Attention Deficit Disorder, Irritability and Serotonin 1 A Neuromodulation

Vernon M Neppe MD, PhD

Educational Objectives

1. To educate in the areas of attention deficit hyperactivity disorder and irritability in children and adolescents.
2. To present early information on the use of the azapirone compounds alone or as adjunct in ADHD and
3. 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.