Recent dramatic advances in the field of psychopharmacology have made possible treatments which were inconceivable ten years ago. Many conditions previously viewed as intractable are now almost trivially simple to treat. Along with these advances in treatment have come much better understanding of the basic neuronal processes involved in psychiatric disorders, and the prospect of far more advanced therapies to come.

Fragile X syndrome is by far the leading cause of inherited mental retardation around the world; it is, arguably, the most common serious genetic disease in humans; it is also a complex and highly variable neuropsychiatric disorder. Many individuals with Fragile X, especially females, exhibit less overt developmental delay, but still suffer from subtler dysfunction of attention or socialization which may be every bit as treatable as more severe behavioral disturbances. Much of the attention given to the psychopharmacology of Fragile X is devoted to treatment of more severely affected individuals; it should not be inferred that these individuals are the only ones “bad enough” to need medications or to respond to them: all medical treatments are more successful in treating the mild-to-moderately ill patient who can best tolerate the treatment and heal on his own in conjunction with it.

This manual is intended as an aid for parents seeking or considering drug treatment of the behavioral and psychiatric sequellae of Fragile X syndrome. It is designed to enhance parents’ ability to make informed decisions about their children’s medical treatment. It is not meant to be a “how-to” book of psychopharmacology, nor can it ever take the place of a qualified physician. In a perfect world this manual would not be necessary: All physicians would have a good working knowledge of Fragile X, every child would be thoroughly evaluated and closely followed for psychiatric as well as physical problems, and the time would be invested in educating patients and families about their treatment. However, in the real world things just don’t always work out this way. So, the following discussion is meant to acquaint the non-medical caretaker with the facts relevant to the psychopharmacology of Fragile X syndrome.

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.



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.

Things to Consider

Who Should Be Treated?

Of course, this is a matter of clinical judgement in any individual case. However, since parents so often ask this question, it is worth considering a few general guidelines.

The presence of symptoms which are likely to respond to currently available medications is usually considered a prerequisite. The severity of these symptoms is not as important a factor as one might otherwise assume: many of the symptoms which respond to psychopharmacologic treatment do so whether mild, moderate, or severe. In practice, however, most people think of medications as a "last resort" and consider their use only when other interventions (i.e. behavioral or educational) fail. Thus, most often we see more serious symptoms when evaluating for medication treatment, even though these treatments will work at least as well for mild or moderate symptoms.

When there is a specific treatment for Fragile X syndrome itself, one that actually helps to compensate for the underlying biochemical defects, we might recommend that all children receive that treatment, much the way all juvenile diabetics are prescribed insulin. Since no such specific treatment for Fragile X exists, however, we must treat the parts of the whole that we can treat, more like treating the pulmonary infections of cystic fibrosis with antibiotics--a life-saving treatment, but one that does not affect the underlying disease process at all. We (psychopharmacologists) refer to these treatable symptoms as "target symptoms", and some familiarity with this concept is essential for parents who want to be fully informed about their child's treatment. A large part of this manual is therefore devoted to discussion of just what we are attempting to treat when medicating a Fragile X patient.

Age is certainly an important factor in the clinical decision to prescribe. Most physicians feel terribly uncomfortable medicating preschool children, and it is quite rare that any child under 3 is ever prescribed psychotropic medication, even with a precise molecular diagnosis like Fragile X in hand. In part, this may be because very little research is done on young children, so doctors do not have the kind of hard evidence of safety and efficacy that they would like to have before prescribing. In addition, since the ultimate goal of medication is to enhance function, impairment is sometimes hard to define concretely until a child starts school, and is required to function outside the home. Parents should always keep in mind that psychotropic medications are supposed to enhance function--this is the only valid reason for their use, and should always be the primary goal of treatment.

Since the symptoms of Fragile X typically seem to change with age, sometimes even with the seasons, treating this condition can be like shooting at a moving target. Anxiety is especially prominent around ages 2-4 for many fra(x) boys; hyperactivity develops (sometimes abruptly) in the 4-10 year age range, often ending (sometimes just as abruptly) with puberty or the adolescent growth spurt. Aggression and "catastrophic reactions" can occur at any age, but seem to intensify in adolescence; this is one of the more common reasons for Fragile X males to be hospitalized or institutionalized. Aggression is also a readily treatable symptom and a clear-cut indication for medication. Irritability often worsens in winter in northerly lattitudes, in some cases requiring only seasonal treatment. The point is that Fragile X usually changes over time, and no one should recommend treating all Fragile X individuals alike, or maintaining one individual on a fixed medication regimen indefinitely.

Since most parents would prefer to try non-medical alternatives if possible, it is entirely reasonable to attempt behavior modification or sensory integration techniques before considering medications. However, no outcome studies of these methods have been conducted, so no advice can be given about relative efficacy or length of treatment necessary. Also, these methods can certainly be used with medications; in other types of psychiatric disorders the combination of medication and other therapies invariably proves more effective in rigorous studies than either treatment alone. It is probably a safe assumption that the same is true for Fragile X syndrome. A good rule of thumb is that if specific symptoms have not improved measurably after six months of treatment (i.e. in PT, OT, SI) evaluation for medication should at least be considered.

The fact is that nearly all Fragile X males will be prescribed psychotropic medication at some point in their lives; in the Age of Prozac, many Fragile X females will be given a trial of medication as well; this need not be considered a tragedy. Psychotropic medication was never meant to be a substitute for anything. It should not be used instead of psychotherapy, OT, PT, speech therapy, special education-- or love, affection, individual attention, family, community, etc. But the judicious use of these agents to treat this devastating neuropsychiatric illness can greatly enhance all other aspects of a person's life, so witholding treatment can be as great a sin as overmedicating. Approaching the topic with an open mind and enough information is key to optimal treatment.

Keeping these things in mind, let's assume that you have made the decision to seek consultation about medication.

Who Should Treat?

What kind of specialist should parents consult? The true experts in this area are ultra-specialists called neuropsychiatrists. They are psychiatrists who have done fellowship training in Child Psychiatry, then gone on to further training in treatment of patients with developmental disorders and brain injury. They will almost certainly have a fair amount of experience in treating individuals with Fragile X, and will be quite astute psychopharmacologists. They are also exceedingly rare, and are hardly ever found outside of major medical centers. (Not to be confused with neuropsychologists, who are not medical doctors, but have doctoral degrees in psychology. Psychologists cannot prescribe medications, although they may be involved in treatment by performing psychometric testing.)

Child psychiatrists are somewhat easier to find (there are about 3000 total in the US) but can be quite variable in their approach to a Fragile X child. Some specialize in psychotherapy and have little training in psychopharmacology or developmental disorders. Others are well versed in psychopharmacology and experienced in treating developmentally disordered patients. How do you find out which is which? Be sure to ask specifically ahead of time.

Developmental pediatricians are experts in the medical care of children with developmental disorders and can be quite astute in treating behavioral problems as well. However, some do not prescribe psychotropic medications, preferring to refer to another specialist. Others may not feel comfortable prescribing some of the medications reviewed in this text. Having a single physician manage most of your child's care is a good idea, so developmental pediatricians can be especially valuable; once again, ask ahead of time to gauge the doctor's "comfort level" in working with Fragile X syndrome.

Pediatric neurologists are often called upon to treat behavioral problems associated with Fragile X syndrome, and some are quite sophisticated in the treatments they utilize, while others feel comfortable only with relatively simple regimens like stimulant trials or clonidine administration. Most are, of course, quite expert in the use of anticonvulsants, both for seizure disorders and behavioral control. The key here is to ask about the prospective physician's experience in treating a broad range of behavioral problems, like mood disorders, aggression, anxiety, self-injurious behavior, etc.

Someone from one of the four sub-specialties mentioned above should be able to help, but if you live in a rather remote area you may have little choice--there may be only primary care doctors in the area. Since it is not a good idea to rely on any doctor who is located too far from home, you (the parent) then will likely assume the responsibility of arranging for some type of consultation between your family doctor or pediatrician and a suitable specialist. The specialist can assist in diagnosing the problem and initiating treatment, with the primary care doctor taking care of follow-up and maintenance.


Target Symptoms


Many parents are familiar with the term ADHD--Attention Deficit Hyperactivity Disorder, and it is often said that upwards of 75% of Fragile X boys have this disorder. This is not true. It is technically impossible for anyone with Fragile X syndrome to have ADHD, simply because anyone with known Pervasive Developmental Disorder is excluded from the diagnosis, and virtually all Fragile X boys have PDD. Hyperactivity and attentional problems are simply a basic part of Fragile X and many other developmental disorders.

Since ADHD is a diagnosis, not a disease, it is not surprising that it is seen in many forms and thought to have many causes. In Fragile X individuals this same heterogeneity holds true: many are quite hyperactive but seem able to concentrate when especially interested; others are rarely hyperactive (or "hyperkinetic") but still have difficulty attending. Attention deficit and hyperactivity can properly be considered two distinct symptoms which interact significantly and are often, but not always, seen together. Indeed, these two symptoms can be treated separately, pharmacologically dissected; therefore, they will each be discussed separately.

This is an appropriate time to discuss the differences between boys and girls with Fragile X, since these differences are most apparent in regard to the treatment of ADHD-like symptoms. It is well known that the average boy with Fragile X is more severely affected, especially cognitively, than the average fra(x) girl (full-mutation female). However, given the variability of expression of Fragile X, it is possible that some girls will actually be more severely affected than some boys. In other words, some girls can present with classic, full-blown Fragile X syndrome; the approach to the treatment of this subset of girls is essentially the same as that for typically-affected boys. Typically-affected girls are mildly affected, most likely showing learning disabilities, ADHD-like symptoms, and possibly anxiety or mood disorders--all of which are quite treatable. Conversely, some Fragile X boys (usually mosaics) have surprisingly little impairment, and for psychopharmacologic purposes can be considered equivalent to Fragile X females. Typically-affected girls will usually be quite a bit less sensitive to the adverse psychiatric effects noted below, and can ordinarily be considered similar in treatment responsiveness to the general population. So, if parents of a Fragile X girl or an unusually mildly-affected boy see side effects listed for stimulants, such as anxiety or aggression, they should keep in mind that their children are likely far less sensitive to these effects than the typical Fragile X male.[tab][tab_item title="Attention Deficit"]Males with Fragile X typically have difficulty paying attention, although this does not mean they cannot find some activities quite engrossing (i.e. watching a favorite TV show, playing with a certain toy). Some full-mutation females also have problems in this regard, usually showing up as difficulty in school. The problem is not that they cannot ever pay attention; the problem is not that they do not want to pay attention; the problem is that they have trouble on a basic level shifting and sustaining attention the way most other people do.

Attention is a very important and complex neural function that we are only beginning to understand. A large part of the brain, especially in the frontal lobes, is devoted to attentional mechanisms: it is easy to see why if one considers the importance of this basic function to the survival of the individual. Our brains are capable of performing some sophisticated tasks, but only if we can focus on the task at hand and ignore distractions. However, if we focus too much we are not alert to our surroundings and are vulnerable to many dangers in the environment. Evolution has developed for us a rather elaborated mechanism which enables us to focus when we need to, yet still maintain a watch, just in case. This represents a rather tricky balancing act--focus too much and you could literally be eaten alive, focus too little and you'll never get anything done. A delicate balance like this is easily disrupted, so it makes sense that a global neuropsychiatric disorder like Fragile X would cause some problems here. In this section we consider the effect of too little focus: attention deficit. Later we discuss the effect of too much focus: obsessive-compulsive behaviour.

These attentional mechanisms in the frontal areas of the brain are thought to utilize dopamine as a primary neurotransmitter. It is thought that subtle deficiencies in this "dopaminergic" system can impair the ability to attend or to shift attention appropriately. Naturally, if a person is unable to pay attention appropriately in a given situation, he may become bored, restless, fidgety, or even disruptive. In this manner, it is theorized that some individuals with attention deficit become secondarily hyperactive, while others might just daydream and become somewhat socially isolated. Other theories of ADHD at large dispute this point, and at the very least it is a gross oversimplification. Nonetheless, individuals with Fragile X do show this type of attentional problem and enhancement of this dopamine transmission does seem to help.

The mainstay of treatment for attention deficit is the use of psychostimulant medication. These are the medications virtually every parent has heard of: Ritalin, Dexedrine, and Cylert (along with generic and newer time-release equivalents). Their use is widespread in the general population and in the treatment of Fragile X syndrome as well; millions of children and adults worldwide are prescribed stimulant medication safely and effectively. However, there are some particular precautions to be observed in treating Fragile X individuals with stimulants. These will be discussed later.

Psychostimulants will increase virtually anyone's attention and focus in a direct, dose- dependent fashion. Response to stimulants is neither specific to, nor diagnostic of, ADHD. You could even say that these medications are the ultimate in "cosmetic psychopharmacology", since most people can derive some enhancement of cognitive function from them. This is evident in the current fad in diagnosing adults with ADHD, including many with no history of childhood academic difficulty. This also explains why psychostimulants are highly controlled substances with significant abuse potential. While medically supervised use in treating attentional problems in school-age children rarely results in any form of dependence (because doses are too low), the illicit use of amphetamines can result in powerful addiction and numerous psychiatric side effects. Therefore, the use of stimulant medication should neither be taken lightly nor feared unnecessarily.

Although the abuse potential of psychostimulants is generally not a problem for Fragile X children, the attendant regulation of their prescription can be a bit of a hassle. Ritalin and Dexedrine, the most commonly used drugs in this class, are both schedule II controlled substances--just like morphine or Dilaudid. In most states one can only receive a 30 day supply of medication, with no refills; identification is necessary to pick up a prescription, so only the parent can do this; usually, the written prescription (no phone-in’s allowed) must be filled within 3 to 7 days, expiring thereafter. This is only an inconvenience, but a potentially major one, and it does often result in interruption in therapy. Cylert is a far less-restricted, schedule IV drug which avoids most of these hassles, but is much less commonly used, for a variety of reasons to be discussed later.

Since all of these medications increase the ability to "focus" on a cognitive task in a dose-dependent fashion, it is possible to become "over-focused", i.e. to get too much of this effect. Sometimes this results in problems with reciprocal social interaction, or just with the normal spontaneity we all associate with childhood. In practice, these are rarely problems for Fragile X children; instead, this may manifest itself as perseverative or "obsessive- compulsive" behavior in the Fragile X population. The anxiogenic (anxiety-inducing) side effects of these medications may also cause an increase in panic anxiety, social anxiety, difficulty with transitions, and other types of anxiety frequently seen in Fragile X. This effect usually limits the use of these medications to relatively low doses.

Another significant psychiatric side-effect of stimulants is the enhancement of aggression. Here again, the effect is neither specific to nor limited to ADHD or Fragile X. Anyone will get more aggressive if given a large enough dose of a psycho-stimulant. Fortunately, in most cases the dose required to produce aggression is much higher than usual therapeutic doses. Unfortunately, Fragile X individuals are usually much more sensitive to this effect than the average person, often limiting the usefulness of stimulants. Typically, Fragile X individuals will experience an increase in aggressive behavior at or near the therapeutic dose range; this can be an especially severe problem if the individual already displays a significant amount of aggression, and should be considered a "relative contraindication".

As a result of the aforementioned limitations, many clinicians have recognized an acute need for other methods to enhance attention in individuals with developmental disorders, especially Fragile X. In the first part of this section we noted the alternativestrategy of treating hyperactivity and hyperarousal selectively; this is often the most effective approach and is discussed at length in the next section. However, psychopharmacologists have more recently become aware of other medications besides stimulants which enhance attentional mechanisms. In particular, the antidepressant class of drugs appears especially promising. While older antidepressants such as desipramine, imipramine, and nortriptyline have been used for many years to treat ADHD, recent concerns about their safety have led to a shift toward newer agents. Bupropion (Wellbutrin), venlafaxine (Effexor), and now atomoxetine (Strattera) all appear to selectively enhance attentional mechanisms in children with ADHD or Fragile X, with relatively little effect on hyperactivity or level of arousal. Other medications sometimes used (though with less certain results) include amantadine (Symmetrel), which increases frontal dopamine activity; folic acid, once thought to be a specific treatment for Fragile X, but now thought to work (at very high doses) for some individuals as a weak psychostimulant; or even caffeine, the most widely used psycho-stimulant of all, which may be useful as test medication to gauge the potential effects of more potent stimulants like Ritalin.

Drugs to be avoided when attentional difficulties are prominent include all tranquilizers, both major (the antipsychotics) and minor (the benzodiazepine anti-anxiety drugs), as well as some of the anticonvulsants (especially phenobarbital). All of these can significantly impair attention, concentration, and memory. Fragile X individuals appear even more sensitive to these effects than most people.


The near universal presence of hyperactivity in Fragile X boys is thought to result from central nervous system hyper-arousal; in other words, Fragile X children may not be able to properly integrate sensory stimuli, resulting in frequent "over-stimulation" and behavioral dyscontrol. Once again, there are specific mechanisms in the brain for regulating the overall level of arousal or alertness. This is obviously another important function from an evolutionary standpoint, and one which is clearly linked to attention: too much or too little arousal can easily disrupt attention and make it impossible to focus on the task at hand. These mechanisms for regulating arousal are thought to reside in the so-called activating formations of the brain located in the brainstem and midbrain, the evolutionarily "primitive" areas that we share with all other vertebrate animals. This includes the "fight-or-flight" center and other areas which regulate heart rate, breathing, blood pressure, and other autonomic functions of the body.

Recent research has noted a particular connection between eye contact and hyper-arousal in Fragile X boys, who may become physiologically hyper-aroused simply by rather benign eye contact from adults. This report is actually quite consistent with previous observation by animal behaviorists that eye contact with predators causes powerful hyper-arousal, and that even dominant members of the same species can "stare down" younger, submissive animals. This response appears quite basic and primitive, as well as universal, and is inhibited by the "higher areas" of the cortex. It is possible that Fragile X boys simply do not have enough of this calming inhibition as a result of impaired development, but that we can enhance this function pharmacologically.

One of the primary neurotransmitters in this system is norepinephrine (also called noradrenaline); in fact, more than half of all the neurons using norepinephrine in the brain are contained in one small formation, the locus ceruleus. It turns out that this anatomical formation of relatively few cells is the "fight-or-flight" center, the brain's own alarm system-- a part which, if electrically stimulated, will produce an immediate panic attack. This alarm system has connections to most other parts of the brain, and its output controls much of the sympathetic nervous system in the rest of the body. Not surprisingly, most of the strategies used to modify the hyperarousal and hyperactivity so often seen in Fragile X target this system.

As previously mentioned, "antidepressant" medications have been used extensively in the treatment of ADHD, so it is not surprising to learn that all antidepressant medications have one thing in common: they cause a "downregulation" (decreased density) of one important class of norepinephrine receptors (beta receptors) in the brain. This may explain why they can help with hyperactivity as well--although this is not fully established yet. In any event, the effect in Fragile X is rather subtle, and often not adequate by itself to control severe hyperactivity, especially when less sedating medications are used.

A more powerful and selective way to decrease this hyperarousal is to directly inhibit the activity of the locus ceruleus and its "noradrenergic" transmission. This is actually a popular way to control high blood pressure, too, and a whole class of medications has been developed for this purpose and so are widely available for our use. This class is generally referred to as alpha-2 agonists, since they activate the alpha-2 subclass of norepinephrine receptors which inhibits the firing of norepinephrine-containing neurons. Clonidine (Catapres) is the prototype of the class, and has been extensively used in psychiatry. Newer drugs such as guanfacine (Tenex) and guanabenz (Wytensin) may work as well or better, but psychopharmacologists have generally not had as much experience with them. These medications are extraordinarily potent in decreasing this "sympathetic outflow", as well as many cognitive aspects of hyperarousal. (They are also used to decrease the nightmares and flashbacks seen in Post-Traumatic Stress Disorder). Despite their potency, they are proven quite safe for very long term administration, and are generally well tolerated, although children with Fragile X typically experience much sedation when starting these medications, or when increasing the dose. A long-lasting skin patch form of clonidine (Catapres Transdermal Therapeutic System-TTS) can decrease side effects and aid in compliance, since it lasts for 3-7 days and releases the drug constantly and gradually.

As mentioned in the previous section, stimulants can help secondarily with hyperactivity by enhancing concentration and attention, and they can be combined with clonidine or antidepressants if necessary for greatest effect. However, they are anxiogenic (anxiety-producing) and can worsen or cause aggression, effectively limiting their use to much lower doses than those prescribed for run-of-the-mill ADHD. Since there is no evidence that Fragile X children are more sensitive than other children to the therapeutic effects of psychostimulants, as they are to the side effects, it stands to reason that parents cannot expect dramatic beneficial effects from these medications; rather, mild improvement is most typical.


Most Fragile X boys begin to show signs of intense and abnormal anxiety at a very early age, often in infancy. Sometimes this presents as excessive separation anxiety, young children becoming hysterical and inconsolable when a parent leaves even briefly. Almost all Fragile X boys have intense anxiety (although it sometimes presents as a tantrum) when they go somewhere unfamiliar or their routine changes significantly. It is important for parents to know that this is not "just the kind of anxiety everyone has now and then" and it is by no means produced voluntarily. This "difficulty with transitions" is very much a primal form of panic, a physiologic kind of anxiety which can be disabling for anyone, especially someone who also suffers from some cognitive impairment.

Some Fragile X girls display significant social anxiety, and this may or may not present with discrete panic attacks or depression. Keep in mind that anxiety disorders and depression are tremendously common in the general population anyhow; Fragile X in girls almost certainly increases the chance of developing these conditions, but fortunately these are among the most treatable of psychiatric disorders.

In either case, medications play an important part in the treatment of anxiety disorders occurring in Fragile X individuals. Many people ask whether medication is really necessary, whether some people might do as well with cognitive or behavioral therapies: while a minority of developmentally normal individuals with anxiety disorders can obtain long-term remission of symptom with these techniques, they clearly do not work as well as medications for the majority. People with severe or recurrent anxiety disorders virtually always require pharmacologic intervention to control symptoms, and Fragile X boys certainly fall into this category. In addition, the people who do best in cognitive/behavioral psychotherapy protocols tend to be the more intelligent, more motivated individuals with greater resources: a profile which does not fit the average Fragile X child.

This is not to imply that many non-medical techniques are not useful, just that they are often not enough. Remember that medications and non-medical therapies work together well, and that not only will medication not interfere with psychotherapy, sensory integration, or speech therapy--it should help them to work better. The skillful combination of behavioral techniques, psychotherapy, and medication will virtually always yield the best result.

What causes anxiety in Fragile X syndrome? While no one fully understands the neural mechanisms underlying anxiety, psychiatric researchers have made great advances over the past 10-15 years, so that now we can at least have a working knowledge of the neurobiology of anxiety. Starting again with the evolutionary perspective, we can easily see the importance of fear in nature: the world can be a dangerous place, and we must, for our own survival, know this instinctually right from the start of life. All animals are innately capable of experiencing fear; generally speaking, fear emanates from the more evolutionarily primitive parts of the brain, the parts that look more or less alike in mice or men. The higher parts, like the cortex, seem to suppress this activity. You could even argue that one of the great benefits of our developing this huge, complex brain of ours is that it allows us to overcome our instinctual fears--to evolve culturally, not just genetically.

We have already mentioned that the brain has a built-in alarm system, the locus ceruleus, and that we already know that directly stimulating this formation will produce a classic panic attack. We theorize that this is essentially preparing the brain and body for conflict. So what is the difference between this primal fear and what we call anxiety? Probably not much. Most people think of anxiety as an intrapsychic phenomenon--the result of internal conflict, not a genuine external threat. This concept has been heavily influenced by generations of psychoanalysts who focused primarily on intrapsychic conflict as the primary origin of psychopathology. However, it has more recently been found that anxiety disorders are not really even related to the sort of everyday anxiety most of us experience. Anxiety disorders are most likely the result of this primal fear surfacing at inappropriate or unexpected times. Much of the anxiety that Fragile X children experience is understandable in these terms.

Most Fragile X parents first notice an abnormal amount of anxiety in their children early on, sometimes in infancy. Typically, this is seen as exaggerated separation anxiety, with the child becoming panicked whenever the parent gets too far away. These children can be inconsolable, and upset beyond all reason; yet, it is tempting to say that they are "spoiled" or somehow trying to "manipulate" the parent. All amateur psychoanalysis aside, this kind of behavior is most certainly not voluntary, nor even controllable. This is primal fear uninhibited by the usual cortical input that would tell most children, "Mommy is coming right back" or "Daddy is just going to get my bottle". Because the Fragile X child is slower to develop the advanced circuitry of the cortex, the "thinking" part of the brain, he has fewer resources to draw on in a difficult situation, and separating from a parent can be a difficult situation for any child.

Likewise, most children experience stranger anxiety at a certain stage of development, instinctively fearing people they do not know, regardless of how dangerous they really are. Eventually, most children learn from family members how to judge other, unfamiliar people. The higher areas of the brain override instinctual fear through learning and conditioning. However, if this is slow to occur or incomplete, persistent social anxiety can result. This is also a type of anxiety frequently seen in Fragile X children, one that can cause great social impairment and difficulty with reciprocal interactions.

Not only new faces, but also new situations can cause anxiety. Change is inherently stressful, and children normally crave routine at certain stages of development, presumably to minimize the resultant anxiety. In keeping with the previously noted pattern, Fragile X children can be exquisitely sensitive to changes in routine, or new situations. Reaction to these stresses can range from simple shyness, to panic, to full-blown tantrums. Parents (and certainly onlookers) might think the child simply does not want to do something, but the extent and the irrationality of the reaction argues for a different interpretation: this primal fear has once again been triggered, and the rest of the brain is unable to suppress it.

The cortical inhibition we refer to comes in many forms (chemically speaking), but one of the most important forms comes via the "serotonin system", the brain's primary regulator of moods and affect. This network of cells acts like the brain's automatic transmission, shifting gears without thinking to meet the demands of the environment, automatically setting our mood to fit the current situation. High levels of the neurotransmitter serotonin powerfully inhibit the locus ceruleus (the alarm system) and result in a sense of calm and contentment. Low serotonin sets a very different tone for the brain, leaving one feeling irritable, unhappy, anxious, or even aggressive. In other words, serotonin sends the signal that everything is OK and we can all relax; no serotonin means something is not right, and we'd better do something about it.

It is thought that derangements of this serotonin system underly most anxiety disorders and depression, and the ability to manipulate brain serotonin has been one of the great accomplishments of modern psychiatry. The medications which make this possible are called Selective Serotonin Re-uptake Inhibitors, or SSRIs; they are marketed under the trade names Prozac, Zoloft, Paxil, Celexa, Lexapro, and Luvox. They all work by blocking the inactivation (re-uptake) of serotonin at the synapse (neuronal junctions), thereby increasing the effect of the naturally occurring neurotransmitter. Other types of "antidepressant" medications do this also; the revolutionary thing about SSRIs is that this is all they do: they are pharmacologically pure and have no true side effects. What side effects they have in practice are simply the result of doing this one thing everywhere in the body.

Antidepressants in general, and the SSRIs in particular, can be quite helpful in the management of anxiety in Fragile X individuals of all ages. They offer the possibility of treating these various forms of anxiety cleanly, without the cognitive impairment usually associated with tranquilizer-type anti-anxiety medications (Valium, Xanax, et al.); indeed, as we described in a previous section, they can enhance attention and concentration. The older antidepressants (this term is a confusing misnomer, since these medications have many uses) such as imipramine and nortriptyline must be used with caution, however, since they can cause many serious side effects, including changes in cardiac conduction. They also affect other neurotransmitter systems which we are not targetting, causing so-called anti-cholinergic effects like blurry vision and dry mouth; in especially vulnerable individuals (like children with Fragile X) they can even cause confusion, memory impairment, or delirium. This safety advantage alone probably explains why most child psychiatrists are increasingly favoring the SSRIs over the older drugs. But these newer medications will likely prove more effective as well, though large-scale comparison studies in children are still in progress.

Clonidine and other centrally-acting alpha2 agonists, effective as they are in reducing CNS hyperarousal, can have some weak anxiolytic (anti-anxiety) effects. They can be combined safely with antidepressants to yield a greater effect, if needed.

Beta-blockers such as Inderal (propranolol) have been used by some child psychiatrists to treat anxiety disorders, but there is little research to support this; it has been conclusively shown that these medications are largely ineffective in serious anxiety disorders in adults, and these are not entirely benign medications.

Buspirone (BuSpar) is a novel anxiolytic with weak antidepressant and antiobsessional properties. While it can help with some forms of anxiety, especially social anxiety, it is not effective against panic anxiety. It is also short-acting, requiring multiple daily doses.

Again, at least as important as the medications to consider for the treatment of anxiety are the ones to avoid. Stimulants (including caffeine) will invariably exacerbate anxiety in a dose-dependent fashion; they can often be used in lower doses to enhance attention, but children should be monitored carefully for a possible increase in anxiety. Minor tranquilizers (benzodiazepines like Valium and Xanax), which are commonly used to treat anxiety in the general population, are generally counterproductive in Fragile X individuals. All of them impair concentration, attention, memory, and motor coordination; they can lead to behavioral disinhibition--inappropriate behavior secondary to intoxication--or to "paradoxical excitement", a state which is anything but tranquil. The important point to remember is that Fragile X individuals as a group do not respond to these medications in the usual way. Major tranquilizers (anti-psychotics like Thorazine or Haldol) are fortunately and deservedly out of favor as treatments for any kind of anxiety, and should be avoided at all cost, since they can cause severe side effects and do very little to relieve anxiety. Nevertheless, some backward clinicians still believe that mentally retarded individuals require the strongest possible "tranquilization" to keep their behavior in check, and thus these drugs are still widely prescribed to non-psychotic individuals, despite a lack of any evidence of efficacy.


Irritabilty can be thought of as the flip side of depression. When most people think of depression, they think of feeling down or blue; just as often, however, people who are depressed are irritable or grouchy. Extreme irritability is often a problem in Fragile X syndrome, and we can best conceptualize this as a disorder of mood. People with Fragile X do seem to have a problem with the serotonin system, the brain's mood-regulating mechanism, and this often results in unstable (labile) moods, with rather sudden shifts from one extreme to another. This, too, can be viewed as a failure of development. Children in early stages of development normally have relatively unstable moods (at least by adult standards); as they develop, this mood-regulating system gradually smoothes things out to such an extent that we take stable moods for granted. However, for Fragile X children this aspect of development, like many others, does not seem to proceed according to plan, leaving them especially susceptible to wild fluctuations in mood. Often, this "switch" appears to be spontaneous, or brought on by only the slightest provocation. Once again, parents and family need to remember that this is not voluntary or intentional, that the child is not "pitching a fit" to get his way. This is simply a manifestation of the affective (mood) instability which is an intrinsic part of Fragile X syndrome, and it can be treated.

Since we conceptualize this irritability and affective instability as related to depression, and presumably involving dysfunction of the serotonin system, we might anticipate that antidepressant medications could improve this particular situation. In fact, this turns out to be quite helpful, and once again the SSRIs seem to be the best-tolerated alternative. Normal adults who take these medications for a variety of reasons most often describe the effect of SSRIs in exactly these words: "Things just don't seem to bother me as much anymore." This is precisely the effect we are hoping for when prescribing SSRIs to people with Fragile X syndrome, and this does seem to be the effect in most cases.

Other medications can help with irritability as well. Clonidine (and similar medications) can decrease irritability by limiting hyperarousal and overstimulation, but many parents find that higher doses or peak levels right after an oral dose can actually cause increased irritability, probably by causing excessive sedation and confusion. This is one reason why the clonidine patch is often a superior method for administering this medication, since there are never any peaks or troughs; just constant, gradual absorption of the drug through the skin.

BuSpar (buspirone) is marketed for treatment of anxiety, but also has some antidepressant effects, and can help with irritability, too. Since it is less convenient and probably less effective than the SSRIs in this situation, it should be considered a second-line treatment option.

Individuals with significant irritability should avoid higher doses of psychostimulants, which may make matters worse. Even caffeine can exacerbate irritability, so monitor dietary intake. Here again, tranquilizers (both minor and major) are not especially effective and may be counterproductive; they should not be considered a routine treatment for this target symptom.


At the opposite end of the mood disorder spectrum from irritability and depression is mania. We often think of mania occurring primarily in adults with manic-depressive illness (Bipolar Disorder), but a surprising number of children with developmental disorders present with a bipolar type of mood disorder, experiencing highs and lows as well as mixed states in between. Mania is usually not hard to recognize, although in Fragile X it can be difficult to distinguish from the commonplace severe hyperactivity. Mania is a persistent elevation of mood, accompanied by increased motor activity, increased impulsivity, decreased need for sleep, and (in extreme cases) psychotic thought processes--"losing touch with reality".
The neurobiology of mania is not well understood, despite the fact that this phenomenon has been observed for thousands of years; but it is thought to arise from dysfunction of the "limbic system", a large, interconnected group of formations in the brain apparently responsible for controlling the full range of emotions. This is not a single- neurotransmitter system, but rather an anatomical array of cell clusters which seem to function together electrically to register and express emotion. This is also an evolutionarily primitive part of the brain, one which we share with many other animals, but which is far more complex in humans.

Since this system does not rely on any one primary neurotransmitter, the approach to pharmacotherapy of mania is somewhat different. The mainstay of treatment is the use of so-called mood stabilizers, drugs which have the net effect of electrically stabilizing the limbic system. This class of drugs includes lithium, carbamazepine, valproic acid, and clonazepam. Lithium is actually not a drug, but a simple salt which was serendipitously discovered to have mood stabilizing effects. The others all started out as anticonvulsants (anti-seizure medicines) and were subsequently found to have beneficial psychotropic effects probably directly related to their ability to stabilize the electrical activity of the limbic system. Not all anticonvulsants have this effect; phenytoin (Dilantin) and phenobarbital act primarily on the cortex and do very little in the limbic areas of the brain. Consequently, they are not effective as mood stabilizers. Since 10-20% of Fragile X boys have seizure disorders and many are treated with anticonvulsants, it makes sense to use one of the anticonvulsants with beneficial psychotropic effects where appropriate. Killing two birds with one stone is good psychopharmacology.

Mania is one of the few symptoms which justifies the use of major tranquilizers (antipsychotics) in Fragile X syndrome. A short course of an antipsychotic (also called neuroleptic) can help to control mania--although a mood stabilizer alone will often do the trick, and is a better long-term solution.

One important consideration in the evaluation of mania is the possibility that the condition could be drug-induced (iatrogenic). The major drawback of the use of antidepressants in Fragile X syndrome is the possibility of manic activation. In studies of antidepressants among the general population, the occurrence of mania during the course of treatment with antidepressants is only about 1-2%--not much of a risk. However, children in general---and Fragile X children in particular---seem to be much more susceptible to this adverse effect; in this population manic activation may occur as much as 10-15% of the time when antidepressants are used. In most cases discontinuation of the offending agent will resolve the mania, but in some cases use of a mood stabilizer is necessary to restore normal mood (euthymia).

Children who have shown this "bipolar" course of illness, or who have had manic episodes when given antidepressants should probably be considered for a trial of buspirone (BuSpar) if the need arises for treatment of irritability, anxiety, or aggression. This medication can be effective for these target symptoms and seems to entail much less risk of manic activation than SSRIs or conventional antidepressants. Many physicians, including psychiatrists, consider buspirone to be generally ineffective; however, numerous studies support its use in the developmentally disabled population and demonstrate consistent efficacy without significant adverse effects.

Medications to be strictly avoided in Fragile X children with a known susceptibility to mania include all psychostimulants. Ritalin, Dexedrine, Cylert, etc.--even caffeine--have all been reported to cause agitation, hypomania, mania, or even frank psychosis in this subgroup. This is generally true throughout the population, but children seem more sensitive, and Fragile X children appear to be especially sensitive. Remember that stimulants can be quite helpful for some children with Fragile X; this is simply one criterion used to decide which children might be most likely to benefit, and which are most at-risk for adverse effects. Keep in mind also that FMR-1 is only one of thousands of human genes; the rest of an individual's genome determines much of his or her susceptibility to disease, or response to pharmacotherapy. So, family history of other psychiatric disorders is still an important factor in determining treatment for a Fragile X individual, and your doctor needs to know this information, too.

Obsessive Compulsive Behavior

Perseverative speech, ritualistic behavior, constant chewing of clothing or other objects, and a general love of routine and repetition are frequently noted traits of people with Fragile X syndrome. These traits have been noted in all age groups, far more often in fully- affected males. While the specific behaviors vary greatly from one person to another, these are all often categorized as obsessive-compulsive behaviors, because of their similarities to aspects of Obsessive-Compulsive Disorder (OCD), one of the major anxiety disorders in the general population. Here again, we draw an analogy between specific symptoms of Fragile X and a discrete disorder seen in developmentally normal people as a way of understanding some of the basic pathophysiology of Fragile X. Unlike Fragile X, OCD has been the subject of enormous amounts of medical research; therefore, even though our knowledge of OCD is far from perfect, we know much more about the basic mechanisms underlying OCD, and many useful inferences can be derived from the comparison of the two disorders.

In fact, many other disorders are thought to share features of OCD, including eating disorders, kleptomania, compulsive gambling, and trichotillomania (compulsive hair-pulling). Many people with Tourette's syndrome, a major neuropsychiatric disorder characterized by motor and vocal tics, also display severe OCD. Frequent comparisons are made between autism and OCD, and many of the OCD-like symptoms seen in Fragile X are also common in autistic children. Since few Fragile X individuals would qualify for the formal diagnosis of OCD, we will simply refer to "O-C behavior" or "O-C symptoms".

A true obsession is technically required to be "ego dystonic", or upsetting and unpleasant to the individual; in this sense, much of the perseveration experienced by fra(x) children does not qualify (they often derive hours of enjoyment from their "obsessions"). However, a common etiology may well underly both phenomena. It is theorized that both arise from an inability to inhibit certain types of thoughts originating in the "planning centers" of the brain, particularly in the frontal lobes. The idea is that thoughts in the brain buzz around through circuits of neurons, which often feed back on themselves, forming a continuous loop. Psychosurgery has even been used to treat particularly intractable cases of OCD, with surprising success (though definitely not appropriate for anyone with Fragile X). Normally, a great deal of inhibition is provided to keep these feedback loops from getting out of control. Much of this inhibition comes via the serotonin system, but in a different part of the brain from the areas which regulate moods and anxiety. Thus, it is thought that hypofunction of this branch of the serotonin system results in OCD, and this has been confirmed in numerous research paradigms: enhancing serotonin improves OCD, decreasing serotonin worsens it consistently.

As one might expect, then, the SSRIs are particularly effective for treating this class of target symptom, just as they are the treatment of choice for bulimia, OCD, trichotillomania, and a variety of other conditions in the general public. The non-selective serotonin re-uptake inhibitors, clomipramine (Anafranil) and venlafaxine (Effexor), are also quite effective in this regard, however with somewhat more side effects and less convenient dosing. Clomipramine, in particular, has been used extensively in the developmentally disabled population with well-documented efficacy.

A good response to these medications can include a dramatic decrease in perseverative behavior, less chewing or mouthing, more fluent and relevant speech, elimination of ritualistic behaviors, and generally greater flexibility--with fewer catastrophic reactions to changes in routine. As mentioned in the section on mania, however, some Fragile X children cannot tolerate the activating effects of antidepressants, and for this subgroup the novel anxiolytic buspirone (BuSpar) can be effective for O-C symptoms, though usually only at high doses, without any apparent risk of activating mania. Another unique medication, fenfluramine (Pondimin), which acts as a serotonin agonist, has been investigated in treating autistic individuals, for the same reasons SSRIs are recommended for so many of the symptoms discussed previously. However, results have been equivocal-- perhaps because of the heterogeneity of autism--and this medication seems to have far more side effects than SSRIs. It is a controlled substance with some potential for causing dependence, and there have been reports of tolerance developing to the therapeutic effects in some individuals who experience a good initial effect. There have also been no specific reports of its use in Fragile X syndrome, so it cannot be recommended, especially with a safe and effective alternative like an SSRI available.

Individuals with Obsessive-Compulsive type symptoms should avoid stimulant drugs, especially at high doses, as well as caffeine; their anxiogenic effects can be expected to consistenly worsen this type of target symptom. Hyperkinetic children with Fragile X can be treated with one of the centrally-acting alpha-2 agonists (clonidine, Tenex, etc.) if concomittant O-C symptoms preclude the use of stimulants; these agents appear to augment the effects of antiobsessional medications in addition to decreasing hyperarousal. Antipsychotic medication was often prescribed inappropriately in the past for all types of people with OCD or O-C symptoms, usually with little effect; this often meant that doses would be increased to dangerously high levels before considering the trial a failure. Fortunately, the increasing awareness of OCD today makes this less likely; however, the developmentally disabled have always been at greatest risk for this kind of mistreatment, and presumably this will not change overnight. Beware of any physician recommending antipsychotic drugs as first-line treatment for these symptoms.

Self Injurious Behavior and Aggression

One of the more frequent reasons for Fragile X males to be hospitalized or even institutionalized is the common occurence of aggressive or violent behavior. This seems to be confined to males and more severely affected females. It should be emphasized that not every Fragile X male has the potential for aggressive behavior, but when it occurs, it can and should be treated. Improvements in the treatment of aggression over the last 10-15 years have been especially dramatic; whereas few effective drugs existed then, this target symptom can be considered readily treatable nowadays.

Aggression in Fragile X males is sometimes seen at an early age, often closely associated with intense anxiety. Some parents note this behavior as early as 2-3 years of age, when the greatest concern is often for the safety of siblings. However, adolescence is strongly associated with an increase in aggressive behavior, which is all the more alarming when these boys rapidly gain size and strength. It is generally assumed that increasing testosterone levels during puberty underlie the timing of this effect. Testosterone increases aggressive behavior in experimental animals, as well as in athletes abusing anabolic steroids for muscle-building. It is likely that most Fragile X individuals are more vulnerable to inappropriate aggression by virtue of the aforementioned serotonergic dysfunction, but that pubescent fluctuations in androgens (male hormones) are most likely to precipitate problems.

Much recent research has shown that certain types of violent behavior, especially involving episodic dyscontrol rather than calculated or sociopathic violence, are strongly correlated with low levels of serotonin metabolites in cerebrospinal fluid (CSF), suggesting a decrease in brain serotonin levels. Curiously enough, a similar finding suggests that low levels of brain serotonin--serotonergic dysfunction--is quite common among people who commit suicide. Studies recently done in the "neuropsych" (developmentally disabled) population of mixed samples of different ages and diagnoses show that self-injurious behavior is likewise strongly associated with low levels of brain serotonin. Therefore, it looks likely that violent behavior is biologically similar whether directed at self or others--a surprising finding which contradicts many earlier hypotheses. Studies of CSF levels of serotonin metabolites (like 5-HIAA) have not yet been done in Fragile X, but should be, and hopefully will be.

By now, just about everyone has heard the "Dogs on Prozac" story; self-injurious behavior is remarkably common among dogs and other animals kept penned-up for too long. Dogs will often bite themselves incessantly, inflicting great harm and causing a major problem for veterinarians. Some ingenious veterinarians have been using Prozac (fluoxetine, an SSRI antidepressant) with great success to stop this behavior. Interestingly, the predisposition to this type of SIB is reported to vary widely among different breeds of dogs, illustrating the strongly genetic basis for this trait.

If this text is starting to read like "The Serotonin Story", rest assured: there are certainly many other neurotransmitter systems involved in all of these symptoms. Psychiatry has simply begun to understand the important role this one neurotransmitter plays in all of these symptoms because we can manipulate this system so well. The serotonin system also seems especially vulnerable to disruption by a variety of factors, not only stress in the environment (leading to depression or an anxiety disorder), but also (most likely) Fragile X.

It also appears to be intimately involved in so many of the things we consider "personality traits" that we are probably especially sensitive to serotonergic dysfunction in another person. Most importantly, we can use this hypothesis to further treatment.

Earlier theories of SIB may still have some utility. One notion conceptualized SIB as an attempt to self-soothe, and speculated that the (usually minor) physical injury provoked a release of endogenous opioid compounds, i.e. endorphins and enkephalins. Thus, autistic or Fragile X children who engage in persistent headbanging might actually be getting a euphoric "rush" from their own natural painkillers, reinforcing the behavior and perhaps even leading to some "addiction". This is the rationale for the use of naltrexone (Trexan, ReVia), an opioid antagonist (blocker) which has shown some success in open trials for treatment of SIB; it simply keeps the endorphins and enkephalins away from their natural receptor sites, where they would otherwise exert their effect. If the effect of the opium-like neurotransmitters can be blocked, then the behavioral cycle reinforcing the SIB can be interrupted. If this treatment is going to work, the individual will most likely (if able to talk) describe in advance that his episodes of SIB are analgesic (painless) and/or euphoric. Asking about this in advance can save a long and pointless trial for an individual who hits himself out of frustration but finds the experience painful and otherwise unpleasant; he will likely not benefit from a trial of naltrexone. (Naltrexone has proven to be remarkably effective as a treatment for individuals in the general population with severe personality disorders who engage in ritualistic “cutting” behaviors---a surprisingly common problem.)

It also helps to define the nature of aggressive behavior. Some younger children with Fragile X will hit playmates and siblings when highly aroused without intending any harm; this is not usually considered true aggression, but simply a reflection of impulsivity and lack of judgment in a hyperaroused state. Behavioral measures to limit the level of arousal or to help the child understand that hitting hurts can be effective in this example. Teaching siblings or playmates not to get the child "riled up" can be even more effective, since they can probably learn more quickly (and have plenty of incentive!). Should these methods fail, treatments of hyperactivity and hyperarousal (such as clonidine) can help with this "pseudo- aggression".

Many episodes of aggressive behavior are preceded by a long period of mounting tension. In this sense, we often think of aggression as related to anxiety, and strategies for decreasing anxiety have also proven effective in reducing aggressive outbursts, presumably by eliminating this long build-up of tension. The analogy has often been made to a spring being wound up tight, until it finally snaps; this also seems to occur in a family of disorders diagnosed in the general population, called Disorders of Impulse Control. This family includes kleptomania, paraphilias, pyromania, pathological gambling, and other, even stranger compulsive behaviors. Most of the individuals suffering from these conditions describe a similar sense of mounting tension with eventual discharge only through the abnormal behavior. Not coincidently, most of these disorders respond quite well to medications with significant anti-obsessional and anti-anxiety effects, such as buspirone, clomipramine, or SSRIs. Thus, the original rationale for utilizing these medications for the treatment of aggression; drugs of this class were noted to be effective in the developmentally disabled patient with aggressive behavior long before studies actually demonstrated any link to serotonergic dysfunction.

In both of the examples above, the obvious links are physical tension, arousal, and adrenaline. Earlier treatments of aggression tended to focus on this aspect of aggression, and for many years beta blockers, drugs that block some of the effects of adrenaline, were the mainstay of specific treatment. While some aggressive individuals do benefit from beta blocker treatment, the effect is rather weak; high doses are often required, and other medications are often required to be used additionally. They are still widely prescribed for this purpose, and are generally considered fairly benign medications whose use entails relatively little risk, though they are gradually being supplanted by newer and more selective agents.

Some Fragile X individuals, as previously noted, may suffer especially unstable moods. This mood lability may well predispose these individuals to violent or aggressive behaviors under certain circumstances, and stabilizing their mood pharmacologically can be a particularly effective way to prevent aggressive outbursts. Resorting again to the evolutionary perspective, we can think of aggression as a natural mood state under certain circumstances. We are all (especially men) designed to be capable of aggression if we feel threatened or our social status in at stake. So, aggression may just be one end of the normal mood spectrum, albeit an extreme that we should not experience too often. People with especially unstable moods may reach this extreme more easily and more often.

It has been known for some time that lithium, the first treatment for manic- depressive illness (bipolar disorder), is quite effective for treatment of aggressive outbursts in some people, even if they clearly do not have bipolar disorder. Newer mood-stabilizers like carbamazepine and valproic acid seem to be even more effective and have been used extensively to treat aggression. These are anticonvulsant medications first and foremost, leading some to speculate that since they are effective for some types of aggression, these forms of "episodic dyscontrol" might be a variant of seizure disorder. However, several studies have indicated they are just as effective for people with entirely normal electroencephalograms as for those with known abnormalities. The leading theory is that these mood-stabilizing drugs exert their effects by decreasing the excitability of the limbic system--the hypothesized seat of emotion. In either case, since many Fragile X boys will require treatment for a seizure disorder, it makes sense to consider use of one of these "psychoactive anticonvulsants" if aggressive behavior is also a problem.

Other medications to treat aggression include trazodone, a novel antidepressant which is non-toxic but quite sedating. The major tranquilizers (antipsychotics like Mellaril, Haldol, and Thorazine) can sometimes work, but with all the aforementioned risks; they are definitely not as effective for aggression in Fragile X children (or adults) as some other, safer treatments. Minor tranquilizers (sedative/anxiolytics like Valium, Ativan, or Xanax) are usually of no benefit, and often make matters worse by causing intoxication, confusion, and disinhibition--just as some people we know are more likely to get in a fight when drunk.

Psychostimulants increase aggressiveness in a dose dependent fashion; while low doses are unlikely to cause aggression de novo, it would be tempting fate to prescribe a stimulant to a Fragile X child who is already having problems with aggressive behavior. Likewise, if a child already on stimulant medication begins to show increasingly aggressive behavior after a dosage increase, the medication is probably to blame. One of the nicest things about this class of medications is that any adverse effects usually subside rapidly once the medication is discontinued, so a careful trial is often worthwhile--as long as everyone knows what to look out for.

Most recently, severe aggression is being treated more and more often with atypical antipsychotics (Risperdal, Zyprexa, Seroquel, Abilify, et al.) when it arises in the context of a developmental disorder. Since Risperdal has been around longest, it has been studied most, with generally good results. Clearly, it can treat aggression relatively rapidly and potently; however, even these “new and improved” antipsychotics can impair attention and cause movement disorders. This is one reason that the introduction of Abilify (aripiprazole) represents a major advance in treatment of developmental disorders. This drug does not simply block dopamine receptors (like conventional antipsychotics), but actually modulates dopamine activity. So, in areas of the brain where dopamine may be excessive, it will decrease dopamine function; at the same time, it can increase dopamine function in other areas if it is low, or have little effect if it is normal. This is an ideal pharmacologic profile for treatment of the psychiatric problems that accompany developmental disorders, since agitation and aggression often go hand in hand with attention deficit and hyperactivity. Clinical experience with Abilify (aripiprazole) in Fragile X has been very good, and this agent is likely to emerge as the treatment of choice for severe behavioral problems in Fragile X, autism, and general developmental disorders.


Insomnia is a frequent complication of Fragile X syndrome, but psychiatrists usually prefer to treat all cases of sleep disturbance according to the presumed cause of the problem, because this usually yields much better results. Treating insomnia symptomatically, without regard to the underlying cause of the symptom, is sometimes successful in the short term; more often, though, the result is a chronic and seemingly intractable struggle.

The most common cause of insomnia in children with Fragile X appears to be hyperarousal, so please refer to the section on hyperarousal for more specific comments. Clonidine is frequently prescribed for hyperactive children with sleep disturbance, and can work very well. It is highly sedating and greatly decreases central nervous system hyperarousal; its half-life is long enough to ensure a good night’s sleep without undue sedation the next day. However, one must be aware of the possibility of behavioral rebound--increased hyperactivity the next day--if clonidine is given only once a day at bed time. The use of a small daytime dose, or the use of the transdermal clonidine patch with a supplemental oral dose at night will minimize the risk of rebound.

Another significant cause of sleep disturbance in individuals with Fragile X is mania; this can often be difficult to distinguish from hyperarousal (as previously discussed). Nevertheless, this is an important distinction, since the use of a mood-stabilizing agent is critical to the management of mania and will be the most effective way to restore regular sleep in a manic individual. Evaluation by an experienced clinician is the best way to make this distinction.

Finally, one factor which must be kept in mind when dealing with a sleep disturbance is seasonal change in sleep patterns. Many people show great sensitivity to seasonal changes, and find that their sleep patterns fluctuate tremendously as the length of the day changes. Typically, people in northern lattitudes sleep more as the days get shorter in the fall; they often have much less energy during the day, and they may eat more and gain weight. In short, they hibernate. This effect is much less pronounced in the Southern U.S. (Florida, for example) than it would be in New England or Canada, because there is significantly less variation in the length of days as one approaches the equator.

In extreme cases, we refer to this as Seasonal Affective Disorder; however, almost everyone experiences a little of this effect, and individuals with Fragile X are no exception. Some individuals actually have “reverse seasonal” effects--they sleep less in the winter--and may respond well to light therapy; this kind of insomnia is often accompanied by irritability and dysphoria, which also improve with light treatment. The key to successful light treatment is to use a lot of light (1000 watts or more of incandescent light, 250 watts of fluorescent), close to the eyes (within 2-3 feet), for 30-60 minutes every day during the dark season. Precise timing is still a bit controversial, but early evening just after sunset seems to be the best time to use the bright lights to trick the body into thinking the days are longer than they really are.

Recently, many people have used melatonin, the hormone which the body uses to regulate the sleep/wake cycle, as a sleep aid. This is promoted as universally effective and completely safe, but in fact it is neither. Little research has been done on the effects of administering huge excesses of this hormone over extended periods of time, and the usual 3 mg dose obtained over the counter is indeed much more than is normally present in the body. It is known that this is not acutely toxic, so it is probably safe for occasional use. Clinical experience suggests that this “nutritional supplement” is not especially effective for treating severe sleep disturbances, and it definitely can cause transient dysphoria and even brief depressive episodes in individuals with bipolar mood disorders. Since many individuals with Fragile X have a bipolar pattern of mood disorder, this should be considered a potential risk.


Basic research in animal models of fragile X has shown that signaling pathways in multiple neurotransmitter systems are probably affected in a similar way. The common denominator is a signaling mechanism in cells known as “Gq”. The best known Gq pathway involved in fragile X is the one linked to mGluR5, and this is certainly the most important one, but there are several others which may be responsible for specific symptoms of fragile X. One of the other neurotransmitter receptors linked to Gq is the alpha 1 receptor for norepinephrine, so it appears that there is excessive activity linked to alpha 1. This would be expected to cause autonomic nervous system dysfunction, including autonomic hyperarousal and insomia, which is consistent with the clinical presentation of fragile X. A similar clinical presentation is seen in Post-Traumatic Stress Disorder, and drugs which block alpha 1 have been used successfully to treat insomnia in PTSD. The prototype of the class is an antihypertensive agent, prazosin, which has demonstrated efficacy in treating the insomnia frequently seen in association with PTSD.


Planning a Pharmacologic Strategy

When treating a complex neuropsychiatric illness like Fragile X syndrome, it is essential that an overall strategy be employed which addresses all the target symptoms, as well as incorporating pertinent negatives. No one should infer from our previous discussion of individual target symptoms that these features of an individual's disorder can be effectively treated in isolation. The most important task of the treating physician is to thoughtfully construct a profile of each patient's symptoms, then carefully match it to the pharmacologic profile of available treatments. A good physician will also plan ahead, attempting to anticipate future problems such as non-response, partial response, or inability to tolerate the initial treatment; as in a chess game, the strategy for the next move in treatment needs to be considered well in advance, so that treatment does not simply consist of reacting to the latest changes in the patient's mental status. Unfortunately, caught up in the everyday pressures of a busy practice, many physicians of all specialties fail at precisely this task. This is where parents and well-informed caretakers can assist greatly, by taking the time to think about overall treatment strategy, so that their Fragile X children do not fall victim to shortsighted attempts to control the most recent, most obvious, or most embarassing symptoms without adequately considering their overall, long-term well-being.

There can be many different, but equally successful ways to approach the Fragile X patient. The simplest, conceptually, is to plan treatment based on a hierarchy of target symptoms. Thus, we would focus our treatment efforts on the most "important" symptoms first, hoping to encompass as many of the subsidiary symptoms along the way as possible. This approach assures us that we will not exacerbate a more significant problem in an attempt to treat a relatively minor one. Let us consider the following, fairly common example:

An 8 year old boy with Fragile X syndrome shows significant hyperactivity at school and at home, causing significant disruption of his education and family life. He appears to be easily "overstimulated", and his behavior can rapidly escalate out of control under certain circumstances. He is also quite prone to aggressive outbursts, most often in situations where he is obviously anxious around transitions, or with strangers in the house, or novel situations. His mother and younger siblings are frequent targets of the aggression, subject to hitting, biting, or scratching. This is also causing problems in the family, leading to fear and aversion among others in the household; this aggressive behavior has been refractory to numerous behavioral interventions; curiously, it is not observed in the structured environment at school. Teachers have recommended an "evaluation for ADHD" and suggested that this may also help with problems at home.

This child is typical of many children with Fragile X in two important ways: he has significant problems with hyperactivity, and there is much more to the story than simple, uncomplicated ADHD. If the treating physician focuses too narrowly on the chief complaint of "ADHD" and ignores the other, significant problems with anxiety and aggression, he may choose a treatment (like a stimulant) which will improve the hyperactivity while simultaneously worsening the other symptoms. In a sense, he has unwittingly prioritized this child's symptoms, attaching primacy to the ADHD-like symptoms, and considering all others subordinate. If he were to consider aggression the primary problem, since it has the greatest potential to cause immediate harm, he would be unlikely to choose a stimulant; rather, he might reason that clonidine would have a favorable effect on the outbursts as well as the anxiety, and that it could decrease the amount of autonomic hyperarousal and control hyperactivity. Thinking ahead, he might also consider that oral clonidine could cause excessive sedation during school, so he might need to switch to the transdermal patch to optimize this particular treatment.

Here we see that the physician has tailored the treatment to "fit" the patient's profile best. All the symptoms can be expected to improve, rather than having to trade improvement in one area for exacerbation in another. This is the simplest and most elegant fundamental of psychopharmacology. Thus, even though clonidine might be considered a second-line treatment for ADHD, and only an adjunctive treatment of aggressive behavior in the general population, for this patient it represents a rational first treatment.

Experts could reasonably debate the proper hierarchy of target symptoms, but this author would suggest the following ranking for Fragile X treatment, with the corresponding rationale:
1. Self-Injurious Behavior--this is the symptom most likely to cause immediate harm to the child, and also likely to become behaviorally entrenched, making later treatment more difficult.
2. Aggression--most likely to cause immediate harm to others, especially in older children, it can also become an entrenched behavior over time, as well as causing irreparable damage to relationships within the family.
3. Mania--this is a serious psychiatric condition, requiring prompt attention; it is usually manageable in younger children, where it is often mistaken for ADHD; children with a history of mania need to be treated differently for a great many psychiatric conditions, so this target symptom requires due consideration before commencing treatment for less severe symptoms such as anxiety or attention deficit.
4. Irritability--severe distubances of mood can make many aspects of everyday life extraordinarily difficult, and (most importantly) impair the individual's quality of life; just as depression in the general population (and Fragile X girls) is a serious disorder not to be taken lightly, irritability and mood lability in Fragile X boys is serious business and should not be neglected.
5. Anxiety--just as developmentally normal people with panic attacks and agoraphobia can be totally disabled by anxiety, Fragile X individuals (male and female) often suffer needlessly and fail to achieve their full potential because of disabling anxiety; this anxiety can be exacerbated by some treatments for the nearly-universal hyperactivity of Fragile X syndrome, so children should always be evaluated for the presence of this target symptom before beginning treatment for ADHD-like symptoms.
6. Hyperactivity--hyperarousal and hyperkinesis cause a large amount of functional impairment in Fragile X children by interfering with education and family life; this symptom rarely exists alone, however, and since some of the primary pharmacologic agents used to treat hyperactivity can worsen other core symptoms of Fragile X, it should be considered the primary target symptom only when other symptoms such as anxiety and aggression have been ruled out.
7. Attention Deficit--since Fragile X causes attentional problems in most affected children, this is a common chief complaint, even in children without hyperactivity; however, attentional problems in Fragile X children are usually multifactorial, and no single treatment can be expected to restore "normal" attentional function; as noted for hyperactivity, some medications used to enhance attention (psychostimulants) can adversely affect other symptoms common to Fragile X syndrome, and must be used with caution.
8. Obsessive-Compulsive Behavior--this target symptom is usually least harmful in the immediate sense, but can still cause great disruption and frustration. Obsessive-compulsive behavior (OCD) is certainly important, just not the first priority.

As a simple way of outlining a treatment strategy based on this hierarchic method, one could move down the list through the 8 target symptom categories, rating each symptom as absent, mild, moderate, or severe for a particular child. Hopefully, only a few will be present to a moderate or marked degree, and these can be addressed in rank order.

For example, let us use for an example a 6 year old boy who presents with the following profile:

1. self-injurious behavior - absent
2. aggression - mild
3. mania - absent
4. irritability - moderate
5. anxiety - severe
6. hyperactivity - severe
7. attention deficit - moderate
8. obsessive-compulsive behavior - mild

This child fortunately has little trouble with SIB or aggression, and has not shown any evidence of mania. However, he does have significant problems with irritability, anxiety, and ADHD-like symptoms. If one considers mood and anxiety disorders to be more "important" than hyperactivity, then the obvious choice is an antidepressant; indeed, attention may well improve significantly on an antidepressant. However, knowing that hyperactivity and attention deficit are also problems should influence the choice of the specific agent, perhaps arguing in favor of a less-activating medication.

Another child, perhaps a more severely affected 10 year old, might present with the following profile:

1. self-injurious behaviour - severe
2. aggression - moderate
3. mania - moderate
4. irritability - moderate
5. anxiety - mild
6. hyperactivity - mild
7. attention deficit - moderate
8. obsessive-compulsive behaviour - moderate

This child has serious problems with behavioral dyscontrol, resulting in violent behavior directed toward self and others, as well as significant mood lability. An anticonvulsant mood stabilizer such as carbamazepine or valproic acid might be effective in controlling this constellation of symptoms. Most importantly, this type of treatment would not exacerbate any of these target symptoms. The mood stabilizing effect would also lay a solid foundation upon which an effective combination regimen could be built; for example, the addition of an antidepressant/antiobsessional medication such as sertraline would carry much less risk of manic activation if this child were already on carbamazepine, because its mood stabilizing properties could be expected to provide some degree of prophyllaxis against mania.


While we do not usually start out with the intention of using multiple medications, it often happens that a single drug is only partially effective. This leaves us with a dilemma: do we discontinue this partially effective treatment in the hope of finding another which will be more effective (but which might be totally ineffective)? Psychiatrists are confronted with this question every day, even in the treatment of relatively simple disorders like depression. In the treatment of Fragile X syndrome, partial responses are probably much more common, making it even more difficult to tell how well a particular treatment is working. However, there is an alternative to switching medications, a technique psychopharmacologists refer to as augmentation.

Augmentation is the addition to a drug regimen of a second agent which can be expected to enhance the overall effect of treatment. While the very idea of combining medications may strike some parents as risky, this technique is quite commonly used and is usually very safe. In treating a Fragile X individual, combinations of medications may be used simultaneously to treat different symptoms. Strictly speaking, this is not always true augmentation, but rather symptomatic treatment of a multi-faceted illness. Many different medications are used in a variety of augmentation strategies, and a detailed discussion of these is well beyond the scope of this manual. However, some familiarity with basic techniques can be helpful.

As mentioned earlier, stimulants are commonly used in Fragile X children, but their use is often limited by side effects to lower doses. Doses in the lower end of the therapeutic range may help somewhat with attention, but are often less helpful in controlling hyperactivity and/or impulsivity. The addition of clonidine or a related medication can often greatly enhance the effectiveness of treatment and also can counteract some of the adverse effects of stimulants. If a particular individual has little trouble with hyperactivity, but simply obtains inadequate enhancement of attention, the addition of an antidepressant medication to a stimulant regimen can be effective.

Antidepressant effects are often partial, and there is a wealth of literature concerning the augmentation of antidepressants. Lithium can greatly enhance the effectiveness of antidepressants in a wide range of conditions, though this is rather involved, requiring frequent blood tests. Buspirone can augment the effect of many antidepressants, and is frequently combined with SSRIs, usually with little or no increase in side effects; this is particularly useful in the treatment of anxiety disorders and aggression. The addition of a second antidepressant (such as trazodone or a tricyclic) to an SSRI can be a potent treatment, though ususally resulting in more side effects. Other strategies employed involve addition of thyroid hormone, the beta blocker pindolol, stimulants, amantadine, antipsychotics, benzodiazepines, and even more esoteric compounds--though most of these are best left to a specialist.

Mood stabilizers often work best in combination, a fact well known to those involved in treating Bipolar Disorder. Typically, lithium is supplemented with an anticonvulsant or an antipsychotic, though the latter is not recommended for routine use in Fragile X syndrome. A completely different class of medications, the calcium channel blockers such as verapamil, otherwise marketed for hypertension, show some promise for use as mood stabilizers, although there is no experience reported thus far with calcium channel blockers in Fragile X.

In any application, augmentation treatment and combination therapies are always more difficult to study rigorously. Not surprisingly, there has been no systematic study of any augmentation strategies in Fragile X, so one must rely entirely on the experience of the physician. Nevertheless, augmentation of existing medications can be quite effective and appropriate, as well as safe and easily tolerated.

Classes of Medications

Four main classes of drugs currently exist: stimulants, antidepressants, sympatholytics, and mood stabilizers.


The psychostimulants, as a class, have been around for a long time. These were some of the first drugs to be used in psychiatry, and so physicians feel fairly comfortable with these medications-- some would say too comfortable. In children, stimulants are by far the most commonly prescribed psychoactive medications, primarily for the treatment of attention deficit/hyperactivity disorder (ADHD). Stimulants are also used, with questionable effectiveness, as appetite suppressants to promote weight loss. They can be valuable for people with narcolepsy, since their stimulating properties can help narcoleptics stay awake and function through the day. Some adults with ADHD also seem to benefit from stimulant medication.

Currently, there is a bit of controversy about the frequency with which stimulants are used; many people (this author included) feel that these medications are overprescribed and that ADHD is overdiagnosed. It is likely that the ability to attend, as a biological trait, exists on a continuum: some individuals are designed to focus narrowly on the task at hand, while others are always open to input from the environment, and are thus "easily distractable". It is also likely that many children and adults nowadays are labeled as having ADHD when they simply are normal individuals at one end of the spectrum. Viewed this way, medicating these individuals constitutes cosmetic psychopharmacology.

This argument certainly does not apply to Fragile X, however. Children with Fragile X have a well-defined, single-gene disorder which causes attentional deficits along with other characteristic symptoms. They (along with a fair number of children who really do have neurologically-based ADHD) have symptoms which offer a clear-cut rationale for the use of psychostimulants to enhance attention. The only reasonable question is whether these medications work for children with Fragile X.

To answer this question we must first consider how these drugs work. Although the mechanism of action is by no means fully understood, the conventional wisdom is that psychostimulants work by promoting release of certain neurotransmitters, especially dopamine (but also norepinephrine, as well as other things secreted along with them). The primary effect of psychostimulants, the enhancement of attention and concentration, is thought to result from the increased release of dopamine in the frontal areas of the brain. But, of course, the drug is present in other areas, too, and exerts effects there as well. The areas of the brain which regulate level of arousal, blood pressure, heart rate and other "autonomic" functions are also stimulated, while the area controlling appetite is inhibited. Under normal circumstances, most people are much more sensitive to the primary effect of facilitating dopaminergic transmission in the frontal lobes, and at most therapeutic doses will experience an enhancement of attention, concentration, and overall cognitive performance (which is why these medications were initially touted as "smart drugs").

As attention and concentration (referred to by some as "focus") increase with increasing doses of a stimulant, physical activity tends to decline, accounting for the paradoxical decrease in hyperactivity (which is ususally the objective of treatment). However, the primary and secondary effects of stimulants, enhancement of attention and reduction of hyperactivity, are known to occur at different dosages. Lower doses of a stimulant are likely to enhance attention optimally and improve cognitive performance, but may not control hyperactivity. Higher doses are likely to reduce hyperactivity, but may actually result in "overfocus", in which attention is focused so narrowly that actual cognitive performance declines. Still higher doses will cause psychiatric symptoms in virtually anyone, including irritability, aggression, anxiety, agitation, paranoia, or hallucinations. Fortunately, for most people the dose required to cause trouble is much higher than usual therapeutic doses. However, the situation is somewhat different for Fragile X individuals.

Fragile X predisposes one to anxiety, aggression, and agitation. On an intuitive level, it seems obvious that care should be taken with any substance which could aggravate these. On a biochemical level, psychostimulants are "sympathomimetic": they mimic the effects of adrenaline in the central nervous system, heightening arousal as well as increasing heart rate and blood pressure. Since Fragile X individuals often have problems with hyperarousal, stimulants may make matters worse in some cases. Many Fragile X individuals are able to achieve significant improvements in attention and cognitive performance with low doses of stimulants, though, and any potential adverse effects are readily reversible should they arise. Therefore, a trial of a stimulant is rational and safe for a Fragile X individual with particular attentional problems, but should be done with caution.

Dosages should be relatively low, and it cannot be expected that significant reduction of hyperactivity will occur, at least compared to the sometimes dramatic response seen in "garden variety" ADHD. Careful monitoring for emergence or exacerbation of anxiety or aggression must occur throughout treatment. Many Fragile X parents are not informed of this risk, are unaware of the connection between stimulants and worsening of aggression or anxiety, and therefore continue administering the medication even when adverse psychiatric side-effects occur--despite the fact that these effects readily reverse upon discontinuation of the drug.

Psychostimulant medications can cause uncommon, but serious, medical problems. Most worrisome is the development of motor tics. This can start as a subtle, almost undetectable twitch, and progress to severe involuntary muscle movement. It usually stops soon after the stimulant is discontinued or the dosage decreased, but sometimes is frighteningly persistent. The key is to catch the tics early on; more persistent tics usually occur following longer treatment in which early signs were ignored. This side-effect is usually dose related, so reducing the dose can be helpful and allow for uninterupted treatment. Also, since most Fragile X children are treated with lower doses of stimulants, this may be less likely to occur in the first place (there are no reliable statistics on the frequency of this side-effect in Fragile X). Tics can also be treated with clonidine if they persist, or if the clinical judgment is made not to interrupt stimulant therapy.

Since they can be potent appetite suppressants, psychostimulants can cause some growth delays during long-term administration. Several studies have shown, however, that children will eventually catch up, even if the medication is continued. Often, "drug holidays" are taken during non-critical times (such as summer vacation) to expedite this process. In any case, growth charts should be carefully monitored for all children on stimulant medications, and significant growth delay is an appropriate reason for discontinuing the medication.

Specific side effects and their medical management are discussed in the individual reviews of medications.

Update 2008: The caveats concerning stimulants noted in this book have proven to be well founded, and just as frequently ignored as ever. Stimulants are nearly irresistible for all concerned, offering the promise of an instant fix for the disabling inattentiveness and the disruptive hyperactivity seen in nearly all children with fragile X. Teachers love stimulants because they help so many kids participate in class. Parents love them because they start working right away, and because they want their kids to get the most out of school. Pediatricians love them because they’re easy to prescribe and have a long safety record. The only problem is that they don’t work very well in kids with fragile X! At least half of all stimulant trials in fragile X kids end abruptly because of immediate psychiatric side effects---usually extreme irritability or increased aggression. Seizures and tics are also seen with alarming frequency in this population following the start of a new stimulant medication. However, these are all fairly obvious and easily recognized, and when the drug is discontinued the adverse effects dissipate rapidly. Perhaps more concerning are the psychiatric side effects which develop insidiously over much longer time frames; I have consulted on many cases in which a fragile X child has an excellent initial response to a stimulant with no apparent side effects, only to have multiples problem emerge months or years later. Most commonly, obsessive-compulsive symptoms worsen over time, as mood deteriorates and tantrums increase. Because stimulants cause significant physiological dependence, everything gets worse if any attempt is made to discontinue the drug, and this is often seen as evidence the stimulant is working well and not to blame. In fact, this is only evidence that stimulants are potentially addictive, and demonstrates why they are highly controlled substances. The appropriate response is a gradual taper of the stimulant dose over the course of many months.

The entire field of Child Psychiatry appears to have come to the realization that excessive and indiscriminate use of stimulants has led to an increase in childhood Bipolar Disorder, Anxiety Disorders, and psychoses. Indeed, the current fad is for overdiagnosis of Bipolar Disorder, after ignoring for decades that this condition can present in childhood. So, the most important lesson is to be vigilant over the long term; most medications which work right away have serious side effects which develop much later.


The term itself is a misnomer, since antidepressant medications are effective for treating much more than just clinical depression. It has long been recognized that most antidepressant medications are effective treatments for certain anxiety disorders, such as Panic Disorder and Generalized Anxiety Disorder. However, psychiatrists have also known that even though all antidepressants approved for use in the U.S. are equally effective in treating depression, there can be a huge disparity between different agents in treating some of these "off-label" indications.

For many years, there were only two classes of antidepressant medications available: the original monoamine oxidase inhibitors (MAOI's) and the tricyclic antidepressants (TCAs). While many derivatives of these original medications were developed during the 1960's and 1970's, nothing really new or more effective came along for more than two decades. This was particularly unfortunate, since neither of theses classes are especially safe or pleasant to take; in fact, the MAOI's are not even reviewed here because they have such enormous potential for lethal interactions with certain foods and many over-the-counter drugs. Only highly compliant and well-educated patients should be considered for a trial of an MAOI, and even then, so many alternatives are available that the risk hardly seems worth taking. TCAs are still used, but mainly by patients on long term maintenance who started these medications before newer drugs were available. Otherwise, they are rapidly being supplanted by agents such as Prozac and Zoloft.

The first real advance in terms of enhanced efficacy came with the release of clomipramine (Anafranil) in the late 1980's. This was the first medication available in the US with proven efficacy in Obsessive-Compulsive Disorder, and it was quickly shown to be effective against a wide variety of anxiety disorders. However, clomipramine (basically an improved TCA) was soon eclipsed by the phenomenon of Prozac (fluoxetine), one of the most successful new medications of any kind, of all time. Fluoxetine has the effectiveness of clomipramine without all the side effects, and it has no toxic effects at any dose--so even massive overdoses are clinically insignificant. This is a very important advantage, since people with depression and anxiety disorders are, unfortunately, at high risk for suicide attempts. Even now, with most people taking the newer, non-toxic antidepressants there are still thousands of deaths each year in the US from intentional tricyclic overdose. No one has exact figures, but many children die each year from unintentional ingestion of TCAs. From a safety perspective alone this new class of antidepressants has been a major advance, but there are other advantages as well.

This newer class of antidepressants, called Selective Serotonin Reuptake Inhibitors (SSRIs), have the advantage of being very "clean" drugs. They only do one thing in the human body:: block the reuptake of the neurotransmitter serotonin at the synapse. This effectively enhances the flow of the body's own naturally occuring serotonin, while still leaving intact other regulatory mechanisms which prevent an individual from getting too much serotonin. Currently, this class includes fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), and citalopram (Celexa). The few side effects these medications do have are the result of increased serotonin transmission in other parts of the body, especially the gastro-intestinal system, which is also a major site of serotonin activity.

No one really anticipated that SSRIs would have such a broad spectrum of activity, but once they were available for widespread use, it became apparent that many conditions previously considered intractable were readily treated with these agents. They are now considered the first-line treatment of choice for Major Depressive Disorder, Dysthymic Disorder, Pre-Menstrual Syndrome, Post-Partum Depression, Panic Disorder, Social Phobia, OCD, Post-Traumatic Stress Disorder, Body Dysmorphic Disorder, Bulimia, Compulsive Overeating (Binge Eating Disorder), a variety of paraphilias (fetishes), and disorders of impulse control such as Kleptomania, Pathological Gambling, Trichotillomania (compulsive hair-pulling), and Onychophagia (compulsive nail-biting). This is not to imply that a simple trial of an SSRI will be 100% effective in every patient with any of these conditions: some people have no response at all, and many obtain varying degrees of partial response. But before SSRIs were available, many people did not achieve any benefit at all from pharmacologic therapies, leading many experts to believe that some disorders were simply not treatable with medications. These new medications have changed our whole view of what is treatable and what is not.

One condition which we now see as treatable is the repetitive/stereotypic/perseverative behavior associated with developmental disorders; this problem is certainly seen in the majority of individuals with Fragile X syndrome. These behaviors are considered to be a variant of Obsessive- Compulsive Disorder, the primary distinction being that an obsession (strictly speaking) must be perceived as unpleasant or intrusive, whereas Fragile X individuals often derive much enjoyment from their "obsessions" and their “compulsive” behaviors. In either case the symptoms can be significantly alleviated by antidepressant medications with sufficient serotonergic activity.
As noted previously, aggressive behavior is another symptom of Fragile X which had always been though of as relatively refractory to treatment, and this continues to be one of the main reasons for Fragile X men to be institutionalized. SSRIs can make a dramatic difference in the quality of life of older Fragile X individuals by decreasing the frequency of episodic dyscontrol or "catastrophic reactions" (in many cases eliminating them altogether).

While this news is encouraging, the best may be yet to come. There has been a flurry of interest in development of new antidepressants which has resulted in a large number of novel compounds coming to the market in the last few years. Venlafaxine is a powerful new medication which not only duplicates the mechanism of action of clomipramine without its overwhelming side effects, but also shows great promise as a treatment for ADHD--making it potentially ideal as a treatment for Fragile X. Nefazodone is an improved version of trazodone which provides an immediate calming effect without excessive sedation; not only is this medication potentially useful for treatment of anxiety and agitation, but its selective blockade of the 5-HT2 subclass of serotonin receptor may afford it particularly potent antiaggressive effects. Furthermore, nefazodone does not appear to cause excessive activation in children (at least not very often), giving it a potential advantage over SSRIs.

In addition to the new medications reviewed in this publication, many compounds are being actively investigated which offer even "cleaner" action, for example working only in the brain or a certain part of it, or working only on one subclass of receptor, rather than mimicking all the actions of a particular neurotransmitter. This is certain to benefit individuals with Fragile X, given the obvious involvement of mood-regulating mechanisms in this disorder.

A number of ominous warnings have been issued by regulatory agencies in the US and Europe concerning potential emergence of suicidal behavior in children treated with SSRIs; this has naturally caused alarm and prompted many questions within the Fragile X community concerning the safety of these widely used medications. Since suicidal behavior is quite rare overall in Fragile X individuals---and none has been reported in association with SSRI treatment, this does not appear to translate directly to treatment of Fragile X. However, this effect may be similar to the excessive activation and increased hyperactivity which is frequently reported in children with Fragile X who are treated with SSRIs. In any case, treatment should never be discontinued or altered based on press reports---always consult with your doctor first if there is any question about the safety of ongoing treatment.

Update 2009: The safety and usefulness of SSRIs in people of all ages with fragile X seems beyond question at this point---no medically significant adverse effects have been described in fragile X patients, other than simple allergic reactions. There are no known cases of suicidal (or homicidal) behavior in anyone with fragile X associated with the use of this drug class. However, the issue of activation continues to present the greatest challenge in the use of this class of medications in children with fragile X; if anything, the sensitivity of younger children to the activating effects of SSRIs was underestimated by most early studies. Prepubertal fragile X children seem to be especially sensitive to this side effect, and their typical hyperactivity can be aggravated by this side effect. Starting at a low dose and increasing gradually, as tolerated, still seems to be the best (perhaps only) way to deal with this problem. This may limit the dose which can be utilized in any given case.

Older children and adults with fragile X appear to be much less sensitive to SSRI-induced activation, and can usually tolerate quite high doses of SSRIs in the “anti-obsessional” range (often 2-3 times the typical dose for depression.)

As a class, SSRIs are still enormously useful in treating the anxiety, irritability, aggression, and obsessive-compulsive behaviors so commonly seen in fragile X. This class is also a mainstay of treatment for autism spectrum disorders generally, and fluoxetine is likely to be approved by the FDA for the treatment of autism in the near future.


These medications are designed to counteract the effects of the sympathetic nervous system (lytic means "that which dissolves or severs") by various neurochemical means. While they are all marketed as treatments for high blood pressure, this effect is of benefit to many individuals with Fragile X who suffer from troublesome hyperarousal or "overstimulation", which may result in hyperactivity, anxiety, mood lability, or even aggression. These agents are broadly divided into two classes: those which act primarily in the brain to decrease "sympathetic outflow", and thereby the release of adrenalin in the general circulation (alpha2 agonists); and those which act primarily in the periphery to block the receptors for adrenalin (beta blockers).

Clonidine is the prototype of the alpha2 agonists, and is one of the most commonly prescribed medications for children with Fragile X. There are other medications in this class which might be potentially useful for treatment of hyperactivity and hyperarousal, but so far only one other, guanfacine has actually been used on any widespead basis. While there is far more experience using clonidine in children, guanfacine is being used more and more by child psychiatrists for ADHD in the general population and hyperactivity in the developmentally disabled population because it is generally less sedating and somewhat longer acting.

Propranolol is the prototype of the beta blockers, but dozens more have been introduced over the last two decades. Atenolol, pindolol, and nadolol have all been used in child and adult psychiatry, but the differences between them are rather minimal. Beta blockers have not been reported to be especially effective in adult psychiatry, and several studies have actually demostrated a lack of efficacy compared to placebo in treating various anxiety disorders; thus, most adult psychiatrists consider them ineffective as psychotropics, with only two specific exceptions. Beta blockers do seem to help some people cope with performance anxiety (such as stage fright or public speaking phobia) by minimizing the "jitters" and "butterflies in the stomach" caused by circulating adrenaline. However, these medications have little or no effect on the brain, and most forms of anxiety involve central mechanisms, not just circulating adrenaline; therefore, the major part of anxiety is unaffected in most cases (including Fragile X). The second exception is that pindolol has been reported to block presynaptic 5-HT1A receptors which normally provide feedback inhibition of serotonin release. This would otherwise be considered a side effect, but it may be clinically useful as a way of speeding up the response to serotonergic antidepressants. It is unclear at this stage whether other beta blockers share this property, but pindolol might be recommended as a way to enhance the effect of an SSRI.

Child psychiatrists have a somewhat different view of beta blockers, and tend to prescribe them more frequently. Several small studies have suggested that these medications may be helpful in treating some forms of anxiety in childhood, but no comparative studies have been done. Based on personal experience and thorough review of the literature, this author cannot recommend beta blockers as a first-line treatment of anxiety disorders in any patient, especially one with Fragile X-- these medications, by themselves, simply are not very effective and not as benign as many people consider them to be (especially at the heroic doses sometimes used).

The case for beta blockers is somewhat stronger in the treatment of aggression, where many studies have reflected positively on these agents. However, their effect appears rather weak compared to other medications now available, such as anticonvulsants, SSRIs, and buspirone. Therefore, propranolol is reviewed here for its potential use as a treatment of aggressive behavior in Fragile X; other beta blockers are too numerous to review individually, but can be considered essentially equivalent.

Mood Stabilizers

This class of medications varies widely from a biochemical perspective; these medications work in very different ways. However, they all have one thing in common: they tend to stabilize moods and decrease affective lability. Most of the clinical experience in the use of these agents has occurred in the treatment of Bipolar Disorder (Manic-Depressive Illness), the best known psychiatric condition involving affective lability, but they have also been used extensively in the developmentally disabled population for many years, with generally good results. In the treatment of Fragile X, these drugs are not entirely equivalent, and should not be considered interchangeable; special uses and contraindications will be noted.

Lithium was the first medication discovered with significant mood stabilizing properties, and has been the mainstay of treatment for Bipolar Disorder for more than 20 years. It requires careful monitoring, including blood levels and thyroid and renal function testing at regular intervals, since it can be quite toxic at doses only slighlty higher than the therapeutic range. While it can be lifesaving for many Bipolar patients, results in most developmental disorders are often underwhelming. It generally seems to work best for those individuals with less frequent, classic manic and depressive episodes. In most cases of "rapid cycling" mood swings, where affect is extremely unstable, lithium is ineffective. This may explain why individuals with developmental disorders such as Fragile X, who typically have very unstable moods, do not appear to benefit from lithium therapy. It is also quite rare to find physicians other than psychiatrists who are willing to prescribe lithium, given the involved nature of its use; so, many Fragile X individuals treated by neurologists or pediatricians are unlikely to even be considered for lithium treatment in the first place.

Carbamazepine, marketed as an anticonvulsant (and a particularly effective one, too), has been used a great deal over the past 10 years in psychiatry as a treatment for Bipolar Disorder. It seems to be more effective than lithium in cases of rapid cycling mood disorders of all kinds; it can be combined with lithium for even greater effect, and many of the side effects of the two cancel each other out. When it was introduced, carbamazepine was thought to have a relatively high incidence of agranulocytosis and aplastic anemia, often fatal suppression of white and red blood cell production, respectively. For that reason, weekly monitoring of drug levels and blood counts was recommended, causing quite a few people significant expense and inconvenience. However, follow-up studies have shown that these events are actually quite rare (about 1 in 100,000), so blood tests are now required much less frequently. Not only has carbamazepine been shown to be an effective mood stabilizer, it has been demonstrated to decrease the frequency of behavioral dyscontrol in many different patient populations, and it widely used as a treatment for aggression and impulsivity in the developmentally disabled.

Valproic acid is also a commonly prescribed anticonvulsant with a chemical structure and mechanism of action completely different from carbamazepine. It has more recently come into favor among psychiatrists as a treatment for mood disorders, and a number of studies supporting its therapeutic efficacy have already been published, with many more under way. It has also been used safely in children for many years, though the range of experience in different patient populations, especially the developmentally disabled, is more limited than with carbamazepine. It can rarely (approx. 1 in 50,000) cause fatal liver toxicity, so monitoring of serum drug levels and liver function tests must be done at about the same frequency as monitoring of carbamazepine.

Clonazepam is a benzodiazepine marketed as an anticonvulsant, but rarely used for that purpose. It, too, has been used in Bipolar Disorder to stabilize moods (especially to treat mania), though its therapeutic effect is generally considered relatively weak compared to lithium and the anticonvulsants. Most of the clonazepam prescribed in the US is for treatment of anxiety, especially Panic Disorder. For the general population, this is an excellent treatment--long acting and very potent in suppressing panic attacks and anticipatory anxiety. However, this medication causes some degree of mental slowing and motor incoordination in most people who take it. This is not usually a problem for the average person at therapeutic doses, and typically goes unnoticed. For Fragile X individuals it often causes more cognitive and motor impairment at therapeutic doses; it can also cause "behavioral disinhibition", or a worsening of behavioral problems--just the opposite of the desired effect--making this a risky treatment from a behavioral standpoint. Fortunately, clonazepam is nontoxic, so a trial involves no medical risk.

Risperidone is a new and revolutionary medication in many ways. It is considered an "atypical antipsychotic", but it bears little resemblance to the old "conventional antipsychotics". It has fewer side effects and is far safer than medications like thioridazine (see review); it has been rigorously demonstrated to treat many symptoms poorly responsive to conventional antipsychotics.
In addition, it is reported to have significant mood stabilizing properties, and is being used in increasing frequency to treat behavioral disturbances associated with developmental disorders. It appears promising as a treatment for agitation and aggression without overwhelming sedation in a wide variety of disorders. However, it has not been around for long, so experience is quite limited-- though all the experience thus far is good. A major disadvantage of risperidone at this time is that it is extremely expensive--anywhere from $2-10 per day, depending on the dose, although most insurance plans will cover it because of its superior safety and efficacy.

In most cases, the anticonvulsants, carbamazepine and valproic acid, will be the first choices as mood stabilizers for Fragile X individuals. Some of the time, a given individual will require an anticonvulsant anyway for treatment of a seizure disorder, and if this is the case it is important to realize that not all anticonvulsants have these same mood stabilizing properties. In particular, phenytoin (Dilantin) and phenobarbital (Luminal) are devoid of mood stabilizing effects, and phenobarbital may even exacerbate affective lability and should be avoided. It would be conservative and sensible to use an anticonvulsant with mood stabilizing effects in any Fragile X child who requires treatment for a seizure disorder. Clonazepam is probably only useful at low doses for Fragile X individuals with extreme anxiety and good cognitive functioning, including many girls with Fragile X. Risperidone may be especially effective in Fragile X individuals with severe agitation and aggressive behavior which is otherwise difficult to control.

Medication Reference Guide
Appendix A: Anxiety and Depression in Parents of Fragile X Children

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