usual recommendation for dosing methylphenidate in the general population is up to 1 mg/kg/d total dose; in other words, a 50 kg (110 lb) child would usually get a maximum of 50 mg of methylphenidate through the course of the day. This author recommends, as a general rule-of-thumb, dosing methylphenidate in fragile X patients in direct proportion to IQ (this is not meant to validate the dubious concept of IQ, but this is useful shorthand for overall functioning.) Thus, a typical fragile X patient with an IQ of 50 (50/100 of normal) should probably receive no more than 0.5 mg/kg/d of methylphenidate (regardless of specific formulation.) A higher functioning individual with an IQ of 70 might be able to tolerate 0.7 mg/kg/d. A lower functioning individual with IQ lower than 40 or so probably shouldn’t be treated with stimulants in the first place, and experience over the past 10 years has reinforced this clinical impression.

Many people with fragile X will still be unable to tolerate useful doses of methylphenidate; for those individuals, an alternative worth considering is Provigil (modafinil), a non-stimulant, schedule IV medication which generally has fewer side effects than methylphenidate or amphetamine.

dextroamphetamine (Dexedrine)

Effectiveness:☺☺
Safety: + +
Cost: $$
Convenience: ☯

Indications and Use

Indications: attention deficit, hyperactivity

Use

Dextroamphetamine is the active form of amphetamine, and is the prototype of the stimulant class of medications. While it is somewhat longer-acting than methylphenidate, it still must be administered at least twice a day to be effective, and rebound symptoms are often prominent. Compared to methylphenidate, it tends to cause more euphoria, more cardiovascular stimulation, and more appetite suppression (although all of these are obviously dose-dependent). It is available in longer-acting “Spansules” which come in three different sizes (5, 10, and 15 mg), making dosing a bit more flexible. Differential response is highly variable–some individuals who respond poorly to methylphenidate will have a good response to dextroamphetamine, and vice versa.

Pros and Cons

Pros

works almost immediately, usually well tolerated; enhances attention and concentration

Cons

high incidence of psychiatric side effects; short acting, requires frequent dosing; no liquid or chewable formulations available

Side effects

Common:
appetite suppression: give after meals to minimize this effect
behavioral rebound: more frequent doses or Spansule formulation should be used insomnia: last dose of the day is too close to bed time–move to an earlier time
anxiety: dosage reduction (at least initially) is indicated
nausea: taking on a full stomach will greatly reduce this effect
headache: Tylenol is fine; temporary dosage reduction may help; usually transient

Uncommon:
motor tics: dosage reduction or discontinuation; can be treated with clonidine palpitations: dosage reduction is indicated
rash: immediated discontinuation is required
psychosis (hallucinations or delusions): immediate discontinuation is required

Usual dosage

children: start with 2.5 mg in morning, increasing in 2.5 mg increments as tolerated to optimal effect; 2 or 3 doses are usually required to provide adequate coverage throughout the day; doses over 20-25 mg per day are not recommended for children with Fragile X.

teens and adults: start with 5 mg twice a day, increasing in 5 mg increments as tolerated to optimal effect, up to 30-40 mg per day total; Spansules will likely have a more sustained, but also less potent effect.

Update

Several new formulations of amphetamine have become available in the past few years, increasing the number of options for fragile X patients who respond better to amphetamine than methylphenidate. Adderall XR has become one of the most popular stimulant formulations, and a new pro-drug formulation, Vyvanse has been introduced. Vyvanse is metabolized into amphetamine, resulting in smoother plasma levels of the active drug. Once again, the basic pharmacology remains the same, and the same “IQ adjustment” recommended for methylphenidate is also recommended for amphetamine preparations (see methylphenidate section.)

Many people with fragile X will still be unable to tolerate useful doses of amphetaminee; for those individuals, an alternative worth considering is Provigil (modafinil), a non-stimulant, schedule IV medication which generally has fewer side effects than methylphenidate or amphetamine.

atomoxetine (Strattera)

Effectiveness:☺☺
Safety: + +
Cost: $$$
Convenience: ☯☯☯
Indications and Use

Indications: attention deficit, hyperactivity

Use

Strattera is a relatively new drug marketed specifically for the treatment of Attention Deficit Disorder; it is similar in its mechanism of action to desipramine and bupropion, and is not a stimulant or a controlled substance. This medication has been used quite a bit in the treatment of individuals with Fragile X, with mixed results. Some find it a useful alternative to stimulant medications, with the added benefit of enhanced antidepressant effects; however, it appears to cause significant behavioral side effects in about half of those treated, especially during the initial phases of treatment. This is probably to be expected, given its mechanism of action: atomoxetine is essentially an antidepressant medication marketed as a stimulant substitute. This means that it will take longer to start working (compared to a stimulant) and will generally cause most of its side effects during the first 2 weeks of treatment, while the body is still adjusting to the presence of the drug. If this different time course of side effects and response (compared to stimulants) is not adequately explained to patients and families, premature discontinuation of treatment may result, based on the assumption that the drug is ineffective. As with antidepressants, the therapeutic effects of atomoxetine will increase over time, while the side effects should decrease; this is the exact opposite of the experience with stimulants, which are effective immediately but then show development of tolerance, with side effects usually negligible at first but increasing with cumulative exposure over the course of months (presumably due to dopamine depletion with long-term use of higher doses.) Children appear to be more sensitive than adults to some of the side effects such as agitation and excessive activation (which is also the case with most antidepressants.)

Pros and Cons

Pros

long-acting; flexible dosages; less rebound than Ritalin; not a controlled substance (refills
allowed); should have distinct antidepressant effects

Cons

delayed onset of action, takes longer to find optimal dose; high incidence of adverse effects (mainly psychiatric)
Side effects:
Common: upset stomach, decreased appetite, nausea or vomiting, dizziness, tiredness, and mood swings
Uncommon: weight loss, allergic reactions, agitation, aggression

Usual dosage

children: start with a low dose to avoid most common side effects—10 mg twice a day for 1-2 weeks, then increase as tolerated to 20-25 mg twice a day; allow 2-4 weeks for full effect (unlike stimulant meds); older and larger children/adolescents can take up to 80 mg/day

adults: can usually start with 25 mg twice a day, increasing as tolerated to 40 mg twice a day; allow 2- 4 weeks for full effect before considering further dose increase; maximum dose quoted by manufacturer is 150 mg/day, but doses above 120 mg/day should be used with caution in Fragile X individuals

doses should be reduced in anyone taking an SSRI, such as Prozac or Zoloft

Update

Strattera continues to offer an attractive option for an on-stimulant treatment of attentional problems; unfortunately, results in the treatment of fragile X have continued to be mixed, at best. Most people with fragile X have difficulty tolerating higher doses of the drug, and lower doses are often ineffective. Overall, less than one third of Strattera trials in fragile X patients are successful — a rather high wash-out rate.

Folic acid

Effectiveness:☺
Safety: + +
Cost: $
Convenience: ☯☯
Indications and Use

Indications: attention deficit, hyperactivity

Use

Folic acid is a vitamin which is essential for several critical biochemical reactions which occur in all human cells. Since the Fragile X chromosome was originally observed in cells which had been deprived of folic acid, one of the first specific attempts to treat Fragile X involved the use of folic acid supplements, on the theory that some sort of error in folic acid metabolism might cause Fragile X syndrome. Systematic studies of the use of folic acid in Fragile X have failed to demonstrate any statistically significant efficacy; however, anecdotal reports and testimonials from parents indicate that some children may benefit from folic acid. It is worth noting that folic acid, in the megadoses used to treat Fragile X, is not an entirely benign treatment. Doses of folic acid in this range can cause significant intestinal malabsorption, especially of zinc and pyridoxine (vitamin B6 ), often leading to diarrhea. Folic acid also lowers the seizure threshold, and seizures have been reported in Fragile X boys on high doses of folic acid (though this is a high risk group anyway).

Since it has now been conclusively shown that Fragile X does not involve any defect in folic acid metabolism, newer theories about the mechanism of action of folic acid in treating Fragile X have arisen. The conventional wisdom holds that folic acid acts as a weak psychostimulant, and that this is the basis of its reported effects. Some parents feel that it enhances their children’s attention while ameliorating behavioral disturbances, but it is most certainly not a cure for Fragile X, or even a specific treatment. Some articles have promoted the use of Leucovorin (folinic acid), a more potent version of the vitamin which is marketed as an antidote to some forms of cancer chemotherapy (for “Leucovorin rescue”). There is no evidence that this medication works, either, and it is astronomically expensive; therefore, this treatment (Leucovorin/folinic acid) cannot be recommended.

Pros and Cons

Pros

inexpensive; unlikely to cause adverse psychiatric effects

Cons

ineffective; difficult to obtain; can cause significant medical side effects

Side effects

Common:
diarrhea: attempt dosage reduction; split dosing; fiber supplement

Uncommon:
malabsorption: vitamin B6, zinc supplements, multivitamins

Usual dosage

start with 1-2 mg twice a day, increasing as tolerated to 5 mg twice a day; some children have been treated with 30-40 mg per day without ill effects; special formulation (usually a suspension) must be prepared by pharmacist with proper prescription–largest commercially available tablet is only 1 mg.

Update

Academic interest in folic acid treatment has essentially disappeared. Virtually all clinicians in the fragile X field have concluded that folic acid simply doesn’t work, though reviews on the subject often note that some parents believe strongly that the treatment has helped their children. In addition, folic acid often serves as a gateway to drug treatment of fragile X—this is still a common first treatment for young children with fragile X.

Oddly enough, recent evidence from basic research in fragile X disease mechanisms indicates that folic acid might actually have an unintended therapeutic action in people with fragile X. FRAXA-funded research by Dr. Iryna Ethell of the University of California at Riverside showed that dendritic spines, the tiny cell structures on the receiving end of neurotransmitter signals in the brain, are kept in an immature and poorly functioning state by excessive activity of enzymes called Matrix Metalloproteinases. These enzymes can be inhibited by certain medications, like minocycline, which can be therapeutic for fragile X. However, these same enzymes also depend on zinc ions inside the protein to give them biological activity (that’s the metal in the metalloproteinase); in a condition of zinc deficiency, MMP activity is impaired (which might be a good thing for someone with fragile X.) Indeed, it appears that zinc concentrations are regulated in the brain as one way of regulating activity of these enzymes. It so happens that high doses of folic acid administered orally impair the absorption of zinc. This is well known, so zinc supplements are routinely recommended for anyone taking more than the usual (ie 400 microgram/day) dose of folic acid.

It is interesting to speculate whether zinc depletion may actually be a therapeutic mechanism of action of folic acid in fragile X, and whether we may be inadvertently defeating this therapeutic effect by co-administration of zinc supplements. Research on the role of zinc in neural function is still in its infancy, so it is still premature to recommend intentional zinc depletion for people with fragile X, but this may explain why some fragile X parents still swear by folic acid.

{If we really want to speculate even further, this could potentially explain why some parents of (non- fragile X) autistic children swear by chelation therapy. They may be doing it to eliminate mercury (which is highly unlikely to be a significant cause of autism), but in so doing, they may be unintentionally lowering zinc levels and suppressing MMP activity.

Antidepressants

fluoxetine (Prozac)

Effectiveness:☺☺☺☺
Safety: + + +
Cost: $$
Convenience: ☯☯☯☯

Indications: aggression, anxiety, irritability, self-injurious behavior, obsessive-compulsive symptoms

Use

SSRIs are rapidly becoming the treatment of choice in a wide variety of neuropsychiatric disorders because of their broad spectrum of efficacy; they can improve disorders of mood, anxiety, and impulse control in a wide variety of patients with essentially no toxicity. Fluoxetine is the prototype of this class, and is distinguished by its ultra-long half-life, allowing every other day dosing. Compared to other drugs in this class, fluoxetine is often more activating, and has a higher incidence of insomnia and restlessness. Though most people find this either pleasant or at least tolerable (and usually transient), this can be a major complication in the treatment of children, who seem to be especially susceptible to this side effect.

The only significant medical concern when using fluoxetine is the potential for drug interactions. SSRIs tend to be potent inhibitors of liver enzymes which metabolize some prescription medications, most notably the tricyclic antidepressants and some anticonvulsants; when these other medications are administered along with an SSRI, they can reach far higher concentrations in the bloodstream.

Keep in mind that these medications all work gradually over a long period of time: most Fragile X families report noticeable effects from SSRIs only after 4-6 weeks of treatment, and the greatest effect will usually occur in 3-4 months. Expect to see a significant decrease in irritability, social and panic anxiety, O-C symptoms, and temper tantrums. Aggression and self-injurious behavior (SIB) may be the first symptoms to respond, even before obvious effects on mood are observed. Attention should be enhanced, though hyperactivity does not always decrease (and could get worse if activation is excessive). If this response does not occur, a higher dose should be considered; however, time is more important than dose in using these medications, and often simply waiting will give the best result.

If one SSRI is not well tolerated, or does not work, it is sensible to try another. Response to these medications (and many others) is highly individual and idiosyncratic–a poor response to one member of this class does not mean that all the others should be avoided.

Pros and Cons

Pros

broad spectrum of action, treats numerous symptoms of Fragile X; not toxic, even in massive overdose; once-a-day dosing with prolonged duration of action; non-sedating; generic available

Cons

can cause excessive activation, even mania in extreme cases; frequent nausea and/or insomnia at initiation

Side effects

Common:
nausea: take with food; Pepto-Bismol may be used; divided doses may result in less initial stomach upset; always transient–will improve in 7-10 days
tremor: benign and transient–will improve in 1-2 weeks; if not, can be treated with a beta blocker
activation/restlessness/insomnia: temporary dosage reduction helpful; take medication as early in the day as possible; usually transient–if not, can be treated with clonidine

Uncommon: headache: temporary dosage reduction or divided dose often helpful; usually transient, but can be treated with any OTC headache remedy
flushing/sweating: benign and transient–maintain proper hydration
mania: if child becomes abnormally active, elated, and is not sleeping at all, the medication should be discontinued immediately. This can be done abruptly without any tapering–no significant withdrawal syndrome can occur. Symptoms of mania will usually subside quickly, over a few days; if symptoms persist, clonidine can help, but in rare cases a mood stabilizer such as carbamazepine or valproic acid may be necessary. Some experts in mood disorders believe that manic activation in the course of antidepressant treatment indicates an innate predisposition to Bipolar Disorder, although this notion is somewhat controversial.

Usual dosage

children: start with 2-4 mg each morning with food; capsule contents are freely soluble in water, taste is well hidden in juices; liquid is available (but expensive) with 4 mg per ml; capsule contents can be mixed ahead of time with a known volume of juice to make an economical and stable solution, i.e. 20 mg of Prozac in 20 ounces of juice will give 1 mg of medication for each ounce of juice; if this method is used, be sure to mark carefully and keep away from other children, (even though no serious toxicity will result from unintentional overdose); increase as tolerated for optimal effect in 3-4 week intervals to 5-20 mg per day; young children will rarely require more than 10 mg/day, some teens can metabolize 40 mg/day and tolerate this dose well.
adults: start with 10 mg per day with food for the first 3-4 weeks (10 mg capsule now available); if needed, increase to 20-40 mg/day for optimal effect; most people respond to 20 mg/day if given enough time.

Notes

Fluoxetine is as useful as ever, though younger children with fragile X do seem especially sensitive to its activating effects; start low and go slow! It is now available in generic form, and this may make it an especially economical alternative. Fluvoxamine (Luvox) may be less activating for most younger children (and is indicated for the treatment of OCD in children.) Neuropharm, a British pharmaceutical company which is also developing fragile X therapeutics, is developing an alternative formulation of fluoxetine as a treatment for autism. This formulation is currently undergoing large-scale Phase III clinical trials, the largest ever for an SSRI in the treatment of MRDD. Numerous other clinical trials have now established the safety and efficacy of fluoxetine in the treatment of many of these same symptoms in autism.

citalopram (Celexa, Lexapro)

Effectiveness:☺☺☺☺
Safety: + + +
Cost: $$
Convenience: ☯☯☯☯

Indications: aggression, anxiety, irritability, self-injurious behavior, obsessive-compulsive symptoms

Use

SSRIs are rapidly becoming the treatment of choice in a wide variety of neuropsychiatric disorders because of their broad spectrum of efficacy; they can improve disorders of mood, anxiety, and impulse control in a wide variety of patients with essentially no toxicity. Citalopram is one of the newer drugs in this class; Lexapro is an “improved” version of Celexa which contains only one stereo-isomer of the drug (the “left-handed” molecule, which is more active.) Since it is newer, there is somewhat less experience in treating children with citalopram than with other SSRIs, but this is likely to change, since this drug is widely prescribed in the general population. It appears to offer a benign side-effect profile, though excessive activation is still likely to be the main problem in the treatment of children.

The only significant medical concern when using citalopram is the potential for drug interactions. SSRIs tend to be potent inhibitors of liver enzymes which metabolize some prescription medications, most notably the tricyclic antidepressants and some anticonvulsants; when these other medications are administered along with an SSRI, they can reach far higher concentrations in the bloodstream. Keep in mind that these medications all work gradually over a long period of time: most Fragile X families report noticeable effects from SSRIs only after 4-6 weeks of treatment, and the greatest effect will usually occur in 3-4 months. Expect to see a significant decrease in irritability, social and panic anxiety, O-C symptoms, and temper tantrums. Aggression and self-injurious behavior (SIB) may be the first symptoms to respond, even before obvious effects on mood are observed. Attention should be enhanced, though hyperactivity does not always decrease (and could get worse if activation is excessive). If this response does not occur, a higher dose should be considered; however, time is more important than dose in using these medications, and often simply waiting will give the best result. If one SSRI is not well tolerated, or does not work, it is sensible to try another. Response to these medications (and many others) is highly individual and idiosyncratic–a poor response to one member of this class does not mean that all the others should be avoided.

Pros and Cons

Pros

broad spectrum of action, treats numerous symptoms of Fragile X; not toxic, even in massive overdose; once-a-day dosing with prolonged duration of action; non-sedating

Cons

moderately expensive; can cause excessive activation, even mania in extreme cases; frequent nausea and/or insomnia at initiation

Side effects

Common:
nausea: take with food; Pepto-Bismol may be used; divided doses may result in less initial stomach upset; always transient–will improve in 7-10 days
tremor: benign and transient–will improve in 1-2 weeks; if not, can be treated with a beta blocker
activation/restlessness/insomnia: temporary dosage reduction helpful; take medication as early in the day as possible; usually transient–if not, can be treated with clonidine

Uncommon:
headache: temporary dosage reduction or divided dose often helpful; usually transient, but can be treated with any OTC headache remedy
flushing/sweating: benign and transient–maintain proper hydration
mania: if child becomes abnormally active, elated, and is not sleeping at all, the medication should be discontinued immediately. This can be done abruptly without tapering–no medically significant withdrawal syndrome can occur. Symptoms of mania will usually subside quickly, over a few days; if symptoms persist, clonidine can help, but in rare cases a mood stabilizer such as carbamazepine or valproic acid may be necessary. Some experts in mood disorders believe that manic activation in the course of antidepressant treatment indicates an innate predisposition to Bipolar Disorder, although this notion is somewhat controversial.

Usual dosage

children: start with 5 mg; increase as tolerated for optimal effect in 3-4 week intervals to 5-20 mg per day; young children will rarely require more than 10 mg/day, some teens can metabolize 40 mg/day and tolerate this dose well.
adults: start with 10 mg per day with food for the first 3-4 weeks; if needed, increase to 20-40 mg/day for optimal effect; most people respond to 20 mg/day if given enough time.

Update

Celexa has gone generic, and a funny thing happened along the way. The company that, until very recently, made Celexa now says that the drug has lots of side effects that it really hadn’t appreciated at first. Fortunately, this same company coincidentally has an “improved” version of citalopram called Lexapro (escitalopram, the S-isomer of the exact same compound.) Unfortunately, wonderful new Lexapro is an expensive name-brand-only drug, while crummy old citalopram (the drug formerly known as Celexa) is a cheap generic. Now, a cynic might say that this is a prime example of a drug company trying to extend its patent by introducing a “new” drug which is new in name only. In this case, the cynics are probably right. Celexa has few side effects, and Lexapro doesn’t seem much better. A few patients who’ve tried both prefer Lexapro, but others prefer Celexa (or generic citalopram.) The point is that Celexa is still a good drug, and citalopram is a useful generic. The makers of Lexapro also claim that the newer version is 4 times as potent as the older citalopram; this does not appear to be true in clinical practice, where higher doses are often needed. In the treatment of fragile X, optimal doses of generic citalopram are typically around 40 mg/day in adults; for Lexapro, 20 mg or more is usually required.

sertraline (Zoloft)

Effectiveness:☺☺☺☺
Safety: + + +
Cost: $$
Convenience: ☯☯☯☯

Indications: aggression, anxiety, irritability, self-injurious behavior, obsessive-compulsive symptoms

Use

SSRIs are rapidly becoming the treatment of choice in a wide variety of neuropsychiatric disorders because of their broad spectrum of efficacy; they can improve disorders of mood, anxiety, and impulse control in a wide variety of patients with essentially no toxicity. Sertraline was introduced to the US market four years after fluoxetine, and became an immediate success, partly because fluoxetine had an undeservedly bad reputation in the popular press, and partly because it has a slightly different side-effect profile, making it better tolerated for some people. Compared to other drugs in this class, sertraline causes more nausea and diarrhea, but somewhat less activation or restlessness. It also causes a very high rate of sexual dysfunction, and while this may not be a concern for most children, it can interrupt treatment of adults.

The only significant medical concern when using sertraline is the potential for drug interactions. SSRIs tend to be potent inhibitors of liver enzymes which metabolize some prescription medications, most notably the tricyclic antidepressants and some anticonvulsants; when these other medications are administered along with an SSRI, they can reach far higher concentrations in the bloodstream; sertraline seems less likely to cause this type of interaction than some other SSRIs, but caution should still be observed.

Keep in mind that these medications all work gradually over a long period of time: most Fragile X families report noticeable effects from SSRIs only after 4-6 weeks of treatment, and the greatest effect will usually occur in 3-4 months. Expect to see a significant decrease in irritability, social and panic anxiety, O-C symptoms, and temper tantrums; aggression and self-injurious behavior (SIB) may be the first symptoms to respond, even before obvious effects on mood are observed. Attention should be enhanced, though hyperactivity does not always decrease. If this response does not occur, a higher dose should be considered; however, time is more important than dose in using these medications, and often simply waiting will give the best result. If one SSRI is not well tolerated, or does not work, it is sensible to try another. Response to these medications (and many others) is highly individual and idiosyncratic–a poor response to one member of this class does not mean that all the others should be avoided.

Pros & Cons

pros

broad spectrum of action, treats numerous symptoms of Fragile X; not toxic–even in massive
overdose; once-a-day dosing with prolonged duration of action; non-sedating

Cons

moderately expensive; can cause excessive activation, even mania in extreme cases; frequent nausea and/or insomnia at initiation

Side effects

Common:
nausea: take with food; Pepto-Bismol may be used; divided doses may result in less initial stomach upset; always transient–will improve in 7-10 days
diarrhea: usually transient–may use any over-the-counter (OTC) remedy; be sure to take with food (this also boosts absorption of sertraline by about 30%)
tremor: benign and transient–will improve in 1-2 weeks; if not, can be treated with a beta blocker
activation/restlessness/insomnia: temporary dosage reduction helpful; take medication as early in the day as possible; usually transient–if not, can be treated with clonidine

Uncommon:
headache: temporary dosage reduction or divided dose often helpful; usually transient, but can be treated with any OTC headache remedy
flushing/sweating: benign and transient–maintain proper hydration
mania: if child becomes abnormally active, elated, and is not sleeping at all, the medication should be discontinued immediately. This can be done abruptly without any tapering–no significant withdrawal syndrome can occur. Symptoms of mania will usually subside quickly, over a few days; if symptoms persist, clonidine can help, but in rare cases a mood stabilizer such as carbamazepine or valproic acid may be necessary. Some experts in mood disorders believe that manic activation in the course of antidepressant treatment indicates an innate predisposition to Bipolar Disorder, although this notion is somewhat controversial.

Usual dosage

children: start with 12.5 mg (1/4 tablet) each morning with food; this pill is rather bitter, but can be hidden in candy or applesauce or peanut butter to mask the taste; increase as tolerated for optimal effect in 3-4 week intervals to 25-75 mg per day; young children will rarely require more than 50 mg/day, some teens can metabolize 100-200 mg/day and tolerate this dose well.
adults: start with 25 mg per day with food for the first 3-4 weeks ; if needed, increase to 50-200 mg/day for optimal effect; most people respond to 100 mg/day if given enough time.

Update

Sertraline is available as a generic, and may be the most effective SSRI in the treatment of fragile X. The response rate to this drug seems to be the highest of the class, and it does not seem to be any more activating than the average for the SSRI class. Sertraline does seem to cause more GI upset than average, and this can be a problem in people with fragile X; loose stools are already an issue in fragile X (probably caused by excessive mGluR5 activity) and this medication can aggravate the problem, occasionally to the point of bowel incontinence. However, some tolerance or accommodation to this side effect usually develops over time, so it is rarely a long-term problem. In general use in the population at large, sertraline cause many problems with sexual dysfunction (both decreased libido and anorgasmia.) This could actually be seen as an advantage in the treatment of some individuals with fragile X, though the clinical presentation is more likely to include hyposexuality.

paroxetine (Paxil)

Effectiveness:☺☺☺☺
Safety: + + +
Cost: $$
Convenience: ☯☯☯☯

Indications: aggression, anxiety, irritability, self-injurious behavior, obsessive-compulsive symptoms

Use

SSRIs are rapidly becoming the treatment of choice in a wide variety of neuropsychiatric disorders because of their broad spectrum of efficacy; they can improve disorders of mood, anxiety, and impulse control in a wide variety of patients with essentially no toxicity. Paroxetine is an older member of this class, introduced to the US market a year after sertraline, and it has been in use even longer in other countries. Compared to other drugs in this class, paroxetine is often more sedating, and has a higher incidence of dry mouth and constipation, though most people taking it find this tolerable and usually transient.
The only significant medical concern when using paroxetine is the potential for drug interactions. SSRIs tend to be potent inhibitors of liver enzymes which metabolize some prescription medications, most notably the tricyclic antidepressants and some anticonvulsants; when these other medications are administered along with an SSRI, they can reach far higher concentrations in the bloodstream.

Keep in mind that these medications all work gradually over a long period of time: most Fragile X families report noticeable effects from SSRIs only after 4-6 weeks of treatment, and the greatest effect will usually occur in 3-4 months. Expect to see a significant decrease in irritability, social and panic anxiety, O-C symptoms, and temper tantrums; aggression and self-injurious behavior (SIB) may be the first symptoms to respond, even before obvious effects on mood are observed. Attention should be enhanced, though hyperactivity does not always decrease. If this response does not occur, a higher dose should be considered; however, time is more important than dose in using these medications, and often simply waiting will give the best result. If one SSRI is not well tolerated, or does not work, it is sensible to try another. Response to these medications (and many others) is highly individual and idiosyncratic–a poor response to one member of this class does not mean that all the others should be avoided.

Pros and Cons

Pros

broad spectrum of action, treats numerous symptoms of Fragile X; not toxic–even in massive
overdose; once-a-day dosing with prolonged duration of action; generic available

Cons

can cause excessive activation, even mania in extreme cases; frequent nausea at initiation; causes dry mouth frequently; can cause some sedation; bitter tablet, no liquid available, no pediatric dosages available

Side effects

Common:
nausea: take with food; Pepto-Bismol may be used; divided doses may result in less initial stomach upset; always transient–will improve in 7-10 days
diarrhea or constipation: usually transient, may use any over-the-counter (OTC) remedy
tremor: benign and transient–will improve in 1-2 weeks; if not, can be treated with a beta blocker
activation/restlessness/insomnia: temporary dosage reduction helpful; take medication as early in the day as possible; usually transient–if not, can be treated with clonidine
sedation: give at bed time

Uncommon:
headache: temporary dosage reduction or divided dose often helpful; usually transient, but can be treated with any OTC headache remedy
flushing/sweating: benign and transient–maintain proper hydration
mania: if child becomes abnormally active, elated, and is not sleeping at all, the medication should be discontinued immediately. This can be done without tapering–no medically significant withdrawal syndrome can occur, though Paxil can cause some uncomfortable (but benign) side effects during withdrawal. Symptoms of mania will usually subside quickly, over a few days; if symptoms persist, clonidine can help, but in rare cases a mood stabilizer such as carbamazepine or valproic acid may be necessary. Some experts in mood disorders believe that manic activation in the course of antidepressant treatment indicates an innate predisposition to Bipolar Disorder, although this notion is somewhat controversial.

Usual dosage

children: start with 5 mg (1/4 tablet) each evening with food; this pill is rather bitter, but can be hidden in candy or applesauce or peanut butter to mask the taste; increase as tolerated for optimal effect in 3-4 week intervals to 5-20 mg per day; young children will rarely require more than 10 mg/day, some teens can metabolize 40 mg/day and tolerate this dose well.
adults: start with 10 mg per day (1/2 tab) with food for the first 3-4 weeks ; if needed, increase to 20-40 mg/day for optimal effect; most people respond to 20 mg/day if given enough time.

Update

Various Paxil formulations, including generic paroxetine, have steadily lost market share over the past few years. This drug has always had more side effects than other SSRI’s, though many people have no difficulty tolerating it. It was also at the center of the recent pediatric suicide controversy surrounding SSRIs, and the actions of the drugs manufacturer in this episode were less- than-stellar. As I have noted previously, suicidal ideation does not appear to be a major treatment consideration for the vast majority of fragile X patients. Dosing also appears to be a bit less predictable than for other SSRIs, so with all the other choices available these days, it’s not surprising that fewer doctors are prescribing paroxetine. Nevertheless, it is a safe and effective medication which is now available in generic form.

fluvoxamine (Luvox)

Effectiveness:☺☺☺☺
Safety: + + +
Cost: $$
Convenience: ☯☯☯☯

Indications: aggression, anxiety, irritability, self-injurious behavior, obsessive-compulsive symptoms

Use

SRIs are rapidly becoming the treatment of choice in a wide variety of neuropsychiatric disorders because of their broad spectrum of efficacy; they can improve disorders of mood, anxiety, and impulse control in a wide variety of patients with essentially no toxicity. Fluvoxamine one of the newer members of this class, and is currently being marketed for the treatment of OCD. Compared to other drugs in this class, fluvoxamine is often more sedating, though most people taking it find this tolerable and usually transient.

The only significant medical concern when using fluvoxamine is the potential for drug interactions. SSRIs tend to be potent inhibitors of liver enzymes which metabolize some prescription medications, most notably the tricyclic antidepressants and some anticonvulsants; when these other medications are administered along with an SSRI, they can reach far higher concentrations in the bloodstream.

Keep in mind that these medications all work gradually over a long period of time: most Fragile X families report noticeable effects from SSRIs only after 4-6 weeks of treatment, and the greatest effect will usually occur in 3-4 months. Expect to see a significant decrease in irritability, social and panic anxiety, O-C symptoms, and temper tantrums; aggression and self-injurious behavior (SIB) may be the first symptoms to respond, even before obvious effects on mood are observed. Attention should be enhanced, though hyperactivity does not always decrease. If this response does not occur, a higher dose should be considered; however, time is more important than dose in using these medications, and often simply waiting will give the best result. If one SSRI is not well tolerated, or does not work, it is sensible to try another. Response to these medications (and many others) is highly individual and idiosyncratic–a poor response to one member of this class does not mean that all the others should be avoided.

Pros and Cons

Pros

broad spectrum of action, treats numerous symptoms of Fragile X; not toxic–even in massive overdose; once-a-day dosing with prolonged duration of action; non-sedating; approved for use in children; generic available

Cons

Can cause excessive activation, even mania in extreme cases; frequent nausea and/or insomnia at initiation

Side effects

Common:
nausea: take with food; Pepto-Bismol may be used; divided doses may result in less initial stomach upset; always transient–will improve in 7-10 days
diarrhea: transient, try any over-the-counter (OTC) remedy
sedation: this medication is usually taken at bedtime for this reason; residual daytime sedation is usually transient and will resolve over 3-7 days
tremor: benign and transient–will improve in 1-2 weeks; if not, can be treated with a beta blocker
activation/restlessness/insomnia: temporary dosage reduction helpful; take medication as early in the day as possible; usually transient–if not, can be treated with clonidine

Uncommon:
headache: temporary dosage reduction or divided dose often helpful; usually transient, but can be treated with any OTC headache remedy
flushing/sweating: benign and transient–maintain proper hydration
mania: if child becomes abnormally active, elated, and is not sleeping at all, the medication should be discontinued immediately. This can be done abruptly without any tapering–no medically significant withdrawal syndrome can occur. Symptoms of mania will usually subside quickly, over a few days; if symptoms persist, clonidine can help, but in rare cases a mood stabilizer such as carbamazepine or valproic acid may be necessary. Some experts in mood disorders believe that manic activation in the course of antidepressant treatment indicates an innate predisposition to Bipolar Disorder, although this notion is somewhat controversial.

Usual dosage

children: start with 12.5 mg each night; increase as tolerated for optimal effect in 3-4 week intervals to 25-100 mg per day; young children may not require more than 50 mg/day, some teens can metabolize 200 mg/day or more and tolerate this dose well.

adults: start with 25 mg per day with food for the first 3-4 weeks ; if needed, increase to 50-300 mg/day for optimal effect; most people respond to 100 mg/day if given enough time.

Update

Luvox has gone generic, but another company has also come out with Luvox CR, a controlled-release formulation of the drug. This makes some sense, since fluvoxamine has one of the shortest half-lives of all SSRIs, so it should help to spread out absorption a bit and increase duration of action somewhat. However, it is not a time-release formulation, so the effect is small; the greatest potential benefit is a likely reduction in acute side effects with larger doses (and larger doses clearly work best for many of the anxiety symptoms associated with fragile X.) Fluvoxamine really never caught on in the US, though it has been more widely prescribed in Europe, but it is a highly effective medication which has a long track record of excellent safety (longest of any SSRI, actually.) Luvox remains an excellent choice for the treatment of the psychiatric manifestations of developmental disorders, especially in children, where its decreased propensity to cause activation is highly desirable.

venlafaxine (Effexor)

Effectiveness:☺☺☺
Safety: + + +
Cost: $$
Convenience: ☯☯

Indications: aggression, anxiety, irritability, self-injurious behavior, obsessive-compulsive symptoms, attention deficit

Use

Venlafaxine is an antidepressant medication which inhibits re-uptake of serotonin and norepinephrine, while causing few other effects; in this regard it can be considered a “clean” version of clomipramine. The original medication is short acting, and must be given 2 or 3 times a day–a major inconvenience; however, this also means that it reaches full therapeutic concentrations almost immediately, and may be effective sooner than others. More recently, an extended-release version (Effexor XR) has been marketed which can be given once or twice a day, and may have fewer side effects for the average person because of more gradual drug absorption. Venlafaxine has been shown to be very effective in a wide variety of mood and anxiety disorders, including OCD and depression which has not responded to tricyclic antidepressants (TCAs) or SSRIs; however, there is relatively little experience thus far in treating children.

Since venlafaxine has a similar spectrum of activity to clomipramine, a medication which has been used fairly widely in the developmentally disabled population, yet is significantly less toxic, venlafaxine can be used to treat Fragile X. Treatment with this medication can be expected to result in a decrease in irritability or mood lability; O-C symptoms and perseverative behavior should be markedly diminished; social and panic anxiety can be expected to decrease dramatically; while there is little experience in treatment of self-injurious behavior or aggression with this agent, it is likely that it will prove quite effective, given its potent serotonergic properties. The only medically significant adverse effect associated with venlafaxine administration is a dose-related increase in blood pressure, which is ordinarily benign and asymptomatic; this is not likely to pose a problem for the average healthy child.

Pros & Cons

Pros

broad spectrum of action, treats numerous symptoms of Fragile X

Cons

can cause excessive activation, even mania in extreme cases; frequent nausea at initiation; some people experience significant sedation; usually requires multiple dosing, no liquid or chewable available

Side effects

Common:
nausea: take with food; Pepto-Bismol recommended; transient–will resolve in 5-7 days
sedation: temporary dosage reduction may help; usually transient
tremor: transient and benign–beta blocker can help, but rarely needed
dry mouth: also transient (unlike TCAs), sugar-free gum or hard candy can help if this is persistent
Uncommon:
activation/restlessness: temporary dosage reduction may help; usually transient; clonidine or beta blocker can be given to treat this, but is rarely necessary
insomnia: take last dose at least 4-5 hours before bedtime

Usual dosage

adults: start with 1/2 of a 37.5 mg tablet twice a day with food; increase as tolerated to 37.5 mg two or three times a day; maximum dose of 450 mg per day is rarely needed

Update

Effexor has been available in an extended release formulation for some time now (Effexor XR), and the standard immediate-release preparation has been discontinued. This typically results in fewer immediate side effects from a dose, along with greater convenience from fewer daily doses (the manufacturer advertises this as a once-a-day formulation, but it is often given twice a day if higher doses are required—still a big improvement over the original immediate-release Effexor.) However, an extended-release formulation does not make a short-acting drug like Effexor into a long-half-life compound; while the venlafaxine in Effexor XR is release gradually over a period of time, it is still metabolized and eliminated rapidly after absorption.

This brings us to a major shortcoming of venlafaxine: it has a nasty “discontinuation syndrome.” While this medication doesn’t cause physiologic dependence, tolerance, or true withdrawal (like Xanax might, for example), it can cause some unpleasant symptoms if it is discontinued suddenly.

s this is now going off-patent, Pristiq (desvenlafaxine) is being introduced as a new drug entity. For all intents and purposes, it should be entirely equivalent to the old Effexor.

trazodone (Desyrel)

Effectiveness:☺☺
Safety: + + +
Cost: $
Convenience: ☯☯

Indications:

most commonly used for non-specific treatment of insomnia and agitation; also effective for irritability, anxiety, and aggression

Use

Trazodone is a novel antidepressant which is little used in general practice for its primary indication because it is simply too sedating: most people cannot tolerate a full, therapeutic dose, especially if one considers that it is also short acting and must be taken during the day to obtain a genuine antidepressant dose. However, these drawbacks are an advantage when sedation is required. Trazodone can provide safe but powerful sedation which lasts for about 8 hours, and carries no risk of abuse, dependence, or toxicity in overdose. Most of the trazodone currently prescribed in the US is used as a sleep aid for people taking SSRIs concurrently, and there is no reason why this should not be considered for Fragile X individuals. Whereas the most commonly used sedatives in adults, the benzodiazepines, are likely to cause confusion or behavioral disinhibition (loss of control) in Fragile X individuals, trazodone does not carry this risk. The most commonly used sedative in children, diphenhydramine (Benadryl), has potent anticholinergic properties which can impair memory; it can also lower the seizure threshold, and is not an especially good choice for use in Fragile X children. Although trazodone is not widely used in the general pediatric population, it is often used in developmentally disabled patients of all ages with some success, particularly as an alternative to antipsychotic medications for the management of aggression and agitation, and for treatment of insomnia. In this regard it is probably underutilized in treating Fragile X children with particularly severe agitation and aggression.
Trazodone shares its mechanism of action with nefazodone, blocking 5HT2 receptors while inhibiting re-uptake of serotonin (and, to a lesser extent, norepinephrine); side effects of sedation and orthostatic hypotension are thought due to interaction with histamine and alpha adrenergic receptors, respectively, making these far-from-clean drugs, but nonetheless free of anticholinergic side effects.

Pros and Cons

Pros

potent, rapid sedation without significant toxicity; an effective antidepressant in its own right; inexpensive (generic)

Cons

in practice, use is limited to low doses by sedation and orthostatic hypotension; no liquid or chewable available

Side effects

Common: residual daytime sedation: dosage reduction may be helpful; taking medication one hour before bedtime (rather than right at bedtime) may allow sedative effects to wear off sooner; some adaptation will usually occur after a few days
orthostatic hypotension (like that dizziness that comes from standing up too quickly): dosage reduction may help; smaller divided doses recommended if daytime use is prescribed

Uncommon:
priapism (persistent penile erection): discontinue medication immediately; seek prompt medical attention if symptoms do not subside quickly (rare, but serious side effect)
nausea: take with food
headache: any OTC remedy is fine

Usual dosage

children: 25 mg at bedtime (1/2 smallest tablet) for insomnia, may increase to 100 mg as tolerated; for treatment of aggression or agitation during the day, start with 25 mg three times a day, may increase as tolerated up to 50 mg three times a day in young children, 100 mg three times a day in older (larger) children and adolescents.

adults: start with 50 mg at bedtime for treatment of insomnia, will likely need to be increased to 100- 150 mg, can go as high as 300 mg dose for relief of insomnia (if this does not work, consider the possibility of mania causing insomnia); for treatment of aggression and/or agitation, start with 50 mg three times a day, can be increased up to 150-200 mg three times a day as tolerated.

Update

Trazodone is one of the safest and most widely prescribed drugs in general psychiatric practice, yet its use in fragile X is still relatively rare. One reason for this state of affairs is that pediatricians have essentially no experience with trazodone, so younger patients will rarely be treated with trazodone. Another reason is the common misunderstanding of the risk of priapism with this medication. Many years ago, the risk of priapism (persistent erection) was greatly overestimated, restricting the use of trazodone. Obviously, there is no risk for females, but even in males, this is an exceedingly rare side effect (this author has prescribed this medication to many hundreds of patients and never seen a single case of priapism, nor heard of one in any colleagues.)

Trazodone has several properties which make it especially useful for the treatment of fragile X: it enhances serotonin transmission (to treat anxiety, irritability, and aggression) while blocking 5HT2, a serotonin receptor which appears to be linked to hyperactive Gq signaling pathways in fragile X. Like mGluR5, 5HT2 is a neurotransmitter receptor which we would like to block in just about anyone with fragile X; 5HT2 antagonism is a major mechanism of action of all atypical antipsycotics. With trazodone, one can obtain some of the efficacy of Abilify or Risperdal without the risks or expense of an antipsychotic. Trazodone also potently antagonizes alpha 1 norepinephrine receptors. Along with mGluR5 and 5HT2, alpha 1 receptors are linked to Gq signaling pathways. Excessive and unregulated activity in these Gq pathways may be the major cause of brain dysfunction in fragile X. While excessive activity in 5HT2 pathways may be responsible for problems with mood and anxiety seen in fragile X, excessive activity of alpha 1 pathways may cause hyperarousal and sleep disturbance. Thus, the aplha 1 antagonism caused by trazodone may be especially helpful with the treatment of insomnia and hyperactivity/hyperarousal.

nefazodone (Serzone)

Effectiveness:☺☺☺
Safety: + + +
Cost: $$
Convenience: ☯☯

Indications: irritability, anxiety, aggression, obsessive-compulsive symptoms

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.

Pros and Cons

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

Side effects

Common: 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:
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

Usual dosage

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

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.

bupropion (Wellbutrin)

Effectiveness:☺☺
Safety: +
Cost: $$
Convenience: ☯

Indications: attention deficit, hyperactivity, irritability/depression in Fragile X girls

Use

Buproprion is a novel antidepressant with an unknown mechanism of action; it is thought to increase dopaminergic transmission, especially in frontal areas of the brain, and so has been promoted for the treatment of ADHD, as well as depression. More recent thinking proposes a primarily noradrenergic mechanism of action, similar to desipramine. It has not been established that this medication is significantly more effective than some other antidepressants in the treatment of ADHD, but this perception is becoming more widespread among psychiatrists. Recent head-to-head comparison with methylphenidate has shown the two drugs to be of equal efficacy in treating uncomplicated ADHD. It has been established that this medication is significantly less effective than most other available antidepressants in the treatment of anxiety disorders, so it should not generally be considered as a first choice for conditions involving significant anxiety symptoms. As noted above, it is generally well tolerated, but is associated with a much higher than average risk of seizures, making it an inappropriate choice for most Fragile X boys, who already have a very high rate of seizure disorders. In the treatment of Fragile X, bupropion is probably most useful for full-mutation girls with significant hyperactivity and symptoms of Major Depression. Bupropion must be taken in multiple doses because it is short-acting, and also to reduce the risk of seizures (which is proportional to peak levels in the bloodstream). A sustained release preparation (Wellbutrin SR) is now available, and is preferred by most doctors because it has fewer reported side effects and probably a lower risk of seizures.

Pros and Cons

Pros

generally few side effects, very mildly activating, non-sedating; may be an especially effective
treatment for adults with ADHD, although research on this subject is ongoing; generic available

Cons

while generally non-toxic, this medication is associated with a relatively high risk of seizures, so its use cannot be recommended in males with Fragile X, or anyone with a pre-existing seizure disorder; it must be given three times a day (twice a day with time release preparation); not effective in treatment of anxiety disorders—may actually aggravate anxiety

Side effects

Common:
nausea: take on a full stomach; usually transient
tremor: benign; can be treated with beta blocker or dosage reduction agitation/restlessness/insomnia: temporary dosage reduction may be helpful; take at meal times–not before bed time
headache: any OTC remedy is OK to use

Uncommon:
constipation: any OTC remedy is fine; usually transient
seizures: immediate discontinuation is necessary; risk can be reduced by taking Wellbutrin SR

Usual dosage

adolescents and adults: start with 75 mg twice a day, increasing as tolerated to 75 mg three times a day; maximum dose of 450 mg per day must be given in at least three or four divided doses and should never be exceeded

Update

Bupropion is still a widely prescribed antidepressant, though recently it has been used a bit less; this is understandable, given all the choices available in newer antidepressants. It has also become more widely appreciated that bupropion does not treat anxiety disorders, an issue which was greatly muddled by the drug manufacturer’s early marketing (which emphasized that anxiety associated with Major Depression could improve during the course of treatment with bupropion.) Indeed, it is now the general consensus that bupropion will worsen most anxiety, and all true Anxiety Disorders, in a dose-dependent fashion—much like the stimulants. Thus, the current niche for bupropion is as an activating antidepressant for people with depression, but without significant anxiety. It may be more helpful with attention than many other antidepressants, and can be used as a substitute for a stimulant, or in combination with other antidepressants (esp SSRIs.) Since most people with fragile X (male and female) have a major anxiety component to their clinical presentation, this medication should probably not be widely used in the treatment of typical fragile X. However, it may find a niche in females with fragile X, without seizures, whose presentation is primarily inattentive.

clomipramine (Anafranil)

Effectiveness:☺☺☺
Safety: +
Cost: $$$$
Convenience: ☯☯

Indications: attention deficit, hyperactivity, enuresis (bedwetting), anxiety, irritability, aggression, O- C behavior

Use

Clomipramine was the first agent available in the US with clinically significant effects on the serotonin system, and it remains one of the most effective treatments for Obsessive-Compulsive Disorder. Chemically, it is a tricyclic antidepressant (TCA), but it has a much broader spectrum of activity than other medications in this class. It also has a relatively high incidence of side effects, even compared to other TCAs. Of particular concern to Fragile X individuals is the possibility that clomipramine can lower the seizure threshold significantly; for this reason, it is recommended that all patients be given this medication in divided doses, and this is especially important in Fragile X. The anticholinergic side effects of this medication can cause confusion and memory loss, even in developmentally normal people, but those with developmental disorders like Fragile X may be at increased risk.
Fortunately, clomipramine has already been used a fair amount in neuropsychiatric (including developmentally disabled) populations, and generally appears to be surprisingly well tolerated. Now that less toxic alternatives are available (SSRIs, venlafaxine, nefazodone) this is not usually considered a first choice, but it is a rational treatment for many of the most problematic symptoms of Fragile X. Therapy must be started at a low dose and titrated upward for best effect; because this medication can cause cardiac conduction anomalies, a baseline EKG is often obtained, along with at least one more during treatment. Also, because blood levels of this medication can vary greatly from one individual to another, therapeutic drug monitoring (measuring blood levels) has become the standard of care–especially for children–and is highly recommended. If any problems arrise during treatment, serum level of the medication should be checked immediately.

Pros and Cons

Pros

effective for many symptoms of Fragile X, long acting, numerous trials reported in neuropsychiatric populations, indicated for children (over 10)

Cons

Toxic in overdose, many side effects, can increase risk of seizures, no chewable or liquid

Side effects

Common:
dry mouth: may be persistent; sugar-free gum or hard candy can help
sedation: usually transient, though sometimes persistent; smaller daytime doses will minimize this
nausea: start with divided doses, taken with food if possible; usually transient
orthostatic hypotension: less of a problem in children; temporary dosage reduction helpful constipation: any OTC remedy is fine; stool softeners and fiber laxatives usually help
blurry vision: temporary dosage reduction or shifting more of dose to bed time will help; usually transient

Uncommon:
mania/psychosis/extreme agitation: discontinue immediately seizures: discontinue immediately
palpitations/irregular heartbeat: probably benign, but call your physician; this type of medication normally causes a small increase in pulse rate, but should not cause arrhythmias
urinary retention: catheterization may be required; call your physician–can be treated with other medications such as bethanacol

Usual dosage

children: begin with 12.5 mg at night (1/2 capsule dissolved in juice), increasing daily dose by 12.5 mg every 3-4 days. During this initial phase the total daily dose should be divided into two or three separate doses; increase as tolerated to 50-100 mg. Can be increased further if there is no response after 4-6 weeks to 3 mg/kg/day or a maximum of 200 mg/day.

adults: start with 25 mg at night; increase in 25 mg increments at 3-4 day intervals to 50 mg three times a day; if no effect after 4-6 weeks, can be increased up to 250 mg/day; blood levels are recommended.

imipramine (Tofranil)

Effectiveness:☺☺
Safety: +
Cost: $
Convenience: ☯☯

Indications: attention deficit, hyperactivity, enuresis (bedwetting), anxiety, irritability

Use

Imipramine was the first tricyclic antidepressant available in the US, released in the late 1950’s, and it remains an effective treatment for depression and some anxiety disorders, as well as ADHD. Chemically, it is related to all other tricyclic antidepressants (TCAs), and it has a typical side effect profile for medications in this class. The anticholinergic side effects of this medication can cause confusion and memory loss, even in developmentally normal people, but those with developmental disorders like Fragile X may be at increased risk.
Fortunately, this medication has already been used a fair amount in neuropsychiatric (including developmentally disabled) populations, and generally appears to be well tolerated in young people. Now that less toxic alternatives are available (SSRIs and venlafaxine) this is not usually considered a first choice, but it is a rational treatment for many of the symptoms of Fragile X. Therapy must be started at a low dose and titrated upward for best effect; because this medication can cause cardiac conduction anomalies, a baseline EKG is often obtained, along with at least one more during treatment. Also, because blood levels of this medication can vary greatly from one individual to another, therapeutic drug monitoring (measuring blood levels) has become the standard of care–especially for children–and is highly recommended. If any problems arrise during treatment, serum level of the medication should be checked immediately.

Pros and Cons

Pros

Long acting, numerous trials reported in neuropsychiatric populations, indicated for children

Cons

toxic in overdose, many side effects, can increase risk of seizures

Side effects

Common:
dry mouth: may be persistent; sugar-free gum or hard candy can help
sedation: usually transient, though sometimes persistent; smaller daytime doses will minimize this; after initial titration, entire dose can be given at bed time
orthostatic hypotension: less of a problem in children; temporary dosage reduction helpful constipation: any OTC remedy is fine; stool softeners and fiber laxatives usually help
blurry vision: temporary dosage reduction or shifting more of dose to bed time will help; usually transient

ncommon:
mania/psychosis/extreme agitation: discontinue immediately seizures: discontinue immediately
palpitations/irregular heartbeat: probably benign, but call your physician; this type of medication normally causes a small increase in pulse rate, but should not cause arrhythmias
urinary retention: catheterization may be required; call your physician–can be treated with other medications such as bethanacol

Usual dosage

children: begin with 10 mg at night , increasing daily dose by 10 mg every 3-4 days. During this initial phase the total daily dose should be divided into two or three separate doses; increase as tolerated to 50-100 mg. Can be increased further (if there is no response after 4-6 weeks) to 3 mg/kg/day or a maximum of 150 mg/day.

adults: start with 25 mg at night; increase in 25 mg increments at 3-4 day intervals to 50 mg three times a day; if no effect after 4-6 weeks, can be increased up to 300 mg/day; blood levels are recommended.

Update

Both imipramine and clomipramine have faded from routine use in child psychiatry, primarily because of safety concerns. While neither drug is especially toxic when used properly, therapeutic drug monitoring (blood level measurement) is considered necessary in most cases, unless very low doses are being used. Some cardiotoxicity can be seen with either drug, especially at higher levels, and in overdose. The anticholinergic side effects, which have made these drugs unpopular in the general population, can actually be useful in treating some symptoms of fragile X. However, there are so many other choices available now that few pediatricians are willing to prescribe these drugs, and child psychiatrists will likely try many other things first.

desipramine (Norpramin)

Effectiveness:☺☺
Safety: +
Cost: $
Convenience: ☯☯

Indications: attention deficit, hyperactivity, enuresis (bedwetting), anxiety, irritability

Use

Desipramine is the active metabolite of imipramine, first tricyclic antidepressant, and it is an effective treatment for depression and some anxiety disorders, as well as ADHD. Chemically, it is related to all other tricyclic antidepressants (TCAs), and it has a typical side effect profile for medications in this class, though with somewhat less sedation than other TCAs. The anticholinergic side effects of this medication can cause confusion and memory loss, even in developmentally normal people, but those with developmental disorders like Fragile X may be at increased risk.

Fortunately, this medication has already been used a fair amount in neuropsychiatric (including developmentally disabled) populations, and generally appears to be well tolerated in young people. Now that less toxic alternatives are available (SSRIs and venlafaxine) this is not usually considered a first choice, but it is a rational treatment for many of the symptoms of Fragile X. Therapy must be started at a low dose and titrated upward for best effect; because this medication can cause cardiac conduction anomalies, a baseline EKG is often obtained, along with at least one more during treatment. Also, because blood levels of this medication can vary greatly from one individual to another, therapeutic drug monitoring (measuring blood levels) has become the standard of care–especially for children–and is highly recommended. If any problems arise during treatment, serum level of the medication should be checked immediately.

Pros and Cons

Pros

long acting, numerous trials reported in children

Cons

toxic in overdose, many side effects, can increase risk of seizures, may be somewhat more cardiotoxic than other drugs in this class

Side effects

Common:
dry mouth: may be persistent; sugar-free gum or hard candy can help
sedation: usually transient, though sometimes persistent; smaller daytime doses will minimize this; after initial titration, entire dose can be given at bed time
orthostatic hypotension: less of a problem in children; temporary dosage reduction helpful constipation: any OTC remedy is fine; stool softeners and fiber laxatives usually help
blurry vision: temporary dosage reduction or shifting more of dose to bed time will help; usually transient
insomnia: can disrupt sleep in some cases; if so, give during the day

Uncommon:
mania/psychosis/extreme agitation: discontinue immediately seizures: discontinue immediately
palpitations/irregular heartbeat: probably benign, but call your physician; this type of medication normally causes a small increase in pulse rate, but should not cause arrhythmias
urinary retention: catheterization may be required; call your physician–can be treated with other medications such as bethanacol

Usual dosage

children: begin with 10 mg at night , increasing daily dose by 10 mg every 3-4 days. During this initial phase the total daily dose should be divided into two or three separate doses; increase as tolerated to 50-100 mg. Can be increased further (if there is no response after 4-6 weeks) to 3 mg/kg/day or a maximum of 150 mg/day.

adults: start with 25 mg at night; increase in 25 mg increments at 3-4 day intervals to 50 mg three times a day; if no effect after 4-6 weeks, can be increased up to 300 mg/day; blood levels are recommended

Update

As is the case with imipramine and clomipramine, desipramine has faded from routine use in child psychiatry, primarily because of safety concerns. While it is not especially toxic when used properly, therapeutic drug monitoring (blood level measurement) is considered necessary in most cases, unless very low doses are being used. Some cardiotoxicity can be seen with desipramine, especially at higher levels, and in overdose—in fact, some studies suggest that it is the most cardiotoxic of all the tricyclics, and some doctors recommend routine EKGs in all patients treated with this drug. The anticholinergic side effects, which have made these drugs unpopular in the general population, can actually be useful in treating some symptoms of fragile X. However, there are so many other choices available now that few pediatricians are willing to prescribe these drugs, and child psychiatrists will likely try many other things first.

nortriptyline (Pamelor)

Effectiveness:☺☺
Safety: +
Cost: $
Convenience: ☯☯

Indications: attention deficit, hyperactivity, enuresis (bedwetting), anxiety, irritability

Use

Nortriptyline is the active metabolite of amitriptyline, one of the first tricyclic antidepressants; however, nortriptyline is significantly less toxic and has fewer side effects than its parent compound, and so has been used far more commonly over the past 10-15 years. It is an effective treatment for depression and some anxiety disorders, as well as ADHD. Chemically, it is related to all other tricyclic antidepressants (TCAs), and it has a typical side effect profile for medications in this class. The anticholinergic side effects of this medication can cause confusion and memory loss, even in developmentally normal people, but those with developmental disorders like Fragile X may be at increased risk.

Fortunately, this medication has already been used a fair amount in neuropsychiatric (including developmentally disabled) populations, and generally appears to be well tolerated in young people. Now that less toxic alternatives are available (SSRIs and venlafaxine) this is not usually considered a first choice, but it is a rational treatment for many of the symptoms of Fragile X. Therapy must be started at a low dose and titrated upward for best effect; because this medication can cause cardiac conduction anomalies, a baseline EKG is often obtained, along with at least one more during treatment. Also, because blood levels of this medication can vary greatly from one individual to another, therapeutic drug monitoring (measuring blood levels) has become the standard of care–especially for children–and is highly recommended. If any problems arrise during treatment, serum level of the medication should be checked immediately.

Pros and Cons

Pros

long acting, somewhat better tolerated than other TCAs

Cons

toxic in overdose, many side effects, can increase risk of seizures

Side effects

Common:
dry mouth: may be persistent; sugar-free gum or hard candy can help
sedation: usually transient, though sometimes persistent; smaller daytime doses will minimize this; after initial titration, entire dose can be given at bed time
orthostatic hypotension: less of a problem in children; temporary dosage reduction helpful constipation: any OTC remedy is fine; stool softeners and fiber laxatives usually help
blurry vision: temporary dosage reduction or shifting more of dose to bed time will help; usually transient
insomnia: can disrupt sleep in some cases; if so, give during the day

Uncommon:
mania/psychosis/extreme agitation: discontinue immediately
seizures: discontinue immediately
palpitations/irregular heartbeat: probably benign, but call your physician; this type of medication normally causes a small increase in pulse rate, but should not cause arrhythmias
urinary retention: catheterization may be required; call your physician–can be treated with other medications such as bethanacol

Usual dosage

children: begin with 10 mg at night , increasing daily dose by 10 mg every 4 days. During this initial phase the total daily dose should be divided into two or three separate doses; increase as tolerated to 50 mg. Can be increased further (if there is no response after 4-6 weeks) to a maximum of 100 mg/day.

adults: start with 25 mg at night; increase in 25 mg increments at 4 day intervals to 50 mg twice a day; if no effect after 4-6 weeks, can be increased up to 150 mg/day; blood levels are recommended, especially since nortriptyline seems to have a “therapeutic window”–too much or too little can be ineffective.

Update

As is the case with imipramine, desipramine, and clomipramine, nortriptyline has faded from routine use in child psychiatry, primarily because of safety concerns. While it is not especially toxic when used properly, therapeutic drug monitoring (blood level measurement) is considered necessary in most cases, unless very low doses are being used. Some cardiotoxicity can be seen with nortriptyline, especially at higher levels, and in overdose—although some studies suggest that it is the least cardiotoxic of all the tricyclics. The anticholinergic side effects, which have made these drugs unpopular in the general population, can actually be useful in treating some symptoms of fragile X. However, there are so many other choices available now that few pediatricians are willing to prescribe these drugs, and child psychiatrists will likely try many other things first.

buspirone (BuSpar)

Effectiveness:☺☺
Safety: + + + +
Cost: $$
Convenience: ☯☯

Indications: anxiety, aggression, obsessive-compulsive behavior, SIB

Use

Buspirone is a novel compound marketed for the treatment of generalized anxiety disorder in the general population; it has also been shown to be a weak antidepressant and antiobsessional agent; however, it has been demonstrated ineffective in treating Panic Disorder in the general population, and it should be presumed ineffective in treating panic anxiety in Fragile X individuals. In developmentally disabled populations, buspirone is most valuable as a treatment for aggression. In this regard it is often dramatically effective, sometimes completely eliminating otherwise intractable aggressive behavior within two or three days. However, this seems to be very much a hit or miss proposition: about half the time it has no discernable effect on the target behavior; the other half of the time it usually works quickly and at surprisingly low doses. In fact, low doses are often reported to work better. It is a common mistake among inexperienced clinicians to increase the dose of this medication too rapidly to heroic levels, when there is likely to be a “therapeutic window”, resulting in a better effect at low to moderate dosages.

Buspirone is technically a 5-HT1A agonist, which means that it stimulates a subclass of serotonin receptors in both presynaptic and postsynaptic sites. It is thought that the postsynaptic 5- HT1A agonism results in the antiaggressive effects by mimicking natural serotonin, but that agonism at the presynaptic receptor inhibits release of serotonin. It is likely that, in most cases, this push- me/pull-you effect results in the therapeutic window–that low doses cause primarily the postsynaptic serotonin agonism (and the therapeutic, antiaggressive effect), and that higher doses cause more and more presynaptic inhibition, cancelling out the therapeutic effect.

Buspirone has many advantages, especially its lack of significant toxicity and benign side effect profile. Unlike the antidepressants, it cannot provoke mania or cause significant activation; it is not toxic, even in massive overdose; and it does not interact significantly with most other medications. However, it does not work as often or for as many core symptoms of Fragile X as some other agents (SSRIs, for example); it does not usually help with irritability or mood instability; it only has weak antiobsessional effects, and is not likely to significantly curtail perseverative behaviors. It should be taken three times a day, and is available only as a poorly-soluble tablet, which is also quite expensive–so this is one of the least convenient medications to administer to a difficult child, and may not be feasible for some Fragile X children.

Pros & Cons

Pro

extraordinarily safe, non-sedating, very few side effects, often effective for aggression in only a few days

Cons

short-acting, so multiple daily doses are necessary (though recent experience indicates most people can take this medication twice a day; no chewable or liquid; not especially effective for panic anxiety

Side effects

Common:
dizziness/lightheadedness: usually transient and always benign; take with food to smoothe absorption
nausea: transient and benign; take with food; may be treated with Pepto-Bismol

Uncommon:
insomnia: take last dose 3-4 hours before bed time headache: any OTC remedy is fine; usually transient

Usual dosage

children: start with 2.5 mg twice a day (with breakfast and dinner) for at least one week; increase if needed to 2.5 mg three times a day with meals; can be increased to 10 mg three times a day, if needed, but this should rarely be necessary and is unlikely to be more effective

teens and adults: start with 5 mg twice a day (with breakfast and dinner) for at least a week; increase if needed to 5 mg three times a day with meals; can be increased in one to two week intervals to 60 mg per day; some patients have reportedly been treated safely and without adverse effects with more than 120 mg per day, but this should not ordinarily be necessary and is unlikely to offer greater efficacy (not to mention the fact that 120 mg of BuSpar costs about $8-10)

Update

Buspirone is enjoying a resurgence, after being dismissed for many years as a useless drug. In part, this may be related to concerns about treatment-emergent suicidal ideation in children treated with SSRIs (something which has not been reported with buspirone.) While buspirone is certainly not the most potent serotonin-enhancing drug, this may be an advantage in some situations. In particular, the relatively mild effect of buspirone (caution: easily confused with bupropion!!!) is much more easily tolerated. This means that children (or adults, for that matter) who experience excessive activation when treated with SSRIs can still get some of the same therapeutic effects from buspirone, but in an easy-to-tolerate package. There are many patients with developmental disorders who cannot tolerate any SSRI or other new antidepressant, but can tolerate buspirone. It should be noted that buspirone is now an inexpensive generic (though all generic drug prices have been increasing precipitously of late!), and longstanding clinical experience has shown that this medication can be dosed twice a day with little or no decrease in efficacy. Thus, two negatives in the original ratings for this drug have improved significantly. Buspirone is also used increasingly as an augmentation strategy for other medications; it is especially useful in enhancing the antiobsessional effects of SSRIs, and can be a useful addition when the maximum tolerated dose of the original drug is yielding only partial effects.

Sympatholytics

clonidine-oral formulation (Catapres)

Effectiveness:☺☺☺
Safety: + +
Cost: $
Convenience: ☯☯

Indications: hyperactivity, attention deficit, aggression, anxiety, insomnia

Use

Clonidine is one of the most frequently used treatments for the behavioral disturbances seen in Fragile X, and it has much to recommend it. It is technically classified as a centrally acting alpha-2 adrenergic agonist, meaning that it stimulates the alpha-2 subclass of adrenaline receptors in the brain. These receptors are located primarily in the locus ceruleus, the so-called “fight or flight” area which regulates autonomic nervous system arousal, and when activated cause feedback inhibition of this system. This is the same mechanism by which clonidine lowers blood pressure (the use for which it is marketed), but in Fragile X individuals this results in a general calming effect and a decreased sensitivity to hyperarousal or “overstimulation”. Toning down this fight or flight mechanism not only decreases the “sympathetic outflow” from the brain to the rest of the body, it has psychotropic effects as well. Since activation of the locus ceruleus is often thought responsible for the phenomenon of panic attacks, it is no surprise that inhibiting it can result in subjective relief of anxiety (although, oddly enough, clonidine is not an effective treatment for Panic Disorder in the general population).

The use of clonidine for behavioral treatment of Fragile X can be expected to result in a significant decrease in hyperactivity/hyperkinesis and hyperarousal. This should be considered the primary target symptom, and when effectively treated will usually result in improved attention and concentration. Aggression is often greatly decreased, especially if an individual displays this target symptom primarily as a result of overstimulation or hyperarousal. Anxiety, as noted above, can be specifically targeted for treatment with clonidine, but this usually responds best when a given individual is also significantly hyperaroused (as in the case of some Fragile X children who have extreme difficulty with eye contact, which provokes such intense social anxiety that it can interfere with school performance).

The major practical problem in using clonidine is the initial sedation most people experience; this peaks about one hour after an oral dose and can be accompanied by dizziness, confusion, irritability, and loss of coordination. Tolerance develops rapidly to these side effects, so the key is to start with very low doses and increase gradually. An elegant (and expensive) way around these side effects is to use the clonidine patch (Catapres TTS), which releases medication continuously for absorption through the skin, avoiding peak drug levels altogether, and greatly reducing side effects.

Clonidine can be combined with many of the other medications used to treat Fragile X. It counteracts most of the adverse physical and psychiatric effects of the stimulants, while adding to the therapeutic effect. Clonidine tends to treat hyperactivity and hyperarousal best, while the stimulants have the greatest direct effect in enhancing attention and concentration. It is not only the treatment of choice for motor and vocal tics which can sometimes develop on stimulants, it can counteract any increase in anxiety or aggression seen with the use of these medications. Clonidine is frequently used as a treatment for insomnia in hyperactive children, particularly when stimulants exacerbate this problem; a bed time dose of oral clonidine will usually result in pleasant, benign sedation without significant “hangover” at the right dose. However, insomnia itself is usually not a target symptom in its own right, but a sign of another problem like mania or extreme hyperarousal, or a side effect of medication.
Clonidine may be combined with antidepressants, especially the SSRIs, for good overall effect. These medications complement one another well, since antidepressants typically enhance attention and concentration but do not affect hyperarousal much at all (and in some cases may even cause excessive activation). And, while clonidine can tone down the physical symptoms of anxiety, the antidepressants have much greater effects on the irritability and panic that are so commonly seen in Fragile X. Interestingly, this combination of clonidine and an antidepressant is frequently used in the general population to treat Post Traumatic Stress Disorder, one of the major anxiety disorders, which involves a similar disturbance of mood and physiologic arousal.

Pros & Cons

Pros

sedative properties can help with insomnia when administered at night; safe for long-term administration; much experience in treatment of developmental disorders; very inexpensive as generic tablets

Cons

sedation can be excessive; need to start with small (subtherapeutic) doses and increase gradually; can cause confusion and irritability at peak levels; rebound and withdrawal syndromes do occur if medication is missed or discontinued abruptly

Side effects

Common:
sedation: temporary dosage reduction will usually help; take 2/3 of total daily dose at bed time; patch form of drug will minimize this side effect
dry mouth: usually transient and benign; sugar-free candy or gum helps
dizziness: temporary dosage reduction will help; blood pressure should be monitored, though this need not be done too frequently, since this medication cannot cause orthostatic hypotension

Uncommon:
urinary retention: discontinue and call your doctor
irritability/confusion: temporary dosage reduction, followed by more gradual increase, will help; smaller and more frequent doses will minimize this side effect

Usual dosage

children: start with 1/4 of a 0.1 mg tablet at bed time, increasing to 1/4 tab twice a day after 3-5 days; can be increased in 1/4 tablet increments at one week intervals as tolerated to achieve best effect, up to 0.3 mg per day

teens and adults: start with 1/2 of a 0.1 mg tablet twice a day, increasing to 0.1 mg twice a day after 3-5 days; increase in 1/2 tablet increments at one week intervals as tolerated to achieve best effect, up to 0.6 mg per day

clonidine patch (Catapres Transdermal Therapeutic System)

Effectiveness:☺☺☺
Safety: + +
Cost: $$$
Convenience: ☯☯☯☯

Indications: hyperactivity, attention deficit, aggression, anxiety, insomnia

Use

Catapres TTS is a skin patch designed to release clonidine into the bloodstream at a steady, controlled rate over 5-7 days. This is a generally superior way to administer clonidine, given the drug’s high incidence of peak level side effects, and it is especially convenient in treating Fragile X children, who may not be fully compliant with oral medications. Clonidine is one of the most frequently used treatments for the behavioral disturbances seen in Fragile X, and it has much to recommend it. It is technically classified as a centrally acting alpha-2 adrenergic agonist, meaning that it stimulates the alpha-2 subclass of adrenaline receptors in the brain. These receptors are located primarily in the locus ceruleus, the so-called “fight or flight” area which regulates autonomic nervous system arousal, and when activated cause feedback inhibition of this system. This is the same mechanism by which clonidine lowers blood pressure (the use for which it is marketed), but in Fragile X individuals this results in a general calming effect and a decreased sensitivity to hyperarousal or “overstimulation”. Toning down this fight or flight mechanism not only decreases the “sympathetic outflow” from the brain to the rest of the body, it has psychotropic effects as well. Since activation of the locus ceruleus is often thought responsible for the phenomenon of panic attacks, it is no surprise that inhibiting it can result in subjective relief of anxiety (although, oddly enough, clonidine is not an effective treatment for Panic Disorder in the general population).

The use of clonidine for behavioral treatment of Fragile X can be expected to result in a significant decrease in hyperactivity/hyperkinesis and hyperarousal. This should be considered the primary target symptom, and when effectively treated will usually result in improved attention and concentration. Aggression is often greatly decreased, especially if an individual displays this target symptom primarily as a result of overstimulation or hyperarousal. Anxiety, as noted above, can be specifically targeted for treatment with clonidine, but this usually responds best when a given individual is also significantly hyperaroused (as in the case of some Fragile X children who have extreme difficulty with eye contact, which provokes such intense social anxiety that it can interfere with school performance). The major practical problem in using clonidine is the initial sedation most people experience; this side effect is dramatically reduced by using the transdermal patch, although it can still occur. Once again, the key is to start with very low doses and increase gradually.

Clonidine can be combined with many of the other medications used to treat Fragile X. It counteracts most of the adverse physical and psychiatric effects of the stimulants, while adding to the therapeutic effect. Clonidine tends to treat hyperactivity and hyperarousal best, (while the stimulants have the greatest direct effect in enhancing attention and concentration). It is not only the treatment of choice for motor and vocal tics which can sometimes develop on stimulants, it can counteract any increase in anxiety or aggression seen with the use of these medications. Clonidine is frequently used as a treatment for insomnia in hyperactive children, particularly when stimulants exacerbate this problem. However, insomnia itself is usually not a target symptom in its own right, but a sign of another problem like mania or extreme hyperarousal, or a side effect of medication.
Clonidine may be combined with antidepressants, especially the SSRIs, for good overall effect. These medications complement one another well, since antidepressants typically enhance attention and concentration but do not affect hyperarousal much at all (and in some cases may even cause excessive activation). And, while clonidine can tone down the physical symptoms of anxiety, the antidepressants have much greater effects on the irritability and panic that are so commonly seen in Fragile X. Interestingly, this combination of clonidine and an antidepressant is frequently used in the general population to treat Post Traumatic Stress Disorder, one of the major anxiety disorders, which involves a similar disturbance of mood along with physiologic arousal.

Pros and Cons

Pros

safe for long-term administration; much experience in treatment of developmental disorders; very convenient to administer; perhaps more effective than oral form, since chances of rebound are reduced; peak level side effects greatly reduced

Cons

sedation can be excessive, even with the patch; need to start with small (subtherapeutic) doses and increase gradually; rebound and withdrawal syndromes can occur if patch is removed, lost or discontinued abruptly; some children will chew on patch, causing overdose; much more expensive than generic tablets

Side effects

Common:
sedation: temporary dosage reduction will usually help; patch form of drug will minimize this side effect; tolerance will develop to this side effect
dry mouth: usually transient and benign; sugar-free candy or gum helps
dizziness: temporary dosage reduction will help; blood pressure should be monitored, though this need not be done too frequently, since this medication cannot cause orthostatic hypotension
skin rash: happens in about 15-20% of all people treated and may require discontinuation; check with your doctor; some rashes are in reaction to adhesive overlay, not patch itself; a topical steroid spray can be used to counteract this side effect
Uncommon:
urinary retention: discontinue and call your doctor
irritability/confusion: temporary dosage reduction, followed by more gradual increase, will help

Usual dosage

children: start with 1/2 of a TTS-1 patch at bed time, increasing to one whole patch after5-7 days (TTS-1 delivers 0.1 mg of clonidine per day); can go up to TTS-3 if needed

teens and adults: start with a TTS-1 patch, increasing gradually and as tolerated to TTS-2 or 3; can go up to 0.6 mg per day (2 TTS-3’s at a time) or more in some cases

Special Notes on the Use of Catapres TTS Patches

1. When to change: even though these patches are designed to last for 7 days in the treatment of hypertension, they rarely seem to last that long for hyperactive children; expect to change patches every 3-5 days, depending on the individual; you will probably be able to tell when it is wearing out by the child’s behavior; new patches should be applied at night, since this changeover usually causes a bit of sedation.

2. Where to place: always place the patch between the shoulder blades of young children, so they cannot reach the patch to remove it; many children have pulled off the patch and chewed it, resulting in serious overdose (the patch actually contains 25 days’ dose of clonidine). Tegaderm (see below) is much harder to peel off, an can solve this problem as well. Always place new patches in a new spot to minimize allergic reactions and allow the skin to breathe.

3. How to keep it on: the patches come with adhesive overlays which can stick the patch back on if it has fallen off; this will work even if the patch washes off in the tub or a swimming pool–so don’t throw away a patch just because it falls off or gets wet (at $7 apiece, you’ll want to get the most out of each); if a child sweats excessively or spends a great deal of time swimming, try Tegaderm, an adhesive but breathable plastic film available at drugstores without a prescription.

4. Minimizing rebound: some children are so sensitive to sedation on medication and rebound off it that they get very sleepy when each new patch is applied, then very hyperactive as an old one is coming to the end of its useful life; patch administration smoothes out the blood levels of the medication considerably, but there are still fluctuations. One way to smoothe the level of the medication even more is to use two smaller patches in staggered fashion, so that there is always one newer patch and one older patch. For example, if a child requires about 0.2 mg of clonidine per day to achieve good control of hyperactivity, rather than using a TTS-2 patch and changing it every 3-5 days, one could use a TTS-1 patch (which has exactly half the clonidine of a TTS-2) for the first 4 days, then add a second patch on day 4, leaving the first one in place; on day 8, change the first patch for a new one, leaving the second patch in place. This staggered arrangement will give the smoothest possible level, but is a bit more elaborate, and requires that you write the date of placenment on each patch so you can tell which one needs changing.

5. Avoiding overdose: one patch actually contains 25 times the daily dose of clonidine in its “reservoir”; even after it has been on for a week, a TTS-1 patch has nearly 2 mg of active drug left in it–plenty to cause overdose if it is consumed. It is, therefore, important that no child is allowed to chew or swallow any patch, whether new or used. The patch is designed to adhere during a bath or shower, but will often come off in a swimming pool during prolonged water play. It is probably wise to remove the patch and save it in a dry, secure place if your child will be in the water for an extended time, so that no other child finds it floating in the water and is tempted to chew it. Also, check daily to be sure your child is still wearing his patch; if it is been chewed or swallowed, seek medical attention immediately (initial symptoms of overdose will most likely be sedation, confusion, and dizziness). Overdoses of clonidine can be serious, but will cause no permanent harm if attended to promptly.

guanfacine (Tenex)

Effectiveness:☺☺☺
Safety: + +
Cost: $$$
Convenience: ☯☯

Indications: hyperactivity, attention deficit, aggression, anxiety, insomnia

Use

Since clonidine is one of the most frequently used treatments for the behavioral disturbances seen in Fragile X, it was practically inevitable that guanfacine, a very closely related member of the same drug class, would eventually come into more widespread use as an alternative. It is technically classified as a centrally acting alpha-2 adrenergic agonist, meaning that it stimulates the alpha-2 subclass of adrenaline receptors in the brain. These receptors are located primarily in the locus ceruleus, the so-called “fight or flight” area which regulates autonomic nervous system arousal, and when activated cause feedback inhibition of this system. This is the same mechanism by which guanfacine lowers blood pressure (the use for which it is marketed), but in Fragile X individuals this results in a general calming effect and a decreased sensitivity to hyperarousal or “overstimulation”. Toning down this fight or flight mechanism not only decreases the “sympathetic outflow” from the brain to the rest of the body, it has psychotropic effects as well. Since activation of the locus ceruleus is often thought responsible for the phenomenon of panic attacks, it is no surprise that inhibiting it can result in subjective relief of anxiety (although, oddly enough, guanfacine is not an effective treatment for Panic Disorder in the general population).

The use of guanfacine for behavioral treatment of Fragile X can be expected to result in a significant decrease in hyperactivity/hyperkinesis and hyperarousal. This should be considered the primary target symptom, and when effectively treated will usually result in improved attention and concentration. Aggression is often greatly decreased, especially if an individual displays this target symptom primarily as a result of overstimulation or hyperarousal. Anxiety, as noted above, can be specifically targeted for treatment with guanfacine, but this usually responds best when a given individual is also significantly hyperaroused (as in the case of some Fragile X children who have extreme difficulty with eye contact, which provokes such intense social anxiety that it can interfere with school performance). The major practical problem in using guanfacine is the initial sedation most people experience, though this is somewhat less than with clonidine; this peaks about one hour after an oral dose and can be accompanied by dizziness, confusion, irritability, and loss of coordination. Tolerance develops rapidly to these side effects, so the key is to start with very low doses and increase gradually.

Guanfacine can be combined with many of the other medications used to treat Fragile X. It counteracts most of the adverse physical and psychiatric effects of the stimulants, while adding to the therapeutic effect. Guanfacine tends to treat hyperactivity and hyperarousal best, while the stimulants have the greatest direct effect in enhancing attention and concentration. It can counteract any increase in anxiety, aggression, or insomnia seen with the use of stimulants.

Guanfacine may be combined with antidepressants, especially the SSRIs, for good overall effect. These medications complement one another well, since antidepressants typically enhance attention and concentration but do not affect hyperarousal much at all (and in some cases may even cause excessive activation). And, while guanfacine can tone down the physical symptoms of anxiety, the antidepressants have much greater effects on the irritability and panic that are so commonly seen in Fragile X.

Pros & Cons

Pros

less sedating and slightly longer acting than oral clonidine

Cons

sedation can still be excessive; need to start with small (subtherapeutic) doses and increase gradually; can cause confusion and irritability at peak levels; rebound and withdrawal syndromes do occur if medication is missed or discontinued abruptly; expensive

Side effects

Common:
sedation: temporary dosage reduction will usually help; take 2/3 of total daily dose at bed time dry mouth: usually transient and benign; sugar-free candy or gum helps
dizziness: temporary dosage reduction will help; blood pressure should be monitored, though this need not be done too frequently, since this medication cannot cause orthostatic hypotension

Uncommon:
urinary retention: discontinue and call your doctor
irritability/confusion: temporary dosage reduction, followed by more gradual increase, will help; smaller and more frequent doses will minimize this side effect

Usual dosage

children: start with 1/4 of a 1 mg tablet at bed time, increasing to 1/4 tab twice a day after 3-5 days; can be increased in 1/4 tablet increments at one week intervals as tolerated to achieve best effect, up to 4 mg per day

teens and adults: start with 1/2 of a 1 mg tablet twice a day, increasing to 1 mg twice a day after 3-5 days; increase in 1/2 tablet increments at one week intervals as tolerated to achieve best effect, up to 6 mg per day

Update

Tenex has gone generic, which has removed industry support from clinical research with this drug; if you’ve followed the history of drug development, you know that this means most of the biggest proponents of Tenex (guanfacine) have lost interest in it entirely. Nevertheless, it’s still a useful alternative to clonidine, a little longer acting and less potent.

propranolol (Inderal)

Effectiveness:☺
Safety: + +
Cost: $
Convenience: ☯☯

Indications: hyperactivity, anxiety, aggression, self-injurious behavior

Use

propranolol is a useful medication in many ways; however, it is often prescribed for anxiety disorders, and its effectiveness in this regard is unclear. Propranolol is sometimes effective in the treatment of aggression and self-injurious behavior, though rarely as monotherapy (that is, without other drugs), and usually at very high doses. While it does have some sympatholytic properties, and can block peripheral effects of adrenaline, it is not an especially effective treatment of hyperactivity or hyperarousal, and is clearly inferior to clonidine and other alpha agonists in Fragile X children. With so many alternative agents available currently, it is unclear whether propranolol and other beta blockers have any front-line role in treatment of Fragile X behavioral problems. Propranolol finds its main psychiatric use nowadays as a treatment for many side effects of other medications; it is the treatment of choice for many types of tremor and restlessness caused by stimulants, lithium, SSRIs, and antipsychotics. In this use, beta blockers are given at low doses, have very few side effects, and are quite safe for children, even for long term administration. Use at high doses involves more risk and more side effects, and this is the type of treatment described below.

Pros & Cons

Pros

inexpensive, available in many pill sizes and formulations

Cons

less effective than other agents for treating anxiety; sometimes effective for aggression or SIB at very high doses

Side effects

Common:
fatigue/lethargy: temporary dosage reduction indicated
decreased exercise tolerance: avoid taking one hour before vigorous exercise; caused by artificial slowing of heart rate (bradycardia)
dizziness: fewer, smaller doses may work better; blood pressure should be monitored after dosage increases

Uncommon:
difficulty breathing: beta blockers can cause bronchospasm, a tightening of the lower airways; no one with asthma should take a beta blocker

Usual dosage

children: start with 10-20 mg three times a day; for treatment of aggression, dose will be increased steadily, in 20-60 mg increments, up to 200-300 mg per day, depending on body weight
teens and adults: start with 20-40 mg three times a day, increasing by 60 mg/day every 3-4 days for desired effect; doses of more than 600 mg per day have been reported, but are not recommended for Fragile X individuals

Similar medications

Can be considered equivalent:
nadolol (Corgard) pindolol (Visken) atenolol (Tenormin)

Mood stabilizers

lithium (Eskalith, Lithobid, Lithonate)

Effectiveness:☺☺☺☺
Safety: +
Cost: $
Convenience: ☯☯

Indications: mania, aggression, irritability

Use

lithium was the first mood stabilizer to enter widespread use, and it is considered the first-line treatment of choice for Bipolar Disorder (Manic-Depressive Illness). There is much clinical experience with lithium in many different patient populations, with well documented efficacy in many other conditions. Lithium is unique among the medications listed here, since it is not actually a drug, but a mineral which is mined rather than manufactured; its mood stabilizing properties were discovered quite accidentally, but have proven a godsend to millions of people around the world. The mechanism of action of lithium remains obscure, though it is thought to affect the serotonin system, but in a way which is distinct from all other known medications.

This is an appropriate treatment for children with mania, and is usually well tolerated; it has been used for many years as a major treatment for aggression; however, experience in treating children with developmental disorders has often been disappointing. Lithium seems to be less effective in stabilizing moods when changes are very frequent (so-called “rapid cycling”), and more effective in classic manic-depressive patiens with sustained highs followed by prolonged lows. Most Fragile X individuals fall into the former category, and are not usually thought of as good lithium candidates, although a discrete and sustained manic episode can certainly occur in a person with Fragile X. Lithium also does not seem to be as potent an anti-aggressive treatment as the newer antidepressants and some anticonvulsants, though some individuals experience dramatic relief from it. Lithium can be combined with many other medications to augment their effects: lithium augmentation of antidepressants is a commonly used and powerful treatment of depression and anxiety disorders; lithium can be combined with other mood stabilizers like carbamazepine and valproic acid for greater effect in hard-to-treat cases.

The greatest disadvantage of lithium is its low therapeutic index: blood levels only a little higher than therapeutic can be toxic. For this reason, careful monitoring is required, and the dose must be fine-tuned to achieve a blood level within the rather narrow therapeutic range. This frequent blood-drawing can be difficult for a tactilely-defensive Fragile X child; fortunately, once a therapeutic dose is found, levels can be checked much less frequently as long as the dose remains unchanged. There is little chance of any significant psychiatric side effects occuring with lithium treatment, though some patients do complain of feeling lethargic or apathetic. The most common, major medical side effect of lithium administration is hypothyroidism: lithium hinders the normal function of the thyroid gland at usual doses, and this can be serious enough to require thyroid hormone supplementaion. Thyroid functions are normally checked regularly along with lithium levels. Lithium has been reported to cause damage to the kidneys in rare instances, and so renal functions are also checked regularly, though this is very unlikely in younger patients.
Recent research suggests an interesting new Fragile X indication for lithium; lithium has been shown to inhibit the same intracellular signalling pathway which functions excessively in Fragile X. When lithium was given to drosophila (fruit flies) which had the fly version of the Fragile X gene knocked out, it completely rescued the cognitive deficits which these flies exhibit. Lithium is now being studied in the Fragile X knockout mouse, with very promising early results. This may lead to Fragile X clinical trials of lithium in the near future—stay tuned for results.

Drug interaction warning: NSAIDs (anti-inflammatory drugs like Motrin, Advil, ibuprofen, Naprosyn, Aleve, and others) should not be taken for prolonged periods while taking lithium; they can cause rapid increases in serum lithium levels. A single dose is no problem.

Pros and Cons

Pros

relatively few side effects, effective mood stabilizer without significant sedation, very inexpensive, liquid available

Cons

potentially toxic; careful monitoring required, including frequent blood levels

Side effects

Common:
nausea/diarrhea: take with food to minimize this; usually transient
tremor: usually mild and only at peak levels; entire dose can be taken at night to minimize this; can be treated with a beta blocker (i.e. propranolol)
frequent urination: since lithium is a salt, it is excreted entirely through the kidneys; as this occurs, water is pulled along, resulting in increased urine volume; be sure to drink plenty of fluids each day to avoid dehydration; if urination is extreme, call your doctor

Uncommon:
sedation: entire dose can be taken at beds time; if sedation or fatigue is extreme, thyroid functions should be checked ASAP
edema (swelling of soft tissues): small amount is probably benign;otherwise call your doctor clumsiness/incoordination: can be signs of neurotoxicity, lithium level may be too high

Usual dosage

In all cases medication should be started at a relatively low dose and titrated upward to achieve a therapeutic serum lithium level; lithium carbonate is available in 150 and 300 mg capsules and tablets, 450 mg controlled-release tablet; lithium citrate is a liquid version which can be mixed into juices (and is reasonably palatable

Update

The lithium story keeps getting better all the time. Lithium has now been shown in a number of animal models to rescue the basic synaptic defects in fragile X and to restore cognitive function. Most impressively, human clinical trials have shown similar benefits.The evidence to date indicates that lithium is likely to be as effective in treating the core deficits of fragile X as the long-awaited mGluR5 antagonists. It has been reasonably well tolerated in clinical trials, and it’s an inexpensive, widely available medication with a long track record. So why isn’t everyone with fragile X on lithium? There are several good reasons, and many more not-so-good reasons.

Most importantly, lithium has a general reputation as a fairly toxic medication; this is partially deserved. Lithium can be toxic if the levels are not maintained within a rather narrow range, though the kind of acute lithium toxicity that results from excessive levels is typically easy to spot and rapidly reversible—it does not usually cause any long term harm, just some unpleasant symptoms. Of course, the only way to stay within this narrow range is to actually measure lithium levels in blood samples. Obtaining these blood samples from individuals with fragile X can be quite an ordeal, and this represents another major obstacle to the acceptance of lithium therapy.
Lithium can also impair thyroid function, and even cause acute hypothyroidism requiring immediate medical attention. However, this is usually an insidious, slowly-developing problem which can be caught early by regular thyroid testing. For this reason, regular testing of thyroid function is a necessary part of medical monitoring for anyone taking lithium. The most sensitive indicator of thyroid function is measurement of Thyroid Stimulating Hormone (TSH) in the blood, but a TSH level can simply be added to regular lithium levels.

carbamazepine (Tegretol)

Effectiveness:☺☺☺
Safety: + +
Cost: $$
Convenience: ☯

Indications: mania, aggression, irritability, self-injurious behavior

Use

carbamazepine is one of the most commonly prescribed anticonvulsants in the U.S.; many Fragile X individuals take this medication for seizure disorders. It is also used quite extensively in psychiatry to treat mood disorders and aggression. Carbamazepine’s mood stabilizing properties were discovered serendipitously after it was marketed as an anticonvulsant, but it has subsequently been demonstrated effective in a number of psychiatric conditions, including Bipolar Disorder (Manic-Depressive Illness), Schizoaffective Disorder, drug withdrawal syndromes, some personality disorders, and many different forms of aggression in virtually all patient populations. Its precise mechanism of action is still unknown, but carbamazepine is thought to work by stabilizing the electical activity of the limbic system, a network of brain structures which appear to control emotions. Carbamazepine is not known to affect specific neurotransmitter systems, so its mechanism of action is distinctly different from most other psychotropic medications, such as SSRIs, and may offer some therapeutic advantages for difficult-to-treat cases. This drug has been used extensively in the treatment of behavioral problems in developmentally disabled populations, initially on the assumption that most of these folks had abnormal brain electrical activity (i.e. on EEG), and that the drug might somehow correct this abnormal activity. It is probably the most commonly used treatment of aggression in this setting, and can be very effective in some cases. However, it has since been shown in a number of different patient populations that an abnormal EEG does not predict mood stabilizing response to carbamazepine; people with normal EEG and no history of neurological problems can derive great benefit from this medication as a treatment for mood disorders.

The most important fact to keep in mind when carbamazepine is employed is that this medication can take a very long time to exert its optimal effect; some patients will improve and stabilize gradually for 6 months or more after reaching therepeutic levels of the drug. Another important consideration is the dose prescribed and the level maintained: the “therapeutic range” quoted by most labs is for the anticonvulsant effect of carbamazepine; using it as a mood stabilizer, a few patients will do well at lower levels, and many will experience no improvement at all until the upper limit of the range is exceeded. Also, this medication causes a phenomenon called autoinduction of liver enzymes: it induces its own metabolism, so people who have taken it for several months metabolize faster than those just starting to take it. This does not continue indefinitely, but it does mean that Tegretol levels will go down over the first few months if the dose remains the same. Initially, this makes frequent dosage adjustment necessary if a therapeutic level is to be maintained. This same increase in drug metabolism can cause concurrently administered medications also to be metabolized more quickly, and this should be considered by the prescribing physician.

When carbamazepine was first introduced, there were several cases of fatal agranulocytosis–a lethal suppression of white blood cell production. Following this catastrophe, rigorous guidelines for monitoring blood counts were issued, at one point recommending weekly testing. It has since been found that this is quite unnecessary, and that this adverse reaction is very rare (about 1 or 2 per 100,000); it can be spotted early with less frequent monitoring and virtually always reverses promptly with discontinuation of the drug, with no long term damage resulting. Nowadays, a complete blood count (CBC) is usually obtained whenever a Tegretol level is ordered, about every 2-4 weeks during the initial dose adjustment phase of treatment, then no more than quarterly.

Pros and Cons

Pros

approved for use in children, safe for long-term administration, avialable in chewable tablets
and suspension

Cons

difficult to dose properly (children develop more rapid metabolism of drug after 1-2 months), multiple daily doses necessary (2-3 times a day), therapeutic drug monitoring required (blood levels)

Side effects

Common:
sedation: usually transient; 2/3 of daily dose can be taken at night to minimise this
clumsiness/incoordination: usually transient (while dose is increasing); temporary dose reduction will help until adaptation occurs
rash: allergic skin rashes are relatively common with this medication; discontinuation may be necessary–consult your physician
Uncommon:
nausea: usually transient–take with food
dizziness: virtually always transient; smaller divided doses will help
excessive bruising: a sign of bone marrow suppression–stop immediately and call your doctor

Usual dosage

children: usually start with 100 mg twice a day, either as a chewable tablet or suspension; titrate up to therapetic range (4-12 micrograms per millilter) in 100 mg increments at 1-2 week intervals

adults: start with 100 mg three times a day, increasing in 100 mg increments at 1 week intervals to achieve therapeutic level; dose may be increased beyond this range if drug appears well tolerated and condition has not improved after 4-6 weeks of treatment

Update

Carbamazepine, now available in several generic formulations, is a good anticonvulsant that has been shown to possess mood-stabilizing and antidepressant qualities. It has proven occasionally helpful in psychiatric treatment of fragile X, though its psychotropic effects are relatively weak; fortunately, it causes little weight gain and little cognitive impairment. It has fallen from favor among psychiatrists, primarily because of the need for therapeutic drug monitoring (ie blood levels) and the availability of Trileptal, which is certainly easier and probably safer to use.

valproic acid/valproate (Depakene/Depakote)

Effectiveness:☺☺☺
Safety: + +
Cost: $$
Convenience: ☯

Indications: mania, aggression, irritability

Use

Like carbamazepine, valproic acid is one of the most commonly prescribed anticonvulsants in the US; many Fragile X individuals take this medication for seizure disorders, but it is also used quite extensively in psychiatry to treat mood disorders and aggression. Its mood stabilizing properties were discovered serendipitously after it was marketed as an anticonvulsant, but it has subsequently been demonstrated effective in some psychiatric conditions, including Bipolar Disorder (Manic- Depressive Illness), Schizoaffective Disorder, some personality disorders, and aggression in developmentally disabled patient populations. Its precise mechanism of action is still unknown, but valproic acid is thought to work by enhancing transmission of GABA (gamma-amino butyric acid), one of the primary inhibitory neurotransmitters in the brain. The psychiatric use of valproic acid is somewhat newer than that of carbamazepine, but otherwise these medications are used in much the same way. They are chemically unrelated, however, and have distinctly different side effects; this medication also has rare but potentially lethal medical complications: it can cause severe hepatotoxicity (liver damage) in about 1 in 50,000 patients, and so its use requires careful monitoring also. In general, valproic acid is more effective in treating or preventing mania than for treating or preventing depression, so it is probably not the best choice for a Fragile X individual who is primarily anxious or irritable without significant manic symptoms. While some clinicians consider this medication an effective anti-aggressive medication, there is neither as much clinical experience nor as much research backing for this indication as there is for carbamazepine or lithium.

Pros & Cons

approved for use in children, safe for long-term administration, avialable as “sprinkles”
capsules, which are easily mixed with soft foods

Cons

difficult to dose properly; multiple daily doses necessary (2-3 times a day), therapeutic drug monitoring required (blood levels); can cause dysphoria, fatigue, or lethargy

Side effects

Common:
nausea/vomiting: can be taken with food to minimize; usually transient
sedation: usually transient–if this becomes a problem, 2/3 of daily dose can be taken at night
fatigue/lethargy: distinct from sedation, since it is not dose-related; may require discontinuation, but temporary dose reduction may help
dysphoria: dosage reduction may help; could require discontinuation, since it defeats the purpose of using this medication as a mood stabilizer

Uncommon:
excessive bruising: can be an early indication of toxicity; consult your physician immediately edema (swelling): also can be an early sign of toxicity; consult your physician immediately
tremor: usually benign and transient
headache: usually benign and transient; given the possibility of hepatotoxicity with this medication and recent reports of liver damage associated with frequent use of acetaminophen (Tylenol), it is probably wise to use ibuprofen or aspirin for symptomatic treatment of headaches while taking this medication

Usual dosage

children: start with 125 mg twice a day (Depakote sprinkles mixed with applesauce or other favorite food); increase as tolerated to achieve therapeutic blood level (50-100 micrograms per milliliter)

adults: start with 250 mg twice a day; increase as tolerated to therapeutic level; some people will experience moderate mood stabilizing effects at levels significantly below the therapeutic range for anticonvulsant effects

Update

Psychiatrists’ love affair with Depakote is well into its second decade, and this medication is prescribed for a wide array of off-label uses. The active ingredient, valproic acid, has attracted the attention of basic scientists and clinical researchers in the fragile X field because of its known ability to alter histone acetylation and reactivate some genes. However, this effect is non- specific and the drug levels required are probably toxic; in vitro results have not been promising.

Nevertheless, the drug was tested in a small fragile X clinical trial, the results of which have been presented at fragile X meeting, but not yet published. The results from this trial showed a small behavioral benefit, as one might expect from the known psychotropic/mood stabilizing properties of valproate, but no evidence of gene reactivation in fragile X patients. No FMRP production was noted in response to valproate treatment, so it is unlikely that valproate can be viewed as a specific treatment for fragile X.



clonazepam (Klonopin)

Effectiveness:☺☺
Safety: + +
Cost: $$$
Convenience: ☯☯

Indications: anxiety, mania, obsessive-compulsive behavior

Use

Clonazepam is a benzodiazepine (chemically related to Valium) which is marketed as an anticonvulsant, but which is used primarily as an anxiolytic and sedative in the US. It is the most potent anti-panic agent currently available and is widely prescribed as a treatment for Panic Disorder. Clonazepam has also been shown effective in the treatment of other anxiety disorders, including OCD and social phobia; it can be quite effective (at very high doses) as a treatment for acute mania, leading some psychiatrists to speculate that this compound may have mood stabilizing properties not shared by other benzodiazepines–a point which is by no means well established. As an anticonvulsant, clonazepam raises the seizure threshold, making seizure activity less likely; however, all benzodiazepines (including this one) cause dose-related cognitive impairment, including decreased fine and gross motor coordination, decreased attention and concentration, and decreased memory. It is no surprise, then, that these medications can cause behavioral problems in developmentally disabled individuals, so-called “paradoxical excitement” or “behavioral disinhibition”. In other words, sedative medications of this type are unlikely to calm Fragile X children, and may have the opposite effect; for this reason, they are not generally recommended as first line treatments for anxiety in fully affected individuals, although clonazepam may have a role in treating higher- functioning Fragile X females with significant, discrete anxiety disorders. There are many other drugs in this class, and they are very widely prescribed (many believe overprescribed); this manual has limited space, and these drugs are mostly quite similar, so it is recommended that other benzodiazepines be considered essentially equivalent to clonazepam. Your doctor can explain any pertinent differences if another benzodiazepine is prescribed.

Pros and Cons

Pros

Cons

causes cognitive impairment, may cause behavioral disinhibition; no pediatric formulations available, expensive

Side effects

Common:
sedation: transient, but dosage reduction is advisable; tolerance develops over the course of 1-2 weeks (which is one reason this class of medications can cause problems when used as a sleep aid)
ataxia (poor balance and difficulty walking): similar to the effect of excessive alcohol; some tolerance develops, but dosage reduction is indicated
rebound anxiety: although clonazepam has a very long half-life in the body, if the medication is not taken regularly, rebound anxiety and even agitation are quite common; it is important to take the medication regularly; ordinarily, two or three missed doses in a row are necessary to provoke rebound

Uncommon:
weight gain: may necessitate discontinuation, since it is not always dose related
stupor: obviously, the result of excessive dose; proper dosage can be difficult to estimate in advance, since metabolism varies widely; hold all sedating medications until mental status returns to normal

Usual dosage

risperidone (Risperdal)

Effectiveness:☺☺☺
Safety: + + +
Cost: $$$$
Convenience: ☯☯☯

Indications: mania, aggression, SIB, irritability, psychosis

Use

risperidone is a newer antipsychotic medication which represents a major advance in the treatment of schizophrenia and other psychoses; however, its safety and efficacy in a wide range of psychiatric disorders is now being increasingly appreciated. For example, risperidone is being prescribed to large numbers of people with Alzheimer’s Disease to treat the agitation and delusional symptoms which are so often a part of that illness. Not only does risperidone appear to treat these symptoms, it often results in improved cognitive functioning as well. This was the first of the class of “atypical antipsychotics” which have largely replaced the older, conventional antipsychotics like Haldol, Thorazine, and Mellaril. Newer agents, like Risperdal, are much safer, having much less propensity to cause the horrific involuntary motor side effects that conventional antipsychotics all can cause. They also do more than the older medications: in schizophrenia, this means that social withdrawal and emotional blunting can respond to treatment. In Alzheimer’s Disease and other dementias, aggression and paranoia, which typically responded poorly to older medications, can be treated with fewer sided effects. In Fragile X and other developmental disorders, more severe forms of aggression, self-injurious behavior, mania, and other psychotic states can be treated effectively and with little risk. This is not to imply that risperidone is a miracle drug: it does not work for everyone, and the effect is not at all specific to Fragile X; nevertheless, it is a significant step forward, and other sophisticated new medications like it have since been marketed. In Fragile X, risperidone should probably be reserved for treatment of more severe behavioral disturbances which pose a significant threat to the afflicted individual or others. Treatment with this medication can be expected to result in significant mood stabilization, a decrease in aggression or SIB, and elimination of psychotic symptoms (if present–the author believes true psychosis to be relatively rare in Fragile X individuals). This effect takes about 1-2 weeks to emerge, but is not maximal for at least 6-8 weeks; once again, a bit of patience is required.

Compared to olanzapine, risperidone is generally considered to have greater intrinsic antidepressant effect; it may not be as useful as olanzapine in treating mania, and may have somewhat less mood- stabilizing effect. It is an ideal choice where an antipsychotic is required, yet a significant amount of dysphoria or irritability is also present.

Pros & Cons

Pros

very effective, easy to take (once-a-day,) relatively non-toxic, few side effects

Cons

extremely expensive, no pediatric formulations available (but liquid is available; instant- dissolving tablet now available)

Side effects

Common:
sedation: usually transient; all of medication can be taken at bed time, although the manufacturer recommends evenly divided morning and night doses; this side effect is much less prominent if dose is started low and titrated upward gradually
muscle stiffness (dystonia): dosage reduction is indicated; hold dose until side effect subsides
orthostatic hypotension (dizziness upon standing): taking at night will greatly reduce this problem; dosage reduction may also be helpful

Uncommon:
restlessness (akathisia): dosage reduction or bed-time aadministration can help; can be treated with propranolol if necessary
nausea: take with food; even a small snack can help

Usual dosage

children: start with the smallest dose, 0.25-0.5 mg at bed time; increase in 1-2 week intervals by 0.5 mg to optimal effect; with limited clinical experience in children, dose range is still unclear; young children usually don not need more than 2 mg/day
teens and adults: start with 0.5 mg twice a day; if needed, increase gradually at 1-2 week intervals up to 2 mg twice a day; doses higher than this are unlikely to be more effective, but will almost certainly have more side effects; entire dose can be given at bed time.

Update

Risperidone has been formally approved by the FDA for the treatment of irritability associated with autism, resulting in much greater use in the general treatment of developmental disorders. Risperidone is also now available as a generic drug, the first of the “atypicals” to go generic. The expiration of the patent has prompted the maker of Risperdal to reformulate and repackage the drug in several ways, seeking to protect its market share (thus Invega and Risperdal Consta) but there is no basic difference between generic risperidone and these new formulations. Since the use of all atypical antipsychotics is increasing in psychiatric treatment generally, and in the developmental disorders field particularly, this is a good point to remind everyone that these medications are not entirely benign, and a number of general “class risks” are always lurking in the shadows. These adverse effects are well known to psychiatrists, but other physicians who may prescribe these drugs may not be as familiar with the risks.
Here is the officially approved class warning for all atypical antipsychotics; many of these risks apply as well to the older, “typical” antipsychotics, and may even be a greater risk with the older drugs. Ordinarily, this statement is added to the drug info for each medication, with the specific brand name pasted in, but the warning is the same for all drugs in this class, though the relative risks of each adverse effect may differ somewhat.

Antipsychotics

IMPORTANT SAFETY INFORMATION FOR ALL ANTIPSYCHOTICS

Elderly Patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. ANTIPSYCHOTICS are not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS) is a rare and potentially fatal side effect reported with ALL ANTIPSYCHOTICS. Call your doctor immediately if the person being treated develops symptoms such as high fever; stiff muscles; shaking; confusion; sweating; changes in pulse, heart rate, or blood pressure; or muscle pain and weakness. Treatment should be stopped if the person being treated has NMS.

One risk of ANY ANTIPSYCHOTIC is that it may change your heart rhythm. This effect is potentially serious, and you should talk to your doctor about any current or past heart problems. Some medications interact with ANTIPSYCHOTICS. Please inform your healthcare professional of any medications or supplements that you are taking.

Tardive Dyskinesia (TD) is a serious, sometimes permanent side effect reported with ALL ANTIPSYCHOTICS. TD includes uncontrollable movements of the face, tongue, and other parts of the body. The risk of developing TD and the chance that it will become permanent is thought to increase with the length of therapy and the overall dose taken by the patient. This condition can develop after a brief period of therapy at low doses, although this is much less common. There is no known treatment for TD, but it may go away partially or completely if therapy is stopped.

High blood sugar and diabetes have been reported with ALL ATYPICAL ANTIPSYCHOTICS. If the person being treated has diabetes or risk factors such as being overweight or a family history of diabetes, blood sugar testing should be performed at the beginning and throughout treatment with ALL ATYPICAL ANTIPSYCHOTICS. Complications of diabetes can be serious and even life threatening. If signs of high blood sugar or diabetes develop, such as being thirsty all the time, going to the bathroom a lot, or feeling weak or hungry, contact your doctor.

ANTIPSYCHOTICS can raise the blood levels of a hormone known as prolactin, causing a condition known as hyperprolactinemia. Blood levels of prolactin remain elevated with continued use. Some side effects seen with these medications include the absence of a menstrual period; breasts producing milk; the development of breasts by males; and the inability to achieve an erection. The connection between prolactin levels and side effects is unknown.

ALL ANTIPSYCHOTICS should be used cautiously in people with a seizure disorder, who have had seizures in the past, or who have conditions that increase their risk for seizures.

Extrapyramidal Symptoms (EPS) are usually persistent movement disorders or muscle disturbances, such as restlessness, tremors, and muscle stiffness. If you observe any of these symptoms, talk to your healthcare professional.

ALL ANTIPSYCHOTICS may make you more sensitive to heat. You may have trouble cooling off, or be more likely to become dehydrated, so take care when exercising or when doing things that make you warm.

The most common side effects that occurred with ALL ANTIPSYCHOTICS were restlessness and extrapyramidal disorder (for example, involuntary movements, tremors and muscle stiffness).

olanzapine (Zyprexa)

Effectiveness:☺☺☺☺
Safety: + +
Cost: $$$$
Convenience: ☯☯☯

Indications: mania, aggression, SIB, irritability, psychosis

Use

Olanzapine is a relatively new antipsychotic medication which, like risperidone, represents a major advance in the treatment of schizophrenia and other psychoses; however, its safety and efficacy in a wide range of psychiatric disorders is now being increasingly appreciated. As with risperidone, it is being prescribed to large numbers of people with Alzheimer’s Disease to treat the agitation and delusional symptoms which are so often a part of that illness. Not only does olanzapine appear to treat these symptoms, it often results in improved cognitive functioning as well.

This new class of “atypical antipsychotics” is replacing the older, conventional antipsychotics like Haldol, Thorazine, and Mellaril. Newer agents, like Zyprexa, are much safer, having much less propensity to cause the horrific involuntary motor side effects that conventional antipsychotics all can cause. They also do more than the older medications: in schizophrenia, this means that social withdrawal and emotional blunting can respond to treatment.

In Alzheimer’s Disease and other dementias, aggression and paranoia, which typically responded poorly to older medications, can be treated with fewer sided effects. In Fragile X and other developmental disorders, more severe forms of aggression, self-injurious behavior, mania, and other psychotic states can be treated effectively and with little risk.

This is not to imply that olanzapine is a miracle drug: it does not work for everyone, and the effect is not at all specific to Fragile X; nevertheless, it is a significant step forward, and other sophisticated new medications like it are on the way. In Fragile X, olanzapine should probably be reserved for treatment of more severe behavioral disturbances which pose a significant threat to the afflicted individual or others. Treatment with this medication can be expected to result in significant mood stabilization, a decrease in aggression or SIB, and elimination of psychotic symptoms (if present–the author believes true psychosis to be relatively rare in Fragile X individuals). This effect takes about 1-2 weeks to emerge, but is not maximal for at least 6-8 weeks; once again, a bit of patience is required.

Compared to risperidone, olanzapine has somewhat less intrinsic antidepressant activity, but appears to be a good mood-stabilizer and anti-manic agent. It is a good choice when an anti-psychotic is required and a bipolar pattern of mood disorder is present. However, experience over the past few years has shown conclusively that olanzapine causes more weight gain than other medications in this class, and this effect is especially prominent in children. Drug-induced diabetes is not uncommon, and massive weight gain is a frequent reason for switching to an alternative atypical antipsychotic. Olanzapine clearly causes a marked increase in appetite, especially in children; this may be treatable by co-administration of H2-blockers such as Axid or Zantac, but this practice is not yet widespread.

Pros & Cons

Pros

very effective, easy to take, relatively non-toxic, few side effects

Cons

extremely expensive, no pediatric formulations available (rapid-dissolving tablet is available;) significant weight gain is common

Side effects

Common:
sedation: usually transient; all of medication can be taken at bed time; this side effect is much less prominent if dose is started low and titrated upward gradually
muscle stiffness (dystonia): dosage reduction is indicated; hold dose until side effect subsides
orthostatic hypotension (dizziness upon standing): taking at night will greatly reduce this problem; dosage reduction may also be helpful
weight gain: may require discontinuation/alternative drug; can be attenuated with H2-blockers such as Axid (nizatidine) or Zantac (ranitidine) et al.

Uncommon:
restlessness (akathisia): dosage reduction or bed-time aadministration can help; can be treated with propranolol if necessary
nausea: take with food; even a small snack can help

Usual dosage

children: start with the smallest dose, one half of a 2.5 mg tablet (1.25 mg) at bed time; increase in 1- 2 week intervals by 1.25 mg to optimal effect; with limited clinical experience in children, dose range is still unclear

teens and adults: start with 2.5 mg at night; if needed, increase gradually at 1-2 week intervals up to 15 mg a day; doses higher than this are unlikely to be more effective, but will almost certainly have more side effects.

Update

As noted above, olanzapine causes more weight gain than the other drugs in the atypical antipsychotic class. Indeed, more recent experience has shown that, especially in younger patients, olanzapine causes more weight gain than any other known medication. This effect appears to be inversely age dependent: younger patients gain more, older patients generally gain less, and elderly patients rarely gain any weight at all. This weight gain is often accompanied by “metabolic syndrome”, a catch-all term encompassing diabetes, hypertension, altered lipid profile, increased cholesterol, and other cardiac risk factors. Potentially most distressing of all, treatment with olanzapine and some other atypical antipsychotics can cause diabetes (in some cases) without obvious weight gain. For this reason, in younger people with fragile X, and especially in children under 12, it is strongly recommended to reserve olanzapine for use as a treatment of last resort—try the other drugs in this class first.

quetiapine (Seroquel)

Effectiveness:☺☺☺
Safety: + + +
Cost: $$$$
Convenience: ☯☯☯

Indications: mania, aggression, SIB, irritability, psychosis

Use

quetiapine is one of the newer “atypical” antipsychotic medications which represent a major advance in the treatment of schizophrenia and other psychoses; however, its safety and efficacy in a wide range of psychiatric disorders is now being increasingly appreciated. For example, quetiapine is being prescribed to large numbers of people with Alzheimer’s Disease to treat the agitation and delusional symptoms which are so often a part of that illness. Not only does quetiapine appear to treat these symptoms, it often results in improved cognitive functioning as well.

This is part of a new class of “atypical antipsychotics” which is replacing the older, conventional antipsychotics like Haldol, Thorazine, and Mellaril. Newer agents, like quetiapine, are much safer, having much less propensity to cause the horrific involuntary motor side effects that conventional antipsychotics all can cause. They also do more than the older medications: in schizophrenia, this means that social withdrawal and emotional blunting can respond to treatment.

In Alzheimer’s Disease and other dementias, aggression and paranoia, which typically responded poorly to older medications, can be treated with few side effects. In Fragile X and other developmental disorders, more severe forms of aggression, self-injurious behavior, mania, and other psychotic states can be treated effectively and with little risk.

This is not to imply that quetiapine is a miracle drug: it does not work for everyone, and the effect is not at all specific to Fragile X; nevertheless, it is a significant step forward, and other sophisticated new medications like it are on the way. In Fragile X, quetiapine should probably be reserved for treatment of more severe behavioral disturbances which pose a significant threat to the afflicted individual or others. Treatment with this medication can be expected to result in significant mood stabilization, a decrease in aggression or SIB, and elimination of psychotic symptoms (if present–the author believes true psychosis to be relatively rare in Fragile X individuals). This effect takes about 1-2 weeks to emerge, but is not maximal for at least 6-8 weeks; once again, a bit of patience is required.

Compared to risperidone, and especially olanzapine, quetiapine causes less weight gain, and is highly unlikely to cause muscle stiffness; it may cause somewhat more sedation during initiation.

Pros and Cons

Pros

very effective, easy to take, relatively non-toxic, few side effects

Cons

extremely expensive, no pediatric formulations available, multiple daily doses required

Side effects

Common:
sedation: usually transient; most of medication can be taken at bed time, although the manufacturer recommends evenly divided morning and night doses; this side effect is much less prominent if dose is started low and titrated upward gradually
muscle stiffness (dystonia): dosage reduction is indicated; hold dose until side effect subsides
orthostatic hypotension (dizziness upon standing): taking at night will greatly reduce this problem; dosage reduction may also be helpful

Uncommon:
restlessness (akathisia): dosage reduction or bed-time aadministration can help; can be treated with propranolol if necessary
nausea: take with food; even a small snack can help

Usual dosage

children: start with the smallest dose, 25 mg at bed time; increase in 1-2 week intervals by 25 mg to optimal effect; typical dose is 100-300 mg per day in divided doses

teens and adults: start with 25 mg twice a day; increase gradually at 1-2 week intervals up to 300 mg twice a day; doses higher than this are unlikely to be more effective, but will almost certainly have more side effects

Update

Quetiapine is actually the most frequently prescribed antipsychotic medication in the US, as of this writing. However, about half of all Seroquel prescriptions are written as an adjunctive sleep aid. In effect, Seroquel has found a niche as a rather expensive sleeping pill. This use cannot be recommended as a general practice, since this exposes the user to the serious adverse effects of antipsychotics, such as TD and NMS (see update in Risperdal review), even though the dose of the drug is subtherapeutic and it is not acting as an antipsychotic.

Seroquel is probably the most sedating of the newer antipsychotics; this is often a problem, preventing adequate dosing (especially since it must be given 2 or 3 times per day.) In some cases, this can be an advantage—especially if a fragile X individual is quite hyperactive and/or hyperaroused. Seroquel is a potent antagonist at alpha 1 and histamine receptors, which probably explains its sedative effects. Some recent studies suggest that quetiapine is not as effective as most other available antipsychotics in the treatment of schizophrenia, even when the full, recommended doses are used (and in real life, it is difficult to use the full dose, because of sedation.) Whether this applies to the treatment of fragile X and other autism spectrum disorders is unknown, but it is clearly most useful for the patient who requires some degree of sedation.

aripiprazole (Abilifiy)

Effectiveness:☺☺☺☺
Safety: + + +
Cost: $$$$
Convenience: ☯☯☯

Indications: mania, aggression, SIB, irritability, psychosis

Use

Aripiprazole is the newestof the “atypical” antipsychotic medications, which represent a major advance in the treatment of schizophrenia, Bipolar Disorder, and other psychoses; however, its safety and efficacy in a wide range of psychiatric disorders is now being increasingly appreciated. For example, aripiprazole is being prescribed to people with Alzheimer’s Disease to treat the agitation and delusional symptoms which are so often a part of that illness. Not only does aripiprazole appear to treat these symptoms, it often results in improved cognitive functioning as well. This is part of a new class of “atypical antipsychotics” which has replaced the older, conventional antipsychotics like Haldol, Thorazine, and Mellaril. Newer agents, like aripiprazole, are much safer, having much less propensity to cause the horrific involuntary motor side effects that conventional antipsychotics all can cause. They also do more than the older medications: in schizophrenia, this means that social withdrawal and emotional blunting can respond to treatment. In Alzheimer’s Disease and other dementias, aggression and paranoia, which typically responded poorly to older medications, can be treated with few sided effects. In Fragile X and other developmental disorders, more severe forms of aggression, self-injurious behavior, mania, and other psychotic states can be treated effectively and with little risk. This is not to imply that aripiprazole is a miracle drug: it does not work for everyone, and the effect is not at all specific to Fragile X; nevertheless, it is a significant step forward, and may be the most effective single agent currently available. In Fragile X, aripiprazole should probably be reserved for treatment of more severe behavioral disturbances which pose a significant threat to the afflicted individual or others. Treatment with this medication can be expected to result in significant mood stabilization, a decrease in aggression or SIB, and elimination of psychotic symptoms (if present–the author believes true psychosis to be relatively rare in Fragile X individuals). This effect takes about 1-2 weeks to emerge, but is not maximal for at least 6-8 weeks; once again, a bit of patience is required.
Compared to risperidone, and especially olanzapine, aripiprazole causes less weight gain (may even cause weight loss), and is highly unlikely to cause muscle stiffness; it has a very long half-life, so levels of the drug accumulate in the system for about 2 weeks—and take a similar time to flush out upon discontinuation. This means that when switching from other atypical antipsychotics to Abilify, some gap in efficacy may be seen while aripiprazole levels build up; this can be avoided by starting a small dose of Abilify before entirely discontinuing the previous medication (a so-called “cross-over”.)
Arpiprazole is unique among the antipsychotics in that it does not block dopamine receptors—it is a “partial agonist” at the D2 receptor; this means that in areas of the brain where dopamine levels are low (thought to be a mechanism of attention deficit), it enhances transmission. In areas of excessive dopamine transmission (long thought to be the basis of psychosis) it will decrease dopamine transmission. This modulatory effect can simulataneously treat agitation and psychosis, while also helping with attention and cognitive performance. Given that many individuals with Fragile X and other developmental disorders are treated with both antipsychotics and stimulant medications (Ritalin and Risperdal are common prescribed together, though this is not recommended because of inherent antagonism), Abilify would seem to be an ideal treatment for this population. Clinical experience with Abilify in Fragile X has been excellent, with efficacy clearly superior to other available antipsychotics and mood stabilizers; side effects have generally been milder than other agents as well. With little risk of weight gain, lower incidence of movement disorders, and little sedation, this medication may be the treatment of choice for serious behavioral and psychiatric problems in Fragile X.

Pros & Cons

Pros

very effective, easy to take, relatively non-toxic, few side effects

Cons

extremely expensive, no pediatric formulations available

Side effects

Common:
sedation: usually transient; medication should be taken at bed time to minimize side effects; this side effect is much less prominent if dose is started low and titrated upward gradually
orthostatic hypotension (dizziness upon standing): taking at night will greatly reduce this problem; dosage reduction may also be helpful

Uncommon:
restlessness (akathisia): dosage reduction or bed-time aadministration can help; can be treated with propranolol if necessary
muscle stiffness (dystonia): dosage reduction is indicated; hold dose until side effect subsides nausea: take with food; even a small snack can help

Usual dosage

children: start with the smallest dose, 2.5 mg at bed time; increase in 1-2 week intervals by 2.5 mg to optimal effect; typical dose is 5-10 mg per day

teens and adults: start with 5 mg at bed time; increase gradually at 1-2 week intervals up to 20 mg per day; doses higher than this are unlikely to be more effective, but will almost certainly have more side effects

Update

At this point, Abilify must be considered the first choice of the atypical antipsychotics for the treatment of developmental disorders, and for virtually any condition requiring an antipsychotic in pediatric patients. It has a huge side effects advantage, in that it rarely causes weight gain in children; it is also more effective in most cases of fragile X, since it enhances mood and attention more than other drugs in its class, by virtue of its unique effects on dopamine transmission. The only drawback is the some kids find it a bit activating, so if sedation is absolutely required, Seroquel or Risperdal might be better choices.

thioridazine (Mellaril)

Effectiveness:☺☺
Safety: +
Cost: $
Convenience: ☯☯

Indications: mania, aggression, psychosis

Use

thioridazine is an antipsychotic medication of the “conventional” type which has been available for many years, and is quite similar in most ways to the many other agents available (under trade names such as Thorazine, Haldol, Loxitane, Serentil, Navane, Prolixin, Trilafon, Stelazine, and others). While these medications differ somewhat in their side effect profiles, they all do basically the same thing: block dopamine receptors. This is the basis of their antipsychotic effect; they are also commonly referred to as neuroleptics or major tranquilizers. The greatest problem with these medications as a class is that they block dopamine receptors indiscriminately throughout the brain; since dopamine is an important neurotransmitter with many different functions, this can cause a wide array of serious side effects. This is the type of medication most people are thinking of when they worry that psychotropic medication will make them “feel like a zombie”. For no good reason, thioridazine is the drug in this class most often chosen by child psychiatrists and pediatric neurologists, and so it is reviewed here as the prototype of the class.

The following comments, however, apply to neuroleptics in general. These medications can provide rapid relief of mania or severe aggression, and they are the standard treatment for psychotic symptoms such as hallucinations and delusions. As previously noted, this author considers true psychosis to be relatively rare in the course of Fragile X; indeed, aggressive behavior is far and away the most common reason for these medications to be prescribed in the developmentally disabled population, including Fragile X. There are now many alternative treatments for aggression, and these should be considered before resorting to an antipsychotic, given the serious adverse effects associated with medications like thioridazine.

The most terrifying adverse effect of neuroleptic treatment is the development of tardive dyskinesia. This is an irreversible movement disorder consisting of involuntary, rhythmic movement of various muscle groups (usually starting in the mouth and face, then progressing to the arms, legs, or trunk) which persist long after the medication is discontinued. There is no effective treatment for this condition. It seems to correlate with cumulative exposure to antipsychotic medications; in other words, it is most likely when an individual has been treated with high doses for many years. Unfortunately, this happens quite often to people with developmental disabilities, since they often are started on these medications early in life, then continued indefinitely. Since these medications are not particularly effective as specific treatments for symptoms of Fragile X, autism, or any other developmental disorder, high doses are often required to eliminate target symptoms like aggression. Thus, today we see hundreds of thousands of older individuals with developmental disorders with permanent tardive dyskinesia–and there has been a dramatic backlash within the psychiatric profession against the indicriminate use of these medications. The government has also issued numerous guidelines and regulations prohibiting the institutional use of neuroleptics in non-psychotic individuals unless they pose an immediate danger to themselves or others. However, most Fragile X individuals are not institutionalized, and are not covered by these regulations. Many physicians still see these medications as an appropriate first-line treatment for all sorts of behavioral disturbances accompanying developmental disorders; they are not, and parents should be suspicious of any physician recommending this type of drug for an initial trial in a Fragile X patient.

Tardive dyskinesia may sound awful enough, but these medications cause other serious movement disorders which are, fortunately, usually reversible. Dystonia is an involutary contraction of a muscle group which can be quite disabling, but is also readily treated with adjunctive medications. It is usually thought that muscular young men are most susceptible to this side effect. Akathisia is a form of motor restlessness which is drug induced, but sometimes difficult to distinguish from hyperactivity or anxiety. It can sometimes be treated with adjunctive medications, but is often a more refractory side effect than dystonia, and usually requires dose reduction. Parkinsonian tremor is a common but usually subtle side effect which is amenable to treatment and not often disabling.

More subtle side effects of antipsychotic drugs include anergia (general sluggishness), impaired concentration and memory, and gradual, long-term weight gain.

It is important to know that antipsychotic medications should not be prescribed in combination with stimulants, because these medications tend to cancel each other out–making treatment pointless. In the section on psychostimulants, the mechanism of action was described as primarily enhancement of dopamine transmission in the frontal lobes (plus some indiscriminate increase in dopamine transmission in other areas which can cause or aggravate psychosis). Antipsychotics, on the other hand, block dopamine transmission throughout the brain, perhaps explaining why they decrease attention and concentration, and clinically appear to prevent stimulants from having any net effect. Nevertheless, children with difficult behavioral problems are prescribed this illogical combination with alarming frequency.

The following recommendations are offered for anyone prescribed this type of medication:

1. get a second opinion, preferably from a qualified psychopharmacologist
2. consider a trial of risperidone or olanzapine—newer, safer, and more effective medications
3. be sure that you are well informed of the significant risks involved in this type of treatment
4. always try to use the minimum effective dose
5. always try to use these medications for a limited time, attempting discontinuation after 3-6 months

Pros & Cons

Pros

inexpensive, rapid tranquilizing effect, suspension available

Cons

highly sedating; powerful anticholinergic side effects can cause confusion and memory loss; can cause a number of movement disorders, including some that are irreversible

Side effects

Common:
sedation: entire dose can be taken at bed time
dry mouth: sugarless gum or hard candy will help
constipation: stool softeners are preferred treatment
blurry vision: bed time administration will minimise this

Uncommon:
dystonia: Cogentin (benztropine) or Benadryl (diphenhydramine) are often used to alleviate this involuntary muscle contraction
akathisia: propranolol is the treatment of choice
seizure: all medications of this class significantly lower the seizure threshold; if seizures occur, discontinue the medication immediately

Many other side effects (too numerous to list here) are possible with these medications; if in doubt, stop the medication; abrupt discontinuation of antipsychotic medication is not hazardous.

dosage

varies too widely for even basic guidelines; best discussed with a qualified physician

Update

No one uses this drug any more, and that is appropriate. Not recommended for any reason.

naltrexone (ReVia, Trexan)

Effectiveness:☺☺
Safety: + +
Cost: $$$$
Convenience: ☯☯☯

Indications: SIB (self-injurious behaviour)

Use

naltrexone is an opiate antagonist; that is, it blocks the effect of exogenously administered opiate drugs, such as morphine and heroine. It was originally marketed under the trade name Trexan to do just that: block the effect of street drugs so that addicts would be able to remain abstinent longer. More recently, it has been shown effective in preventing relapse of alcoholics, presumably by blocking the effects of endogenous opioids (naturally occuring substances thought to block pain signals, mediate reinforcement, satiety, and some pleasurable sensations). Subsequently, it was remarketed under the new name ReVia, at a higher price but otherwise unchanged.

It has long been thought that some individuals, regardless of diagnosis, who engage in self- injurious behavior manage to provoke release of these endogenous opioids (endorphins and enkephalins are the best known of this group), resulting in sensations which might be soothing, anxiolytic, euphoric, or otherwise pleasurable. In essentially all cases of SIB of this type, the individual (if verbal) describes analgesia during the self-injury, i.e. there is no sensation of pain. Dramatic self-mutilation is often seen in patients with severe personality disorders or dissociative disorders (like multiple personality disorder); this is relatively rare in Fragile X individuals, unless they have been subjected to deprived institutional settings. When these self-mutilators are given naltrexone, the injury once again hurts, rather than provoking this paradoxical “rush”, or pleasurable sensation; the behavior usually subsides rapidly thereafter.

While some cases of SIB in Fragile X may fit this pattern, this is by no means the rule. In many cases, Fragile X children injure themselves during periods of great anxiety or overstimulation, and the actual injury is quite minimal. Handbiting is the classic example of this type of SIB, and is not likely to respond to naltrexone treatment. Compare this to institutionalized children who might bang their heads against a concrete wall for hours if not restrained, sometimes causing massive tissue damage. This is the type of SIB which does often respond to naltrexone treatment. The critical distinction for predicting drug response seems to be the presence of this profound analgesia, which can be effectively eliminated by the naltrexone. This may be why the literature shows such conflicting results in trials of naltrexone: some studies achieve dramatic results while some actually see a worsening of certain forms of SIB.

Naltrexone has no true psychoactive properties under most circumstances; it simply prevents an undesirable behavior. Nor does it have any notable side effects for the vast majority of people who take it. However, in rare cases naltrexone (at high doses) has caused signs of mild liver toxicity, so some physicians like to monitor liver function to catch any possible problem early. The major disadvantage is the outrageous cost of the drug: more than $5 per tablet, despite the fact that this drug has been on the market for many years.

Pros & Cons

Pros

few side effects, can result in rapid decrease in SIB–in some cases; once a day or every-other-
day dosing

Cons

extremely expensive; no pediatric formulation; rare cases of toxicity

Side effects

Common:
nausea: take with food

Uncommon:
blockade of opioid analgesia: occasionally an individual who has been taking regular doses of a narcotic (Percocet for headaches, for example) will experience opioid withdrawal precipitated by initiation of naltrexone; this is uncomfortable but rarely dangerous

Usual dosage

children and adults are usually begun at 25-50 mg by mouth once a day (any time);
some individuals will obtain a better response at 100 mg/day, but higher doses are not usually recommended

Update

Naltrexone never quite lived up to its initial promise, and has largely faded from use. It has never been demonstrated that naltrexone can have any beneficial effect on the core symptoms of any autism spectrum disorder, as was initially hoped. However, this medication could still be useful in rare cases of fragile X or autism where self-injurious behavior is especially severe.

Leave a Reply

Your email address will not be published.