        
               PHARMACOTHERAPY FOR ADHD IN ADULTS
        
                               by
        
          John J. Ratey, M.D., Edward M. Hallowell, M.D. and
          Catherine L. Lereroni, B.A.
        
        
             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 phenomenologically into
        problems with inhibition and control in ADHD patients --
        problems with stopping the flow of attention, thoughts,
        emotions, movements, ideas.  The precise patho-physiology 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 neuro-chemical 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
        (imipramine) 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 considerable 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.  Further, 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 patient's
        life such as higher test 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 Reimherr, 1990).
        
        
        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 (Barkely, 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 the 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 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 a history of drug and/or
        alcohol abuse who has been diagnosed with ADHD 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 prescriber as
        well as with other involved mental health professionals. 
        Further, 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"
        (Huessy, 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 possible 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 hyperresponsiveness 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, Depakoate (valproate), and Tegretol
        (carbamazepine) can also be very useful adjuncts in violent
        and difficult to manage individuals, especially in those who
        behavior is secondary to extreme fluctuations of mood.
        
             Another drug that is often useful as an adjuctive 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 qAM 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 with ADHD adults, the
        enhancement of these functions is an important aspect or
        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 co-workers, 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 quandry without
        medication as a treatment option.
        
        
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