Non-Stimulant Medications in ADHD

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Rationale for use of medication

Although the research evidence suggests that medication is effective alone, and may be the most effective part of comprehensive multimodal management (Wilens and Biederman 1992; Greenhill 1992), it is the general consensus that educational and behavioural strategies add to the success of management and are essential if medication is ineffective.

There is considerable pressure to treat ADHD with its disruptive symptoms, associated learning, behavioural and emotional problems, family stress, and possible persistence into adolescence and adulthood. For a minority the outcome is antisocial behaviour, criminality and substance abuse. The multiplicity of aetiology, heterogeneity of presentations, changes over time, and intervention and range of possible treatments, make management complex and confusing. Approaches to diagnosis and treatment are not equally validated and support is compromised by the lack of, or long waiting lists for, support services. This context emphasises the use of medication which can have powerful short-term benefits for disrupted behaviour and performance.

The need for medication and its effectiveness is relative to the nature and severity of problems and the use of other interventions. A multimodal approach, especially with educational and behavioural supports, should be used if available. Although medication is the most effective short-term treatment for the disruptive behaviours of ADHD, other approaches may add to the success of medication and be essential if medication is ineffective.

Comprehensive assessment and management is emphasised in managing ADHD. Day-to-day support for the vulnerable individual at home, and in other settings, should be provided. Management is, however, complex and time consuming and requires collaboration. Medication, whilst the best validated of the various interventions, is likely to be better accepted when accompanied by advice regarding other supports. Referral to supports should be vigorously pursued, though other services may be scanty (Hazell, McDowell, Walton et al 1996). The prescribing of medication is exclusive to the medical practitioner, but few can provide intensive, prolonged behavioural and emotional management. ADHD usually requires, among other services, psychological or psychiatric support.

North American practice and research dominates paediatric psychopharmacy, particularly in ADHD, reflecting the prevalence of disruptive behaviours responding to medication. The stimulants are methylphenidate, which is most studied, and dexamphetamine, which is less so, and other medications are used (Werry 1994). A very recent extensive review by Spencer, Biederman, Wilens et al (1996) describes medication in the treatment of ADHD for children and adults. This refers to 155 controlled studies in over 5700 individuals documenting the efficacy of stimulant medications. Other authors have stated that stimulants are safe and effective drugs (Gadow 1992) and have few side-effects when used in children under proper medical supervision (Werry 1988).

The place of medication may decrease in importance as other vulnerabilities in the child or the child’s environment are dealt with, and as the child moves away from the threshold of the disorder. Indeed, stimulant medications have been shown to have similar types of effect in children with diagnosed ADHD and individuals regarded as normal controls (Peloquin and Klorman 1986; Rapoport, Buschsbaum and Monte 1980; Rapoport, Buschsbaum and Zahn 1978). These results emphasise that the diagnosis of ADHD cannot be determined by a positive response to medication.

Non-stimulant medications

There are few studies of ADHD management with medications other than stimulants, with useful reviews by Green (1992) and Spencer, Biederman, Wilens et al (1996). There is little quality of evidence rating II or III-1 (see Introduction, p2). The more recent references quoted in Table 1 report on open trials or case reports to allow practitioners to pursue what information does exist, even if it currently carries a lower level of evidence. If medications other than stimulants appear to be indicated, further expert opinion should be considered, particularly if multiple medications are used.

The demonstrated efficacy and safety of stimulants for ADHD and its co-morbid conditions encourage their use over other medications that have been less extensively studied. Nevertheless, the prescription of ADHD stimulant medication is restricted under ‘drugs and poisons’ legislation across the States and Territories as a ‘drug of addiction’. Follow-up studies, however, show no evidence for addiction when stimulants are prescribed appropriately for ADHD (Klein and Mannuzza 1991).

Practitioners can prescribe without restriction other medications, which may have partial effects, no rigorously proven benefits in ADHD and more serious side-effects. Lack of precision in titration of dose and lack of immediate effect of nonstimulant drugs can encourage arbitrary use, imprecise diagnosis of ADHD, risk of side-effects and can confuse the wider public and professionals about management of ADHD. Mechanisms that are in place for monitoring the use of stimulants have no jurisdiction over these other medications. They may be useful, however, for children for whom stimulants are ineffective, have unacceptable side-effects, or who have significant co-morbid anxiety, depression or tic disorder or may potentially abuse prescribed stimulants. Use of nonstimulant medications should be used with caution, with knowledge of recent literature and up-to-date clinical advice, particularly for newly available medications and those used in combination.

The artificial nature of diagnostic boundaries means that professionals may differ in how they perceive, interpret and categorise the same qualities and dimensions in one child, and may reach different diagnoses and, as a result, prescribe different medication. At present there are no reliable criteria for widespread clinical use that can identify groups and individuals with different aetiology, target symptoms and responses. Some neuroimaging and neurophysiological assessment tools may have this potential, but their usefulness has yet to be proven in rigorous research, let alone translated into widespread clinical practice. Australian work has suggested in a single-dose study that auditory event-related potentials can predict methylphenidate response in 81 per cent of individuals (Young, Perros, Price et al 1995). Suffin and Emory (1995) claim robust correlations between neurometric quantitative electroencephalogram (QEEG) subgroups, clinical outcome and response to stimulants, antidepressants and anticonvulsants. However, these techniques are largely confined to research studies and their validity and specificity is vigorously debated (Chabot, Merkin, Wood et al 1996; Duffy, Hughes, Miranda et al 1994; Levy and Ward 1995). Most practitioners do not have experience and training in the use and interpretation of such methods and they do not form part of the primary management of ADHD.

Medications have been used for decades to affect behaviour and mood, particularly with other brain impairments. Thioridazine (Melleril¨) for intellectual disability or anticonvulsants, such as carbamazepine (Tegretol¨), for seizure disorders are two such medications. Most others, such as fluoxetine (Prozac¨), moclobemide (Aurorix¨) and sertraline (Zoloft¨), are newly developed and not extensively evaluated or officially approved for the treatment of ADHD or for use in children. Such drugs have many appropriate indications for other developmental behavioural conditions or brain impairments eg seizures, parkinsonism and mood disorders (such as depression, anxiety, obsessions or compulsions). There may be empirical improvement in ADHD symptoms, which are more common in preexisting brain dysfunction. Any of these drugs may worsen behaviour, learning or attention and most have major potential physical side-effects. The use of nonstimulant drugs in ADHD is well summarised by Green (1992) and Spencer, Biederman, Wilens et al (1996), in developmental disability by Mercugliano (1993), and for adults by Wilens, Biederman, Spencer et al (1995). These reviews have extensive bibliographies and clinical advice on relative indications, dosage regimes and side-effects.

Paediatricians in isolated practice and those with a specialised interest in learning and behaviour problems are likely to use various medications. In teaching centres and urban practice, referral of complex cases to child psychiatrists is more available. Kaplan, Simms and Busner (1994) reported that North American child psychiatrists used medication appropriately for an indicated diagnosis but were generally restrained in use of medication. Audits of Australian psychopharmacology treatments hardly exist.

Monitoring reactions to the use of nonstimulant medications in the school environment is particularly important. These drugs are used less often, for more complex symptoms and with far more potential adverse effects. Extensive studies of the effects of medication in naturalistic settings ÷ playground, sports and classroom ÷ are reviewed by Whalen and Henker (1992). Detailed procedures for assessing effects of stimulants (Gadow, Nolan, Paolicelli et al 1991) can be adapted for these other medications. More elaborate evaluations are detailed for single subject randomised trails by Langer, Winthrop and Issenman (1993) and for double-blind crossover trials by McBride (1988) and Di Traglia (1991). Medication studies often report effects of single doses, while two or three doses a day may overlap to produce a cumulative effective dose, higher than intended. This may maximise benefits and/or predispose to minor side-effects, as reported for three stimulant doses a day by Ahmann, Waltonen, Olson et al (1993).

Clonidine

Clonidine (Catapres¨) is an alpha-2 noradrenergic agonist which acts most on aggression, impulsivity and aggression, often with co-morbid oppositional defiant disorder or conduct disorder. The use of clonidine is more widespread than the small published literature would suggest. Its use in young children, possibly to avoid the bureaucratic restrictions on the better-validated stimulants, has no published studies. Use in ADHD with and without tics is retrospectively studied by Steingard, Biederman, Spencer et al (1993) and the evidence for its use is briefly summarised by Spencer, Biederman, Wilens et al (1996). The only detailed controlled study is that of the thesis by Gunning (1992).

Its sedative effect is most marked within an hour or two of dosage and may help sleep problems, whether or not they are exacerbated by stimulants, or may show tolerance over a few weeks. As one of the treatments for chronic tic disorder/Tourette syndrome it may be useful for the common co-morbidity with ADHD. Clonidine is usually given twice a day (Hunt, Minderaa and Cohen 1985). Side-effects of sedation and hypotension are a concern, particularly when used in young children only to avoid restrictions placed on prescribing stimulants. Gradual increase of dose and tailing off are needed, effects may take several days or some weeks to be maximal. The use of clonidine is more recently reviewed, including its use in conjunction with a stimulant and with transdermal patches (Hunt, Capper and O’Connell 1990). This is a good example of where use is entirely empirical, changes in practice are led by impression and, even by vague anecdote, sometimes given more apparent authority by appearing in professional correspondence and newsletters. There is growing anecdotal concern about possible side-effects of Clonidine when taken alone or in conjunction with stimulants (Pearson 1996; Swanson, Flockhart, Udrea et al 1996; Walkup 1995). In presenting a case study, Cantwell, Swanson and Connor (1997) discuss clonidine toxicity and suggest approaches to screening and monitoring for side-effects. Newer medications in North America include guanfacine (Tenex¨) which may be as successful and without side-effects (Hunt, Arnsten and Asbell 1995).

Antidepressants

antidepressants such as tricyclic medications ÷ eg imipramine (Tofranil¨) and desipramine (Pertofran¨) ÷ may help alleviate accompanying anxiety, sadness and depression, as well as improve clarity of thinking and attention (Pataki, Carlson, Kelly et al 1993). Spencer, Biederman, Wilens et al (1996) thoroughly reviewed 29 studies of tricyclic antidepressant (TCA) treatment for ADHD, summarised as having a generally robust or moderate response at various ages. The reviewed studies are both controlled and open, use different antidepressants and for different durations and doses. Concerns about rare toxicity for cardiac rhythm and underlying heart disease, and the risk of inadvertent poisoning of young children through possible lapses in drug safety procedures, discourage their use. An ECG is usually performed before starting and on follow-up. Varley and McClellan (1997) have reported additional cases of sudden death in children receiving tricyclic antidepressants for treatment of disruptive behaviour disorders. Dose increase and cessation should be gradual. Imipramine may be as effective as methylphenidate, but many more children discontinue because of side-effects or eventual tolerance (Ambrosini, Bianchi, Rabinovich et al 1993). Clomipramine (Anafranil¨) is most useful for obsessionality.

Selective serotonin release inhibitors

Selective serotonin release inhibitors (SSRI) such as fluoxetine and more recently venlafaxine, may help ADHD symptoms accompanied by aggression, depression and obsessionality. Extrapolation from adult psychopharmacology (Wilens, Biederman, Spencer et al 1995) awaits appropriate clinical and research experience in children.

Ineffective medication for ADHD

Some medications may have superficial rationale for possible benefit in ADHD. Fenfluramine is related to dexamphetamine and its use in intellectually handicapped individuals with major eating disorders, eg Prader Willi syndrome, may suggest hope for benefits in coexisting hyperactive disruptive behaviours. It is not effective, however, when compared with methylphenidate (Aman, Kern, McGhee et al 1993) nor dexamphetamine in ADHD children of normal ability (Donnelly, Rapoport and Potter 1989).

Benzodiazepines with their general sedative, hypnotic, anxiolytic and anticonvulsant effects might be presumed to be useful in ADHD, given the association with sleep disorder or various brain impairments. Three decades ago, chlordiazepoxide and diazepam (Valium¨) were shown to be less effective than dexamphetamine and placebo to be better than diazepam (Zrull, Westman, Arthur et al 1964). Depression and mania should not be confused with ADHD, though they may be co-morbid conditions. Lithium is very rarely used to treat children because of its toxicity; it has shown no benefit and may exacerbate symptoms.

Medication compared to and combined with other treatments

The complexity, persistence, heterogeneity and variability of aetiology, presentation and co-morbidity of ADHD will demand various treatments. Study of multimodal management involving psychosocial, behavioural and educational interventions and medication has several main thrusts, including relative global efficacy; relative action on specific symptoms; selection of treatment; generalising from a research or instruction setting to naturalistic activities; one modality priming other interventions and their long-term success, and the duration of the combined treatment required to alter outcome (Weiss 1992; Shaywitz and Shaywitz 1992).

Unlike medication, non-medication therapies cannot be titrated or placebo-controlled. Their effects may vary with how precisely symptoms and generalisation of effect are targeted. It may be difficult to guarantee sustained consistent combination therapy in all settings. The majority of studies show that stimulant medication is more effective than any other treatment used singly. Symptoms are normalised in more children when combined treatment is used and additive effects only persist while all components are used.

Medication used for short periods does not ‘prime’ psychosocial and educational interventions to initially engage an effect, which is then sustained without medication. Ialongo, Horn, Pascoe et al (1993) showed this in a nine-month follow-up after brief multimodal intervention. They evaluated 96 children with ADHD for the effects of methylphenidate at low and high doses alone and in combination with behavioural parent training and child self-control instruction. Stimulant medication benefits increased linearly with dose and facilitated self-esteem and problem solving instructions with no additive benefit of behavioural instructions. Nine months after all treatments were stopped, there was no evidence that short-term medication had enhanced the effect of behavioural intervention. Cardinal features of ADHD on parent ratings, but not teacher ratings or laboratory measures, were slightly improved in those who had behavioural instructions, perhaps from an ‘expectation effect’.

Combined behaviour treatment may allow lower doses of medication to be used, though Abikoff (1991) emphasises the lack of proof of sustained additive effects of behaviour treatment over time and across settings. Carlson, Pelham, Milich et al (1992) showed in a treatment classroom that behavioural intervention and low-dose methylphenidate (0.3 mg/kg/dose) are equivalent and, when combined, are as effective as a higher dose alone (0.6 mg/kg/dose) for improving disruptive off-task behaviour. Only stimulant medication enhanced work output, confirming the lack of effect on academic performance in controlled studies of a four-month behavioural program added to medication (Abikoff, Ganeles, Reiter et al 1988) or on home or school behaviour (Abikoff and Klein 1985). While combined medication and behavioural techniques are complementary in improving playground interactions, only combined treatment normalises behaviour (Hinshaw, Henker and Whalen 1984).

Medication for ADHD in special populations and with other disorders

More complex, thoughtful and collaborative management is required in special populations and situations, often with ADHD coexisting with other disorders.

Special education needs

Children receiving special education for specific or global cognitive deficits or physical and emotionally handicapping conditions have a higher prevalence of ADHD. United States studies show a much higher use of stimulant medication in special education settings ÷ 26 per cent compared to 6 per cent in regular classes (Safer and Krager 1988). Teachers find medication more acceptable if used with behaviour interventions (Kasten, Courey and Heron 1992). Acceptability may be unrelated to knowledge of ADHD or years of teaching experience (Power, Hess and Bennett 1995). Disruptive behaviour is the greatest challenge to treating and maintaining special needs students in any educational setting. Philosophies and practices of integration and inclusion of students with special needs into mainstream schooling amplify the difficulty. Managing ADHD is hard enough for most schools and ADHD often occurs with, and predisposes to, other conditions such as conduct disorder, anxiety or depression (Biederman, Newcorn and Sprich 1991). Forness, Swanson, Cantwell et al (1992a,b) discuss the complex interaction between symptoms, learning performance, drug effects and the length of treatment with medication. They emphasise the academic heterogeneity of students with ADHD, the improvement of reading comprehension as a predictor of drug response and the impact of Oppositional and conduct disorder on academic attainment and medication treatment.

Different single medications may have different benefits for behaviour, mood and learning. Children with the most severe, complex or intractable problems may be treated with multiple drugs (Wilens, Spencer, Biederman et al 1995) and sometimes by more than one doctor at the same time. Paediatrician, psychiatrist and neurologist may all be involved concurrently, and requesting teacher observations for the effects of stimulants, antidepressants, anticonvulsants and treatments for other medical disorders. With multiple medications, potential side-effects, pharmacological interactions and effects on symptoms are more worrying and need even closer collaboration. Some combinations, however, such as stimulants and tricyclic antidepressants may be well tolerated and additive in benefits as discussed by Pataki, Carlson, Kelly et al (1993). Aggression, oppositional defiant disorder and Conduct Disorder often require combined drugs such as stimulants and clonidine. There is, however, some anecdotal concern about co-administration of stimulants and clonidine and suggested recommendations for cautious use (Cantwell, Swanson and Connor 1997). The use of SSRI medications in ADHD and comorbid conditions has no published controlled studies to support it. Discussion of open treatment in seven children suggests that SSRI and stimulants combined might be safe and effective intervention for ADHD coexisting with major depression (Findling 1996).

Tics and Tourette syndrome

Tic disorders are common in children, with or without ADHD.

Tourette syndrome is a childhood onset neuropsychiatric disorder characterised by multiple motor and vocal tics which wax and wane (Hyde and Weinberger 1995; Robertson 1994). It is uncommon (about one in 2000 children) with an average onset age of seven years and with 80 per cent having coexisting ADHD and learning disabilities. Tourette symptoms usually appear later than ADHD symptoms which may be far more constant and disabling than tics which naturally wax and wane (Park, Como, Cui et al 1991). The co-occurrence of Tourette syndrome, ADHD and other academic, behavioural and developmental problems is complex (Nolan, Sverd, Gadow et al 1996). Influences include familial history (Pauls, Leckerman and Cohen 1993) and family functioning (Carter, Pauls, Leckman et al 1994). In a pilot study of one school district, Kurlan, Whitmore, Irvine et al (1994) report tics in 26 per cent of students in special education programs compared with 6 per cent in regular classes. One half of students with tics had ADHD, observed disruptive behaviours and one third had Tourette syndrome. All drugs used to treat ADHD or Tourette syndrome and tics can both induce and inhibit tics. The controversy surrounding stimulants and exacerbation of symptoms in Tourette Syndrome is thoroughly discussed by Robertson and Eapen (1992) and beginning to be clarified with more recent studies. Gadow, Nolan and Sverd (1992) and Gadow, Sverd, Sprafkin et al (1995) treated students with Tourette syndrome with methylphenidate and found ADHD symptoms were improved with no increase in motor tics and a reduction of motor tics in the classroom and lunchtime. No prospective study has shown that stimulants worsen the long-term severity of tics (Spencer, Biederman, Wilens et al 1996). Combined medications should be used with great caution as little scientific evidence exists regarding toxicity and long-term side-effects (Cantwell, Swanson and Connor 1997; Levy, Einfeld and Looi 1996). Prescribers should be well acquainted with recent literature and up-to-date expert clinical advice.

Castellanos, Giedo, Elia et al (1997) compared dexamphetamine, methylphenidate and placebo at different doses in treating ADHD and comorbid Tourette Syndrome, again showing the difference between the stimulants. Higher doses of either stimulant increased tic frequency, with dexamphetamine associated with more tics lasting for longer. Stimulant-associated adverse effects, including tic exacerbation, were reversible in all cases. In their small study of 20 subjects, more children continued on methylphenidate. Nolan and Gadow (1997) showed that even their highest dose of 0.5mg/kg/dose of methylphenidate normalised classroom behaviour in only 32 per cent of their subjects with ADHD and tic disorder compared with controls. There is no published study comparing benefits and disadvantages of the use of stimulants against other medication in the treatment of Tourette syndrome/tic disorder with ADHD. However, stimulant use is considered appropriate with cautious dosage and close monitoring, as recommended in the current NSW guidelines (NSW Department of Health 1994).

Extremes of intellectual ability

Attention deficits and language learning difficulties are often more subtle in individuals of high ability whose other strengths may allow them to compensate and escape detection by functioning appropriately for their age but not their ability. Able individuals more often exhibit the inattentive ADHD type, presenting later in high school or even in adulthood, as their abilities and compensatory strategies are overwhelmed by the complexity and extent of cognitive and performance demands, and the added anxiety of formal examinations, life planning and employment. Medication can work similarly across the range of cognitive ability and age (Mayes, Crites, Bixler et al 1994).

Developmental and behavioural symptoms, including ADHD, can be severe and complex in existing brain abnormality such as seizure disorder, intellectual handicap and genetic or acquired organic brain and neurological disorders. The intrinsic brain abnormality and epileptic processes of seizure disorders are the main influences on the accompanying cognitive and attention problems (Stores, Williams, Styles et al 1992). Anticonvulsant effects on concentration and attention may differ with type of seizure disorder and medication. Feldman, Crumrine, Handen et al (1989) found no effect of stimulant treatment on seizure frequency, electroencephalogram (EEG) patterns or regulating anticonvulsant blood levels.

With intellectual handicap, signs of ADHD are more common (Biederman, Newcorn and Sprich 1991) and influence classroom behaviour (Handen, Janosky, McAulliffe et al 1992) and treatment (Beitchman, Wilson, Brownlie et al 1996b). Making the diagnosis using scales which rate hyperactivity and attention needs careful evaluation (Pearson and Aman 1994). Medication requires detailed behavioural observations and monitoring to distinguish real effects and side-effects (Handen, McAulliffe, Janosky et al 1994). This demands active collaboration between family, teachers and other professionals. This interactive support may itself improve behaviour without medication (Mercugliano 1993; Johnson, Handen, Lubetsky et al 1994). In moderate or severe intellectual disability and in autism, stimulants may have less efficacy and more side-effects, though still be useful.

ADHD and language disorders frequently co-occur and confuse differential diagnosis and treatment. Severe hearing impairment also interacts with ADHD (Kelly, Forney, Parker-Fisher et al 1993), and most particularly with inattentive type ADHD (Moss and Sheiffele 1994; Lahat, Avital, Barr et al 1995). Keith and Engineer (1991) showed that methylphenidate improved auditory processing, although Balthazar, Wagner and Pelham (1991) suggested that reading comprehension improved with general processing efficiency rather than specific effects on phonemic awareness. The impact of conductive hearing loss on the normal development of auditory processing and its association with ADHD has not been well studied.

Adverse environments

genetic traits, parents’ responses and the behaviour models observed by the child contribute to uninhibited aggressive and antisocial behaviour, causing and compounding economic, social and health disadvantage. These strong adverse intrinsic and environmental circumstances may all contribute to ADHD, as well as compromise its management, but medication may still have significant benefits. Appropriate use of medication and other supports may be very difficult in such settings. The child’s extreme vulnerability and poor prognosis renders treatment even more necessary. Recognition and treatment of ADHD and other learning, behaviour and emotional problems in parents may be crucial in managing the child, as described by Schubiner, Tzelepis, Isaacson et al (1995). Whether children with pervasive hyperactivity are referred is influenced by factors such as emotional disorder in the child, and parental approaches to discipline (Woodward, Dowdney and Taylor 1997).

Psychosis

Though paranoid psychosis can occur with the use of stimulants in substance abusers and adult volunteers, this requires doses much larger than those used in treatment of ADHD. Delusions or mania induced by stimulants are very rare and can occur more frequently with many other psychotropic medications, such as antidepressants. Psychosis is a contraindication to stimulant use.

Recommendations

Co-morbid conditions frequently exist with ADHD and need to be addressed in management. Where drugs other than stimulants and/or multiple drugs are considered, expert opinion should be sought.

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