New Medications for Adults with AD/HD
Revised July 2006
Carol E. Watkins, M.D.
|It has long appeared that the medication situation for AD/HD was reversed from that of other psychiatric conditions. For other conditions, psychiatrists who treated children and adolescents had relatively fewer medications that had actually been tested on children. We had to extrapolate from adult data, make do with fewer medications, and base our prescribing practices on less research data. Child psychopharmacology seemed like the stepchild of adult psychopharmacology. The exception was AD/HD. This was the condition child psychiatrists could call their own. Although medication choices were still more limited than they are today, clinicians still had more information on how the medications affected AD/HD children than they did on how the same medications affected adults. The tables were turned. The adults were the ones with less data and fewer medication options. It used to be quite controversial to give stimulant medication to older adolescents, let alone adults. However, some adults did get stimulant medication for AD/HD. Usually it involved adolescents who simply continued treatmrnt after they turned 18. Second opinions or special permission from the Drug Enforcement Agency were necessary if one wanted to prescribe stimulants to an adult with AD/HD. Tricyclic antidepressants could be a less controversial choice.
Over the past 10-15 years, it has become easier and less controversial to diagnose and treat adult AD/HD. Medication options have expanded, but stimulant medications, usually methylphenidate (Ritalin) and dextroamphetamine compounds (Dextrostat, Dexedrine Spansules and Adderall) are still a frequent starting place in the pharmacological treatment of AD/HD.
Adults and children may have different medical considerations:
Although there is still more information on pediatric AD/HD, there is an emerging body of knowledge specific to medication for adult AD/HD. Many of the medications are the same as those used for children and adolescents. However, when treating adults, there are several general differences to consider. Although adults are generally larger, their liver and kidney function may not be as robust as children. Thus an adult may need less of a particular medication per pound of body weight. A given dose of medication may hang around longer in the adult’s system.
Adults are more likely to be taking medications for other medical conditions such as high blood pressure or diabetes. These may interact with the AD/HD medication. Conversely, some of these other medications may cause inattention and thus exacerbate or mimic AD/HD. For example, a clinician from another state referred me a patient with possible AD/HD. It turned out that an anxiety disorder, along with two medications she was taking, caused her inattention.
Polypharmacy, (prescribing several psychiatric medications at the same time) has become more common. Adult AD/HD by itself often requires more than one medication to control all of the AD/HD symptoms. If the individual has another disorder, such as depression, one may need to medicate this too. I have mixed feelings about the trend towards polypharmacy. When done carefully and systematically, it can bring relief to individuals who have experienced distressing symptoms. However, if done in a rapid or cavalier fashion, it can lead to medical side effects, or it can exacerbate the very symptoms it was meant to treat.
The stimulants, including methylphenidate (Ritalin) and amphetamine (Dexedrine and others) along with some tricyclics (such as Desipramine), have demonstrated efficacy in the treatment of adult and childhood AD/HD. The stimulants have a 60 to 80% response rate. However, some individuals respond partially or not at all. Others develop uncomfortable side effects. Atomoxetine (see below) is a non-stimulant medication approved for the treatment of AD/HD Currently we have several second-line medications (not FDA approved for AD/HD), but we need more medication choices. We also need more high-quality research, particularly in how adults with AD/HD respond to pharmacological treatment. The following is a brief overview of some of the emerging developments in the field.
Current Second and Third-Line Medications: Alpha agonists, bupropion, (Wellbutrin) and the tricyclic antidepressants. Other medications often used for comorbid disorders or ADHD-related symptoms: SSRIs (eg. Prozac, Zoloft and others) mood stabilizers (Lithium, Depakote, Tegretol) and the atypical antipsychotics.
Slow Release Methylphenidate
Methylphenidate (Ritalin) is a short-acting drug. It can be difficult to remember several doses per day.
Ritalin SR, one of the older slow-release stimulants, often seems to show inconsistent results. It comes in 20mg pills and cannot be split into smaller fragments. The duration of effects may not always be consistent. Metadate-ER manufactured by Celltech, was released in 10mg and 20mg sizes. Metadate-ER is similar to Ritalin-SR. The active component, methylphenidate, is in a wax-like matrix that releases the drug over time. It lasts about 4-8 hours.
Metadate CD: Released by Celltech in 2001, uses a delivery system called Diffucaps. more recently released which uses a different delivery system. Its peak effect is generally around 5 hours and its effect lasts 8 hours. Metadate CD capsules contain two types of beads. About 30% of the medication is released immediately. The remainder is released over time through beads with a release-control membrane. If the individual cannot swallow the capsule, one can open the capsule and sprinkle the beads on food. The medication has a first peak at about 1.5 hours and a second, larger peak at about 4.5 hours after ingestion.
Ritalin LA: Released in 2002 by Novartis (the makers of brand name Ritalin) this medication is a capsule in which 50% of the beads release the methylphenidate immediately and 50% are released abour four hours later. As compared to Concerta and Metadate CD, this medication gives a stronger earlier dose and relatively less medication in the afternoon. the duration of efficacy is about 6-8 hours.
Concerta (McNeil Pharmaceuticals) is a form of Methylphenidate that uses an osmotic system to deliver methylphenidate in a pulsed pattern. This allows a 12 hour response from a single daily dose. It may prove to be more reliable than Ritalin-SR. Concerta was released in August 2000. The osmotic “oros” system has been used successfully for several years for a diabetes medication and a bladder control medication. With Concerta, the methylphenidate level does not rise as fast as it would with Metadate CD, but the Concerta lasts longer than Metadate CD or Ritalin SR. Drug studies suggest that its duration of action is 12 hours, but I have seen a number of patients who seem to get a shorter duration of effect at all dosage levels.
Focalin and Focalin XR: Novartis, the manufacturer of brand name Ritalin, has released a non-racemic form of methylphenidate. Other forms of methylphenidate such as Concerta and Metadate are mixtures of two mirror images (isomers) of the methylphenidate molecule. The body may metabolize the dextro (right handed) form of a compound differently from its mirror image the levo (left handed) form. In the case of methylphenidate, the dextro isomer is the active componentactive and the levo isomer you switch from regular methylphenidate to Focalin, you start with half as much Focalin.
Daytrana: Shire released a skin patch form of methylphenidate. The FDA has only approved its use in children aged 6-12. It’s commercial release was delayed because of FDA safety concerns but after extended testing was done the FDA gave its approval. There are some theoretical concerns about skin sensitization. I would recommend that adults defer using this medication until there is further testing in other age groups. For more information on this medication, see our article on Daytrana.
Slow Release amphetamines:
Dexedrine Spansules, a long-acting form of d-amphetamine, has been on the market for years. It has a peak effect in 1-4 hours and lasts 6-10 hours. It tends to have a more gradual tapering and thus may have less of a rebound effect. Adderall is a mixture of four salts of d-amphetamine combined with a smaller amount of the less active r-amphetamine. Some clinicians felt that Adderall had a longer duration of action than regular d-amphetamine. However, there are as of yet, no published studies showing that it lasts any longer than short-acting d-amphetamine. Thus we cannot really classify regular Adderall as a long-acting stimulant.
Adderall XR: In 2001, Shire, the manufacturer of Adderall, released Adderall XR. In this formulation, the Adderall is encapsulated in coated beads inside of a capsule. Half of the beads dissolve immediately, and the other half dissolve about 4-6 hours later. There are, as yet, no published studies comparing Adderall XR to the less expensive Dexedrine Spansules. However some patients appear to do better on Adderall XR with its d and r-dextroamphetamine combination. Others do better on Dexedrine Spansules–the all d-amphetamine compound.
SPD465 Shire Pharmaceuticals is working an a compound with the same active ingredient as Adderall (mixed salts amphetamine) which will last 16 hours. It will be marketed for adults and children.
NRP104 New River Pharmaceuticals is developing a medication which would be marketed by Shire Pharmaceuticals. (lisdexamfetamine dimesylate) D-Amphetamine is bonded to l-lyseine, an amino acid. The drug is not active until it is converted into d-amphetamine in the body. Early results suggest that ti has a lower abuse liability than do the other amphetamines. The peak effect is later than that of regular d-amphetamine and it appears less likely to cause euphoria.
Generic methylphenidate or d-amphetamine are fairly inexpensive. However, many of the longer acting stimulants can be quite expensive for those without a good pharmacy plan.
Non Stimulant Medications
Atomoxetine (Strattera, from Lilly Pharmaceuticals), was approved by the FDA for distribution in November 2002. It became available in US pharmacies in early 2003. Despite its hefty price tag, it is becoming widely used for adults and children with Attention Deficit Hyperactivity Disorder. (AD/HD) It is a non-stimulant medication approved for the treatment of AD/HD in both children and adults. It was the first medication that the FDA specifically approved for the treatment of ADHD in adults. Atomoxetine is a selective norepinephrine reuptake inhibitor. This means that it strengthens the chemical signal between those nerves that use norepinephrine to send messages. Atomoxetine does not appear to affect the dopamine systems as directly as do the stimulants. It is often prescribed once per day, but those who have trouble with gastrointestinal upset, can take a smaller dose twice a day. Common side effects are headache, abdominal pain, nausea, vomiting, weight loss anxiety, sleepiness and insomnia. It can also interfere with sexual performance in adults. It appeared to cause less insomnia and appetite suppression than methylphenidate. However it may cause a higher incidence of sleepiness and vomiting than methylphenidate. It is most commonly administered once a day. The clinical effect appears to last all day and even into the next morning. I sometimes prescribe it twice a day to minimize the nausea. It can be quite helpful to those who cannot tolerate stimulants. However, some patients say that it does not give as strong an effect as what they get from the stimulants. See our expanded article on Atomoxetine
Modafinil (Provigil) has been approved for treatment of narcolepsy in adults. It is chemically unrelated to methylphenidate or amphetamine. When compared to methylphenidate and amphetamine, it seems less likely to cause irritability and jitteriness. It appears to act on the frontal cortex and is more selective in its area of action than the traditional stimulants. Cephalon In studies of adults with ADHD, there was a small, promising study suggesting that it might be effective for adults with ADHD. However a larger study sponsored by Cephalon indicated that Modafinil was no more effective than placebo. Some of their studies suggested a positive effect on children when larger doses are used. In the summer of 2006, the FDA announced that it would not approve Modafinil for children with AD/HD. The FDA felt that the medicaiton did not show significant advantages over existing ADHD medications, and expressed concern about side effects in the higher doses necessary to effectively treat AD/HD.
Bupropion SR and XL (Wellbutrin) has been used to treat AD/HD for several years. A recent controlled study showed that it is effective in the treatment of AD/HD symptoms in adults. Its structure is chemically similar to amphetamine, but does not have the same abuse potential. It should not be used in individuals with bulimia or a seizure disorder. In my experience, it is not as powerful as the stimulants, but is useful for individuals who cannot tolerate stimulants or for whom a Schedule II drug is inadvisable.
Alpha-2A-adrenoceptor agonist: Clonidine (Catapress) and guanfacine (Tenex) have been used in adults for the contol of high blood pressure. However, they are also useful in AD/HD, particularly for those with tics, impulsivity or aggression. Like clonidine, guanfacine can reduce tics for individuals with Tourette Syndrome. Because of its sedating properties, clonidine is sometimes used to help people with ADHD fall asleep. Since both clonidine and guanfacine can affect blood pressure and heart rate, it is a good idea to monitor blood pressure and get an EKG to check the heart rhythm. There have been a few reports of sudden death in children associated with the stimulant/clonidine combination, but some researchers have questioned whether some of those deaths were truly related to the medication. Because cuanfacine lasts longer than clonidine, only one or two doses are needed each day. Recent research confirmed that it can be useful in children, especially the 30% who have difficulty tolerating stimulants. These medications can help all of the symptoms of AD/HD but often seem to help impulsivity motor hyperactivity and irritability more than attention. In some cases, clonidine or guanfacine is combined with a stimulant if the stimulant does not have enough effect on irritability and impulsivity. Shire Pharmaceuticals is working on a long-acting form of guanfacine (Connexyn) which it will market as a non-stimulant drug for ADHD for children aged 6-17 years.
Selegiline (Eldepryl) is a monoamine oxidase inhibitor used to treat symptoms of Parkinson’s Disease. If one uses low doses, it may not be necessary to follow the restrictive diet associated with its cousins, the antidepressants Parnate and Nardil. A small controlled study showed that children with severe AD/HD and co-morbid conditions, demonstrated improvement in learning and classroom behavior on 5 mg twice a day. However there have been mixed results in adults with AD/HD.
Effexor and Effexor-XR (venlafaxine) An open trial (not a controlled study) with adults suggested that it might be helpful for some adults with AD/HD. In an open, 5-week study of children and adolescents with AD/HD, some individuals showed an improvement in behavioral but not cognitive measures. Several experienced worsening of their AD/HD symptoms and 25% could not tolerate the medication due to side effects. It is a good idea to monitor blood pressure since some individuals on Effexor show a rise in blood pressure. Sudden discontinuation of Effexor may lead to nausea and vomiting.
Mood Stabilizers are traditionally used for Bipolar Disorder. (Manic Depressive Disorder) These medications include Lithium and several anticonvulsant (seizure) medications such as Depakote (valproate) Tegretol (carbamazepine) and others. There is debate among psychiatrists about the percentage of AD/HD individuals who also have Bipolar Disorder. Some see the mood swings as part of the AD/HD. Others see it as a sign of a separate, co-existing disorder. In either case, the mood stabilizers may be useful to help modulate irritability and rapid mood shifts. These medications require closer medical monitoring. Blood tests and sometimes an EKG may be required. If an adult appears to have both AD/HD and Bipolar Disorder, one often treats the Bipolar Disorder first and then treats the AD/HD. Individuals with both conditions have a significantly increased incidence of substance abuse. Since illegal drugs can have dangerous interactions with some prescribed medications, drug screens may be advisable.
Estrogen Supplementation Some women report that their AD/HD symptoms worsen in the premenstrual period and during the peri-menopausal years. Low or fluctuating levels of estrogen might lead to depressed mood or a worsening of one’s ADHD. Some women with and without AD/HD have reported improvement in memory and attention span after estrogen supplementation. A women who has hormone-related exacerbation of mood or attention span might benefit from a stimulant, estrogen supplementation, an SSRI or a combination of these medications. Since estrogen affects many systems in the body, each woman should review the risks and benefits with her gynecologist. More systematic research is needed. (See Pat Quinn’s article in Nov/Dec 2000 Attention Magazine. Recent data reported in this spring in JAMA from the WHMS study suggested that estrogen-progesterone supplementation might actually accelerate the progress of memory impairment and dementia in postmenopausal women. Information on the effect of estrogen alone (on women with hysterectomies) has not yet been released.
Nicotinic Analogues (Medications that act on some of the same brain receptors as nicotine.) Much of the work on the neurological basis for AD/HD has focused on the regulation of dopamine and noradrenergic neurotransmitters. However, there has been a suggestion that poor regulation of the nicotinic receptors may also be involved. Nicotine enhances dopaminergic neurotransmission. Individuals with AD/HD have an increased rate of cigarette smoking. A small study suggested that a transdermal nicotine patch improved AD/HD symptoms in ADHD adults. Studies may focus on more selective compounds in this category that produce an effect without the negative side effects of nicotine. (selective cholinergic channel activators.)
Pemoline (Cylert) The FDA has recommended that individuals who are still taking this medication be switched over to other treatments. This revised recommendation was made in response to several reported cases of liver failure.
Stimulant Medications: Duration of Action
Table adapted from Greenhill, Laurence, “Are New Stimulants Really Better?” AACAP Oct. 2001 Annual Meeting
See our article on Strattera (atomoxetine)
See our article on Daytrana (not FDA approved for adults)
Carol Watkins, M.D.
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