Attention deficit disorder, irritability and serotonin 1 A neuromodulation
Vernon M Neppe MD, PhD
To educate in the areas of attention deficit hyperactivity disorder and
irritability in children and adolescents.
To present early information on the use of the azapirone compounds alone
or as adjunct in ADHD and
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
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
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
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 DSM 3R ADHD patients with
Connors scores of more than 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 more than 90% of ADHDs and 74% of non-ADHD patients.
Efficacy occurred within a week but took more than 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 (less than 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.