Attention Deficit Disorder, Irritability and Serotonin
1 A Neuromodulation
Vernon M Neppe MD, PhD
Educational Objectives
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To educate in the areas of attention
deficit hyperactivity disorder and irritability
in children and adolescents.
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To present early information
on the use of the azapirone compounds alone or
as adjunct in ADHD and
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To link aggression and ADHD with
the serotonin 1A receptor and show the limitations
of this approach.
Attention deficit hyperactivity disorder
(ADHD) patients often present with school or behavioral
problems linked with difficulty concentrating / distractibility
and an impulsivity manifesting often as irritability
and low frustration tolerance (3%-5% of children with
75%-90% males). Hyperactivity is marked in three quarters
of these patients. Subtle organic cerebral deficits
are common (a quarter). Biochemically psychostimulants
commonly diminish hyperactivity. Disputably up to
half such patients have emotional problems at home
sometimes secondary to the ADHD, leading to a heterogeneity
of diagnosis for the condition. A common scale for
measurement is the Connors Teacher and Parent Scale
particularly an abbreviated version, where the cutoff
score of 15 on 10 special items (each ordinally ranked
0 to 3) for ADHD is traditional.
Psychostimulants such as methyl-phenidate
(Ritalin) (Schedule 2) or pemoline (Cylert) (Sched
4) are the most common treatments for ADHD but are
not benign agents. Their mechanism is poorly understood,
linked with dopamine and "paradoxical" effects on
the reticular activating system. Dependence problems
may occur particularly in other family members. Poorly
controlled patients have received adjunctive or alternative
therapies to the psychostimulants such as tricyclic
antidepressant (e.g. imipramine, phenothiazines e.g.
thioridazine and clonidine) with limited success or
potential accentuation of side-effects.
A significant ADHD symptom that is
commonly poorly controlled with psychostimulants is
irritability. This suggests that at least in this
subpopulation a partially different biochemical mechanism
is involved. Exploration of aggression spectrum concepts
such as anger, aggression, hostility, irritability
and impulsivity are compromised by the general equivalent
use of these terms, measuring difficulties, lack of
research in the area and particularly no current diagnostic
framework for aggression in DSM 3R or DSM-IV, with
consequently no FDA approved drugs for aggression.
All treatments being therefore innovative psychopharmacotherapy.
Evidence exists for serotonin receptor
involvement in the aggression spectrum using animal
models and human studies (clinical and post-mortem).
The serotonin 1A receptor is promising using non-specific
models such as lithium carbonate, beta-adrenergic
blocking agents and benzodioxines. The only selective
group for serotonin 1A in therapeutic doses is the
azapirones. Animal models suggest the azapirones are
potent anti-aggressive agents. This should be via
their specific serotonin 1A partial agonist effects
at postsynaptic doses or specific full agonist effects
at the autoreceptor level in lower doses. The only
currently marketed azapirone is buspirone. Irritability
is an early target symptom of response with buspirone
in generalized anxiety disorder possibly implying
persistent low-dose effects. Moreover, buspirone improves
concentration.
Preliminary open experience
by Neppe suggests a biphasic dose effect for buspirone:
Low dose buspirone (5-25 mg per day) was effective
after a few days in alleviating irritability, anger
and hostility without associated significant anxiety
(N>50); higher doses such as 60-90 mg per day almost
immediately greatly relieved manic irritability, agitation,
restlessness and mood lability (N=12). This data requires
adequate controlled studies. Ratey's work is similar
but in mental retardates. McCormick, 1994 found 9/10
children improved in a short (2 weeks buspirone),
randomized double-blind crossover ADHD study of buspirone
alone in very low doses (5mg q8am and q11am on weekdays)
versus placebo, using the 10 point abbreviated Connors
rating scale.
In our large open pilot study in Reno,
Nevada led by Dr Zo Young, buspirone was hypothesized
to improve ADHD target symptoms such as irritability
and concentration (N=40). Children and adolescents
(aged 5-15 years at entry and mainly males) in DSM3R
ADHD patients with Connors scores of >15 who had
only partly responded to psychostimulant received
buspirone (usually 10mg tid; range 10-45mg
/day) as adjunct to conventional doses of methyl-phenidate
(usually 10-20mg tid) or rarely pemoline (37.5
mg bid or tid).
Buspirone clinically improved several
target symptoms: concentration / distractibility
/ school functioning; irritability / anger
/ temper tantrums / low frustration tolerance.
Additionally these children, improved in sleep
disturbance and where present anxiety or anxiety-depression.
A further population of aggressive
non-ADHD children also responded well to buspirone
alone in similar doses (ultimately 20/27). Because
of the open, clinical nature of the study, statistics
have limited meaning but relevant clinical improvements
ostensibly occurred in > 90% of ADHDs and 74 %
of non-ADHD patients. Efficacy occurred within a week
but took >four weeks for full effects. Follow-up
periods have been up to 5 years with no loss of efficacy.
The buspirone was well tolerated. Overall, side-effects
were reported only rarely (<6% usually dizziness.
Further clinical study, suggests buspirone alone
does not apparently improve hyperactivity (N=5) again
suggesting a special functional limitation for serotonin
1A probes.