ADHD in adults is very responsive to pharmacotherapy; however, treatment strategies for the disorder have not been as well established as they have for children. In this paper we will discuss our clinical experience in treating adults with ADHD, in hopes that others will benefit from the years of trial and error.

The challenge to treating the ADHD adult is finding the drug or combination of drugs that work for the individual. Zametkin et al. (1990) found evidence of hypometabolism of the brains of ADHD adults as compared with matched controls, and the constellation of symptoms found in the individual with ADHD, particularly the distractibility and motor hyperactivity, may be explained by these differences. A useful metaphor for ADHD that we have adopted, supported in part by Zametkin's findings, may be the problem of underactivity in the frontal lobes.

The frontal lobes are thought to be mainly inhibitory and integrative in function, thus hypoactivity may translate phenomenologicaily into problems with inhibition and control in ADHD patients-problems with stopping the flow of attention, thoughts, emotions, movements, ideas. The precise pathophysiology of ADHD, however, has yet to be determined, and the inconsistent results of research and clinical drug trials indicate that ADHD is not of homogeneous neurochemical or anatomical origin. It is thus difficult to predict to which drug an individual will best respond. The clinician and the patient should try several medications at carefully adjusted doses until the individual's optimal response is found and side effects are minimized. There's no cookbook recipe and no cure for ADHD, however the positive effect of the right drug or the right combination of medications is often life changing for the patient and for those affected by the patient.

ANTIDEPRESSANTS
Research and clinical experience have shown that the antidepressants Norpramin (desipramine) and Tofranil (imipranine) effectively increase attentiveness and reduce distractibility in children and adults. Tricyclic antidepressants exert their effect by acting upon norepinephrine and dopamine, the two major neurotransmitters in the attention system. They block the re-uptake of norepinephrine and dopamine into the presynaptic neuron and indirectly modify the rate of release, thus increase the activity of these two chemicals in the brain (McCracken, 1991).

In our clinical experience, 40% or more of ADHD adults respond to between 5 mg/day and 40 mg/day of Norpramin. This dose range is considerably lower than that reported in current research reports (Biederman et al, 1985; Biederman, 1988). We see the return to the use of low doses as a significant contribution to the practice of pharmacotherapy for ADHD because we have found the most dramatic responses at low dose levels. Furthermore, most of our patients report that the positive effect experienced at a very low dose range is often lost as the dose is increased. In the mid 1960's, Rapoport reported that the majority of children with "behavior problems" he studied showed marked improvement on 10 mg/day of Tofranil; in fact, a number responded most dramatically to 5 mg/day, and were maintained at that dose without a waning of response (Rapoport, 1965).

As experience with antidepressants accumulated, researchers and clinicians became aware that large doses and therapeutic blood levels of antidepressants were useful in treating refractory depression. This conflicted, buried, and colored the early experience of using lower doses for anxiety, panic and especially for ADHD. The rapid time frame for drug effect in ADHD patients, however, suggests that tricyclics have a different mechanism of action in ADHD than they do in depression. It makes sense, then, that the therapeutic dose range for ADHD would be different. In clinical practice the superior efficacy of low doses has been documented throughout the years (Heussy, 1983, 1989, 1992; Bellak et al., 1987). In fact, Heussy has contended that there is a 90% chance individuals with ADHD will have a positive response to a low dose of tricyclics, which is between 1/10 to 1/3 of the dose used for depression.

We typically start people on 10 mg/day for a week to 10 days to see if there is any improvement in the individual's ability to sustain attention and regulate mood, and then proceed to raise the dose to 20 or 30 mg/day if there is little or no response. We have found that Norpramin not only increases the ability to direct and maintain attention, but also can have a calming effect on the individual. It can decrease impulsive behavior, stop temper tantrums, regulate frequent mood shifts and increase reading and learning abilities. Norpramin also effectively treats the "mini panic state" to which so many individuals with ADHD are prone. This state begins as a startle response when the individual is flooded with stimulation, and develops into a full blown feeling of panic which predisposes the individual towards impulsive action, defense rumination or the repetition of trauma experiences. This is a particularly salient problem for ADHD adults, whose tolerance for stimulation is lowered because they have spent most of their lives trying to sustain focus over an inner state of chaos and turbulence.

The effect of the antidepressant in treating ADHD symptoms, especially the mood instability, mini panic episodes, fuzziness of the environment, and the chronic state of disorganization can be sometimes altered with the first dose of medication. In others the effect can be subtle and gradual. These changes can be very exciting for people who have struggled with these symptoms for their entire life. Often patients will call the clinician proclaiming Norpramin to be a "miracle drug." Both the patient and physician should be skeptical of this effect until they see positive markers of change in the patients life such as higher tests scores and assignments completed in class for adolescents and young adults; projects done on time, punctuality in meetings, checkbooks balanced, tantrums a distant memory, and loved ones finding a new attentive, intimate being for adults. The use of low doses also protects against the adverse effects on memory and learning that is seen at higher doses.

Another antidepressant that is currently popular among clinicians treating adult ADHD is Wellbutrin (buproprion), which is a potent dopamine re-uptake inhibitor. Research reports have attested to the moderate efficacy of this agent (Wender and Reimhen; 1940).

STIMULANTS
If response to antidepressants is not apparent or begins to wane within 4-6 weeks, we would try psychostimulants such as Ritalin (methylphenidate), Dexedrine (amphetamine), and Cylert (pemoline). The calming effect of these agents in hyperactive children is paradoxical, but advances in the understanding of how these drugs work have provided insight into their clinical effect. These drugs potently increase the concentration and activity of both dopamine and norepinephrine, and thus possibly enhance activity and inhibition in the brain. According to some reports, Ritalin and Dexedrine increase attentiveness, reduce distractibility, enhance concentration, and decrease motor restlessness and hyperactivity in roughly 70% of adults with ADD (Barkley, 1977).

We would typically begin by starting Ritalin at 5 mg twice daily, then increase the dose upward, with most people ending at a dose between 30-40 mg/day. Many people find adequate calming and attention enhancing effects at lower doses (10-30 mg/day). This response can be immediate, and often dramatic. If the individual does not respond to Ritalin we switch to Dexedrine. It is crucial to note that Ritalin and Dexedrine, while widely regarded as very similar drugs, are not. They have a different pharmacological profile, a different mechanism of action at the cellular level, and a not so subtly different effect on patients. The two drugs act upon separate neurotransmitter storage pools. For instance, Ritalin is a more potent re-uptake blocker of dopamine, while Dexedrine may exert some of its effect through feedback inhibition (Zametkin et al, 1985). We have found that when Dexedrine is successfully tried on people who have had an unsatisfactory trial of Ritalin, they report that the Dexedrine is a "softer drug." Some patients feel Dexedrine is enormously beneficial in alerting their brain to activity without causing them to feel somatically driven, as compared to Ritalin which sometimes makes patients feel like their body is in "overdrive." One patient described Dexedrine as a "caffeine-less" Ritalin. Most clinicians, however, use Dexedrine as the second or third choice stimulant because of its reputation in the drug abusing community.

Side effects with the psychostimulants on the whole are low as compared to other psychoactive agents that psychiatrists and neurologists use. Major complaints involve appetite suppression, insomnia or multiple varieties of sleep disturbance such as waking up in middle of the night and interference with dreams. Ten percent of patients on Ritalin complain of headaches, and the clinician must watch blood pressure and pulse when either psychostimulant is used. A more important issue in prescribing psychostimulants is the difficulty in achieving a therapeutic dose of medication. Sometimes a patient needs very little medication, for instance we have those in our practice who find that as little as 1/4 mg Ritalin or Dexedrine a few times a day provides them with the necessary enhancement of focusing ability. Others need much higher doses to sustain an effect, and require levels well beyond the recommended upper limit of 60 mg/day of Ritalin.

Gittleman-Klein has stated that the most commonly made error in the treatment of ADHD is inadequate dosing (Gittleman-Klein, 1987). This is most likely due to habit, worry about addiction, or a cognitive commitment to a cookbook dogma that deflates the role of the patient's report as the primary measure of drug response. For these individuals there is the problem of maintaining an adequate dose of medication. The drug is available in 5 mg tablets, and adults may need 20 mg per dose to get a calming, focusing effect, and this lasts only 3-4 hours. For many people there is a limit to the number of pills that one can take or will remember to take. We sometimes use a slow release stimulant to counter this problem particularly in individuals who are likely to forget to take a 2nd or 3rd dose of medication; however, it has been our observation that Cylert generally does not induce as dramatic results as Ritalin or Dexedrine. Dexedrine slow release, which is available in 10 mg spansules, seems to be more effective than slow release Ritalin. It would be wonderful to have a long acting stimulant, but currently there is not a clinically efficacious one available.

Scientists have discovered a way to chemically purify Ritalin into a more effective drug with fewer side effects; however, the development of this specifically targeted drug is pending funding (Jaffe, 1992). Another frequently encountered problem in prescribing psychostimulants is negotiating with pharmacists. There is a persistent dark cloud hanging over the use of stimulants because of their tarnished history as drugs of abuse. Even in the most enlightened states it is difficult to prescribe psychostimulants for adults due to the prevailing myths that ADHD is 1) not a disorder but merely moral corruptness and 2) something that disappears in adolescence. It is thus often thought that adults who are taking prescription psychostimulants are simply looking for their next high. In many cases, the physician must call the pharmacy before the drug will be dispensed.

This brings up the issue frequently faced by mental health professionals, parents, and concerned others of whether it is wise to use stimulant medication in individuals with a history of drug or alcohol abuse. This is fraught with anxiety on everyone's part; however it has been our experience that an adult with history of drug and/or alcohol abuse who has been diagnosed with ADHD and is committed to changing his/her life will not use the medication in an illegal or abusive fashion. This obviously presupposes a very strong therapeutic relationship with the prescribed as well as with other involved mental health professionals. Furthermore, Huessey has written that no cases of psychostimulant abuse in ADHD adolescents have been reported because the drugs are not used to "tune out" of the environment as are most recreational drugs, but to "tune in" (Huessey, 1985).

OTHER AGENTS
It has been suggested that a number of other agents, such as fenfluramine, L-dopa, and amantadine, may be used to treat ADHD. These are possibly useful drugs where others fail, but neither research (Zametkin and Rapoport, 1987) nor clinical experience has shown these agents to be as effective as the psychostimulants and tricyclic antidepressants. These drugs should be tried as a last resort in the rare case of a treatment failure to the latter agents.

ADJUNCTS
While treatment with stimulants and tricyclics are extremely effective in enhancing concentration and attention, they often cannot sufficiently ameliorate the concomitant impulsivity, explosiveness, and irritability experienced by many ADHD adults. There are many adjunct medications that can be added to the treatment regimen to help with these symptoms.

Beta-blockers can be used to decrease anxiety and tension. They also reduce hyper-responsiveness to stimulation, and the agitation that predisposes many ADHD adults to impulsive behavior and tantrums. Corgard (nadolol) is preferable to Inderal (propranol) because it can be taken once a day and it mainly has a peripheral mechanism of action, therefore reduces the chronic somatic tension, hyperarousal, and impulsivity without interfering with the effects of other medications. Lithium, Depakote (valproate), and Tegretol (carbamazepine) can also be very useful adjuncts in violent and difficult to manage individuals, especially in those whose behavior is secondary to extreme fluctuations of mood.

Another drug that is often useful as an adjunctive treatment for ADHD is Clonidine, an agent which alters alpha-adrenergic functioning (Hunt, 1987). Clonidine is especially helpful in increasing calmness and frustration tolerance, particularly in a patient who cannot take beta-blockers because of a past history of asthma. Clonidine may also enhance the efficacy of a stimulant at the receptor level (Hunt, 1985), thus enabling the clinician to lower the stimulant dose. Clonidine's use in adults, however, can be complicated because of its tendency to induce somnolence.

An extremely common concurrent complaint in ADHD adults is that of depression and irritability, particularly in ADHD women who suffer from PMS. It seems no matter how effective the stimulants or tricyclics are in increasing the ability to focus, symptoms in these individuals fluctuate with the monthly variations in mood. These symptoms respond very well to the serotonergic agents BuSpar (buspirone) and Prozac (fluoxetine). The improvement gained with the addition of these drugs to the treatment regimen of individuals prone to irritability and depression is often dramatic. We typically start patients on standard doses, 10 mg/T.I.D., of Buspar or 20 mg q AM of Prozac for an entire month until symptoms have been obliterated, then switch to an attempt to use medication only 2 weeks of the month. Prozac can also reduce the obsessive/compulsive symptoms some patients develop in response to their ADHD. We have not found traditional doses of Anafranil (clomipramine) to be useful in adults with ADHD.

It is important to note that none of the drugs used as adjuncts induce cognitive impairment. This is crucial because as the ability to remember, learn, organize, and relate all tend to be impaired in ADHD adults, the enhancement of these functions is an important aspect of treatment.

THE MYTH THAT THE DOCTOR KNOWS ALL
In assessing an individual's response to a particular medication or dose, the best advice we have is to listen carefully to the patient because their feelings are more accurate gages of drug efficacy than are so-called objective scales or doctor's impressions. This can be complicated because many ADHD adults are poor observers of their own activity, and have difficulty with retrospective assessments of their behavior or mood state. It is also helpful to enlist the help of other observers such as spouses, friends, and coworkers, as these people are often the most sensitive to changes in ADHD adults once treatment has begun.

The treating clinician should also be aware that there are a few patients among ADHD adults, perhaps 1 in 10, who have extremely sensitive brains. There are many possible causes of this hypersensitivity, such as a history of brain injury, premature delivery or birth trauma. It is important that this reaction not be interpreted as resistance, a negative therapeutic reaction, or passive-aggression. We have seen a number of individuals for whom even 10 mg of antidepressant or 5 mg of methylphenidate is far too much. Unfortunately for some of these patients there is not a dose low enough: even if they chop off tiny pieces of medication, they still have too many side effects. In these cases, both the clinician and patient are left in a quandary without medication as a treatment option.