Attention deficit hyperactivity disorder (ADHD)
This is a heterogeneous disorder of inattention, hyperactivity and impulsivity that starts in childhood and may persist into adulthood. Children with the disorder can be identified by their inattention which leads to daydreaming, distractability and difficulty in sustaining an effort to complete a task. Their impulsivity makes them accident prone and disruptive while their hyperactivity, combined with excessive talking, is poorly tolerated particularly in schools. As teenagers, the hyperactivity and impulsivity tend to diminish but other symptoms persist. The adolescent with ADHD often has low self-esteem, poor relationships with peers and often becomes subject to drug abuse. To what extent ADHD persists into adulthood is open to debate, but some longitudinal, family and genetic studies would favour this view. ADHD is often co-morbid with conduct, depressive, bipolar and anxiety disorders.
Psychopathology of ADHD
Evidence of fronto-limbic dysfunction with poor inhibitory control of the cortex over the limbic system would appear to account for many of the physical and psychological symptoms. Neuroimaging studies have implicated a disorder of the right frontal cortex while PET imaging studies have shown that there is an approximate increase of 70% in the dopamine transporter in this brain region. Genetic and twin studies have shown that the heritability of the hyperactivity of ADHD is greater than 65%, while that of the attention deficit is greater than 70%. In molecular genetic studies there is evidence of an association between ADHD and a defect in the D4 receptor gene, but it must be emphasized that not all studies have replicated this. D4 receptor ‘‘knock-out’’ mice show supersensitivity to cocaine and methamphetamine that may have some bearing on the pathology of ADHD in children. ADHD is also associated with an abnormal allelic form of the dopamine transporter protein.
The catecholamine hypothesis of ADHD is the most widely supported hypothesis at the present time. This is largely based on the efficacy of the drugs used to treat the disorder and which act on the noradrenergic and dopaminergic systems. The drugs would appear to be most effective during the initial phase of the daily treatment when the plasma drug concentration is rising. This parallels the acute release of noradrenaline and dopamine and it has been argued that these changes in the catecholamines increase the inhibitory effect of the pre-frontal cortex on the subcortical regions of the brain. There is less convincing evidence regarding the involvement of 5-HT in ADHD; SSRIs have little benefit in treating the disorder. Recently, evidence has emerged that the nicotinic cholinergic receptors are defective, a view which is supported by the finding that nicotine applied as transdermal patches can improve some of the symptoms of the disorder.
Nicotinic receptors can act as heteroceptors on dopaminergic terminals in the frontal cortex, which again serves to emphasize the importance of the dopaminergic system in the pathology of this disorder.
Pharmacological treatment of ADHD
The stimulants methamphetamine, dexamphetamine, methylphenidate and pemoline have been shown to improve the main symptoms of the disorder in up to 70% of children; they may be of some benefit in adults also.
Conduct disorders
The symptoms consist of a collection of symptoms such as defiance, disobedience, temper tantrums, fighting, destructiveness, stealing and lying. These disorders frequently lead to the child being brought to the child psychiatric clinic and requiring treatment as they predict potentially serious outcomes in terms of later psychiatric disorders. While there has been an emphasis on the use of different psychotherapeutic techniques for treating these disorders, there is increasing evidence that psychotropic drugs have an important role to play. Neuroleptics such as chlorpromazine and haloperidol have been used to treat aggressive behaviour in mentally handicapped children, but there is always a risk that such drugs have a negative impact on the cognitive, social, emotional and developmental aspects. Such side effects necessitate the use of such drugs for a very short period only. Whether the atypical antipsychotics such as risperidone could be used as safer alternatives to the first-generation neuroleptics is unnown but because of their better side effects, are worthy of consideration.
Anticonvulsants have sedative side effects and therefore drugs such as carbamazepine have occasionally been used to treat conduct disorders. There is no evidence that such drugs are useful in the control of aggressive symptoms.
Lithium may be of some value in the treatment of difficult, impulsive and aggressive adolescents and children but the results from the studies in which lithium was used are few and the outcome uncertain. Thus, at present, there is little evidence that psychotropic drugs have a major role to play in the treatment of conduct disorders.
Emotional disorders
These disorders in children are considered to be particularly amenable to psychological treatment and therefore there has been a reluctance to use psychotropic drugs to treat them. In addition, problems of diagnostic classification have confounded research into drug treatment. Nevertheless the benzodiazepines and tricyclic antidepressants have been used. Thus the benzodiazepines have been used for childhood emotional disorders but there are no satisfactory controlled studies regarding their efficacy. Clearly only the short-term use, using short half-life drugs such as temazepam, is acceptable. So far there is no evidence of benzodiazepine dependence occurring in children. Of the tricyclic antidepressants used, clomipramine has been shown to be effective in the treatment of children with obsessional symptoms, effects which have been shown to be independent of the antidepressant action of the drug. More recent studies have provided evidence that the SSRI antidepressants such as fluoxetine are as effective, with fewer side effects.
Tic disorders
These range from transient disorders lasting a few weeks or months to chronic conditions lasting more than a year. The most severe form of a tic disorder is Tourette’s syndrome. Neuroleptics are the drugs of choice in the treatment of tic disorders but they should only be considered in situations where the life of the child is seriously affected and when behavioural treatments have failed. Of the classical neuroleptics which have been used, haloperidol and pimozide have shown success but so far there have been no adequately controlled trials of any neuroleptic to objectively validate their efficacy. It would appear that only low doses of haloperidol are necessary (2–3mg/day) to obtain a significant reduction in tic frequency. It would seem reasonable to consider the use of the atypical antipsychotics for these disorders but, to date, there is no evidence of their efficacy in children. Recently there have been studies in which clonidine was used in the effective treatment of motor tics. The side effects are similar to those seen in the adult and include sedation, headache, irritability and sinus bradycardia.
Nocturnal enuresis
This is quite a common condition affecting some 7% of 7 year olds who continue to wet the bed at least once a week. The cause of nocturnal enuresis is complex and beyond the scope of this volume. It is evident, however, that various treatments are available including retention control, dry-bed training, enuretic night alarms and waking the child to urinate during the night. The most effective treatment (estimated at 80%) is the use of the enuretic night alarm. Drug treatments include sympathomimetic stimulants, anticholinergics, tricyclic antidepressants and synthetic antidiuretics. Of these, imipramine and desmopressin have been found to be the most effective. The efficacy of imipramine has been repeatedly demonstrated in controlled trials; about 85% of children treated within a week of the start of medication, but tolerance frequently develops after a number of weeks and relapse is high after discontinuation of the treatment. Relatively low doses of imipramine only are needed, but the typical side effects of tricyclic antidepressants limit the prolonged use of the drug. The mechanism of action of imipramine in the treatment of nocturnal enuresis is unclear but one possible action is through a direct anticholinergic action on the bladder wall.
The synthetic vasopressin peptide, desmopressin, has been extensively investigated and shown to be effective as tricyclic antidepressants in the control of nocturnal enuresis and to enhace the enuretic night alarm treatment. The side effects are relatively few (nasal pain, conjunctivitis) when given by nasal spray. The precise mechanism of action of this peptide is unknown.
Affective disorders of childhood and adolescence
There is much controversy regarding the occurrence of major depressive disorder in prepubertal children. However, several studies in both the United States and Britain have suggested that depressive disorder does exist, although the frequency appears to be lower than in adolescents. There is endocrinological evidence, based on the hypersecretion of cortisol and an abnormal growth hormone response to insulin-induced hypoglycaemia, to suggest that children with major depressive disorder show similar endocrine abnormalities to those of adolescents and adults. However, the number of patients in these studies is small and clearly more thorough investigations must be undertaken before any conclusion may be reached. Regarding the drug treatment of depression in children, there is so far a paucity of good clinical trials to show that antidepressants are effective. Several small studies suggest that daily doses of up to 5mg/kg of imipramine may be beneficial, but there is no data to show whether other types of antidepressant medication are effective. The side effects and toxicity of tricyclic antidepressants are legion and have been discussed in detail elsewhere. Undoubtedly the SSRIs should now be the drugs of first choice in the treatment of depression in children.
Manic disorders would appear to be extremely rare in young children and only single case reports have appeared in the clinical literature. They are more common in adolescence but not as frequent as among adults. Some authorities have argued that the extent of mania among adolescents is underestimated and that many patients have been misdiagnosed as schizophrenics. Regarding treatment, lithium would appear to be the drug of choice. Since children and adolescents appear to have a higher lithium renal clearance than adults, it is occasionally necessary to give the drug in a higher oral dose than would be usual for the adult. Apart from the possible detrimental effect of lithium on bone growth in children, the monitoring of the young patient should follow the same procedures as outlined for the adult.
Anxiety disorders
The DSM–IV classifies anxiety disorders in children into four categories, namely social anxiety, over-anxious disorder, phobias and separation anxiety. Only separation anxiety, a fear of losing a loved one or a close attachment, has been reasonably well studied from the point of view of drug treatment. School phobia is perhaps the most severe form of separation anxiety and there are several trials to show that imipramine, in daily doses of up to 5 mg/kg, is effective. Many patients require drug treatment for at least 6 to 8 weeks before an optimal response is achieved. Frequently, children remain symptom free after a 3–4 month course of treatment. In addition to the usual anticholinergic effects of imipramine, it should be noted that children are often susceptible to withdrawal symptoms such as nausea and gastrointestinal spasm. This may be reduced if the drug is slowly withdrawn over a 2-week period.
Obsessive–compulsive disorders
These occur only rarely in children but more frequently in adolescents. There have been no extensive studies of drug treatments of this condition in young patients, but anecdotal reports suggest that tricyclic antidepressants such as clomipramine may be as effective as they are in adults but the SSRI antidepressants should be considered as first line treatments.
This is a heterogeneous disorder of inattention, hyperactivity and impulsivity that starts in childhood and may persist into adulthood. Children with the disorder can be identified by their inattention which leads to daydreaming, distractability and difficulty in sustaining an effort to complete a task. Their impulsivity makes them accident prone and disruptive while their hyperactivity, combined with excessive talking, is poorly tolerated particularly in schools. As teenagers, the hyperactivity and impulsivity tend to diminish but other symptoms persist. The adolescent with ADHD often has low self-esteem, poor relationships with peers and often becomes subject to drug abuse. To what extent ADHD persists into adulthood is open to debate, but some longitudinal, family and genetic studies would favour this view. ADHD is often co-morbid with conduct, depressive, bipolar and anxiety disorders.
Psychopathology of ADHD
Evidence of fronto-limbic dysfunction with poor inhibitory control of the cortex over the limbic system would appear to account for many of the physical and psychological symptoms. Neuroimaging studies have implicated a disorder of the right frontal cortex while PET imaging studies have shown that there is an approximate increase of 70% in the dopamine transporter in this brain region. Genetic and twin studies have shown that the heritability of the hyperactivity of ADHD is greater than 65%, while that of the attention deficit is greater than 70%. In molecular genetic studies there is evidence of an association between ADHD and a defect in the D4 receptor gene, but it must be emphasized that not all studies have replicated this. D4 receptor ‘‘knock-out’’ mice show supersensitivity to cocaine and methamphetamine that may have some bearing on the pathology of ADHD in children. ADHD is also associated with an abnormal allelic form of the dopamine transporter protein.
The catecholamine hypothesis of ADHD is the most widely supported hypothesis at the present time. This is largely based on the efficacy of the drugs used to treat the disorder and which act on the noradrenergic and dopaminergic systems. The drugs would appear to be most effective during the initial phase of the daily treatment when the plasma drug concentration is rising. This parallels the acute release of noradrenaline and dopamine and it has been argued that these changes in the catecholamines increase the inhibitory effect of the pre-frontal cortex on the subcortical regions of the brain. There is less convincing evidence regarding the involvement of 5-HT in ADHD; SSRIs have little benefit in treating the disorder. Recently, evidence has emerged that the nicotinic cholinergic receptors are defective, a view which is supported by the finding that nicotine applied as transdermal patches can improve some of the symptoms of the disorder.
Nicotinic receptors can act as heteroceptors on dopaminergic terminals in the frontal cortex, which again serves to emphasize the importance of the dopaminergic system in the pathology of this disorder.
Pharmacological treatment of ADHD
The stimulants methamphetamine, dexamphetamine, methylphenidate and pemoline have been shown to improve the main symptoms of the disorder in up to 70% of children; they may be of some benefit in adults also.
Conduct disorders
The symptoms consist of a collection of symptoms such as defiance, disobedience, temper tantrums, fighting, destructiveness, stealing and lying. These disorders frequently lead to the child being brought to the child psychiatric clinic and requiring treatment as they predict potentially serious outcomes in terms of later psychiatric disorders. While there has been an emphasis on the use of different psychotherapeutic techniques for treating these disorders, there is increasing evidence that psychotropic drugs have an important role to play. Neuroleptics such as chlorpromazine and haloperidol have been used to treat aggressive behaviour in mentally handicapped children, but there is always a risk that such drugs have a negative impact on the cognitive, social, emotional and developmental aspects. Such side effects necessitate the use of such drugs for a very short period only. Whether the atypical antipsychotics such as risperidone could be used as safer alternatives to the first-generation neuroleptics is unnown but because of their better side effects, are worthy of consideration.
Anticonvulsants have sedative side effects and therefore drugs such as carbamazepine have occasionally been used to treat conduct disorders. There is no evidence that such drugs are useful in the control of aggressive symptoms.
Lithium may be of some value in the treatment of difficult, impulsive and aggressive adolescents and children but the results from the studies in which lithium was used are few and the outcome uncertain. Thus, at present, there is little evidence that psychotropic drugs have a major role to play in the treatment of conduct disorders.
Emotional disorders
These disorders in children are considered to be particularly amenable to psychological treatment and therefore there has been a reluctance to use psychotropic drugs to treat them. In addition, problems of diagnostic classification have confounded research into drug treatment. Nevertheless the benzodiazepines and tricyclic antidepressants have been used. Thus the benzodiazepines have been used for childhood emotional disorders but there are no satisfactory controlled studies regarding their efficacy. Clearly only the short-term use, using short half-life drugs such as temazepam, is acceptable. So far there is no evidence of benzodiazepine dependence occurring in children. Of the tricyclic antidepressants used, clomipramine has been shown to be effective in the treatment of children with obsessional symptoms, effects which have been shown to be independent of the antidepressant action of the drug. More recent studies have provided evidence that the SSRI antidepressants such as fluoxetine are as effective, with fewer side effects.
Tic disorders
These range from transient disorders lasting a few weeks or months to chronic conditions lasting more than a year. The most severe form of a tic disorder is Tourette’s syndrome. Neuroleptics are the drugs of choice in the treatment of tic disorders but they should only be considered in situations where the life of the child is seriously affected and when behavioural treatments have failed. Of the classical neuroleptics which have been used, haloperidol and pimozide have shown success but so far there have been no adequately controlled trials of any neuroleptic to objectively validate their efficacy. It would appear that only low doses of haloperidol are necessary (2–3mg/day) to obtain a significant reduction in tic frequency. It would seem reasonable to consider the use of the atypical antipsychotics for these disorders but, to date, there is no evidence of their efficacy in children. Recently there have been studies in which clonidine was used in the effective treatment of motor tics. The side effects are similar to those seen in the adult and include sedation, headache, irritability and sinus bradycardia.
Nocturnal enuresis
This is quite a common condition affecting some 7% of 7 year olds who continue to wet the bed at least once a week. The cause of nocturnal enuresis is complex and beyond the scope of this volume. It is evident, however, that various treatments are available including retention control, dry-bed training, enuretic night alarms and waking the child to urinate during the night. The most effective treatment (estimated at 80%) is the use of the enuretic night alarm. Drug treatments include sympathomimetic stimulants, anticholinergics, tricyclic antidepressants and synthetic antidiuretics. Of these, imipramine and desmopressin have been found to be the most effective. The efficacy of imipramine has been repeatedly demonstrated in controlled trials; about 85% of children treated within a week of the start of medication, but tolerance frequently develops after a number of weeks and relapse is high after discontinuation of the treatment. Relatively low doses of imipramine only are needed, but the typical side effects of tricyclic antidepressants limit the prolonged use of the drug. The mechanism of action of imipramine in the treatment of nocturnal enuresis is unclear but one possible action is through a direct anticholinergic action on the bladder wall.
The synthetic vasopressin peptide, desmopressin, has been extensively investigated and shown to be effective as tricyclic antidepressants in the control of nocturnal enuresis and to enhace the enuretic night alarm treatment. The side effects are relatively few (nasal pain, conjunctivitis) when given by nasal spray. The precise mechanism of action of this peptide is unknown.
Affective disorders of childhood and adolescence
There is much controversy regarding the occurrence of major depressive disorder in prepubertal children. However, several studies in both the United States and Britain have suggested that depressive disorder does exist, although the frequency appears to be lower than in adolescents. There is endocrinological evidence, based on the hypersecretion of cortisol and an abnormal growth hormone response to insulin-induced hypoglycaemia, to suggest that children with major depressive disorder show similar endocrine abnormalities to those of adolescents and adults. However, the number of patients in these studies is small and clearly more thorough investigations must be undertaken before any conclusion may be reached. Regarding the drug treatment of depression in children, there is so far a paucity of good clinical trials to show that antidepressants are effective. Several small studies suggest that daily doses of up to 5mg/kg of imipramine may be beneficial, but there is no data to show whether other types of antidepressant medication are effective. The side effects and toxicity of tricyclic antidepressants are legion and have been discussed in detail elsewhere. Undoubtedly the SSRIs should now be the drugs of first choice in the treatment of depression in children.
Manic disorders would appear to be extremely rare in young children and only single case reports have appeared in the clinical literature. They are more common in adolescence but not as frequent as among adults. Some authorities have argued that the extent of mania among adolescents is underestimated and that many patients have been misdiagnosed as schizophrenics. Regarding treatment, lithium would appear to be the drug of choice. Since children and adolescents appear to have a higher lithium renal clearance than adults, it is occasionally necessary to give the drug in a higher oral dose than would be usual for the adult. Apart from the possible detrimental effect of lithium on bone growth in children, the monitoring of the young patient should follow the same procedures as outlined for the adult.
Anxiety disorders
The DSM–IV classifies anxiety disorders in children into four categories, namely social anxiety, over-anxious disorder, phobias and separation anxiety. Only separation anxiety, a fear of losing a loved one or a close attachment, has been reasonably well studied from the point of view of drug treatment. School phobia is perhaps the most severe form of separation anxiety and there are several trials to show that imipramine, in daily doses of up to 5 mg/kg, is effective. Many patients require drug treatment for at least 6 to 8 weeks before an optimal response is achieved. Frequently, children remain symptom free after a 3–4 month course of treatment. In addition to the usual anticholinergic effects of imipramine, it should be noted that children are often susceptible to withdrawal symptoms such as nausea and gastrointestinal spasm. This may be reduced if the drug is slowly withdrawn over a 2-week period.
Obsessive–compulsive disorders
These occur only rarely in children but more frequently in adolescents. There have been no extensive studies of drug treatments of this condition in young patients, but anecdotal reports suggest that tricyclic antidepressants such as clomipramine may be as effective as they are in adults but the SSRI antidepressants should be considered as first line treatments.
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