Etiological Factors


About 25 years ago, I advanced the hypothesis that the etiology of (as it was then called) minimal brain dysfunction (MBD) might be genetic in origin and produced by decreased catecholaminergic functioning (Wender 1971, 1972). My conjectures about a genetic origin were based on an apparently increased frequency of MBD symptoms among the siblings of children with that disorder and an increased frequency of other forms of psychopathology (alcohol abuse, antisocial personality disorder) among the parents of these patients, as well as the absence of such psychopathology in the adoptive parents of MBD children. Since that time there has been a large number of genetic studies of ADHD. These have been investigations of the familial association of ADHD; of psychopathology in the parents and siblings of ADHD children; of the concordance for ADHD in monozygotic and dizygotic twins; and of foster or adopted children with ADHD, which allows one to separate the contributions of genetic and rearing factors. The initial family studies reported an increased frequency of alcohol abuse, antisocial personality disorder and, possibly, Briquet's syndrome in the biological parents of "hyperactive" children as compared to controls; and an increased frequency of "hyperactivity" in the siblings of hyperactive children (Cantwell 1972; Morrison and Stewart; Morrison; Biederman and others 1992; Faraone and others). The clustering of ADHD, antisocial personality disorder and alcohol abuse is of interest because family studies conducted by investigators at Washington University also found that these three disorders coexist in the same families, which suggests a genetic basis for this clustering (Guze). Subsequent family studies of ADHD have indicated that the psychopathology in the parents of ADHD children correlates with ADHD children who are comorbid for conduct disorder. Nonetheless, there is clearly an increase of such parental psychopathology in the parents of children with "pure" ADHD. Using other methods, a relationship between ADHD and alcohol abuse was reported by Tarter and others and Wood and colleagues (1983), both of whom found that ADHD was associated with early-onset alcoholism. Furthermore, Goodwin and colleagues found that the adopted-away sons of alcoholics who were alcoholic were more likely than the nonalcoholics to have had symptoms of "hyperactivity" in childhood. Since the familial clustering of psychiatric disorders may be due either to genetic or to psychological transmission, other methods are necessary to differentiate between these two modes of transmission. One technique is to determine the concordance for ADHD among monozygotic and dizygotic twins. Ostensibly both types of twins share the same familial psychological environment and an increased frequency of concordance in monozygotic twin pairs, as compared to concordance in dizygotic twin pairs, is a manifestation of genetic factors. In a large sample of twins Goodman and Stevenson found an increased concordance of ADHD among monozygotic as compared to dizygotic twins (1989a,b). This method allows an estimation of "hereditability," expressed by genetic linkage, which was found to be 64 percent. Monozygotic twins, however, may in reality experience a different psychological environment from that experienced by dizygotic twins, and the twin methodology cannot completely control for this effect. The appropriate strategy to resolve this question is to study foster and adopted children. Safer investigated the status of full and half-siblings of ADHD children who had been placed in foster care. He found among the siblings an increase of ADHD-like psychopathology which was twice as great among the full as the half-siblings (as would be expected on genetic grounds). Two other adoption studies (Cantwell 1975; Deutsch) investigated the psychiatric status of the biological parents of children with ADHD, the adoptive parents of children with ADHD and the biological parents of children without psychiatric disorder. They found an increased frequency of ADHD-like psychopathology only among the biological parents of ADHD children. Taken together these studies have demonstrated the presence of genetic factors in the transmission of ADHD and suggest that children with ADHD may be at an increased risk for antisocial personality disorder and alcohol abuse. (For fuller detail, see Wender 1995.) The second etiological hypothesis was a neurophysiological one. The reasons behind the catecholaminergic hypothesis were based on several observations: the first were reports of behavioral problems among children who had contracted von Economo's encephalitis during the pandemic that occurred in the late teens and early '20s of this century. Many children who recovered from the acute illness developed a postencephalitic behavior disorder whose symptoms were very similar to those of mixed ADHD and conduct disorder. Another finding of interest is that adults who recovered from the acute encephalitis frequently manifested symptoms of Parkinson's disorder and that postmortem examination of adults who had died from the disorder revealed lesions in the basal ganglia and substantia nigra. Von Economo reported that the histopathological changes seen in children dying of the disease were identical with those found in adults. These observations tie in with a later finding that idiopathic Parkinson's disorder is associated with decreased dopaminergic functioning in the brain. This is due to degeneration of dopaminergic neurons in the brain areas mentioned and is associated with decreased levels of the principal metabolite of dopamine, homovanillic acid (HVA), in the cerebrospinal fluid (CSF). A second reason for a dopaminergic hypothesis is that some of the drugs that are dramatically effective in reducing or eliminating the symptoms of ADHD, the amphetamines and methylphenidate, are indirect dopamine agonists. Since the 1960s, I had wanted to do the experiments detailed below on children with ADHD but felt one could not legitimately obtain fully informed consent to conduct invasive biological tests on children. Our studies of adults allowed us to conduct these experiments. The first was to investigate the level of HVA, the principal metabolite of dopamine, in the CSF of adults with ADHD and with controls. Such a study (Reimherr and others) found a decreased level of HVA in the adults with ADHD who responded to treatment with methylphenidate, and increased levels of HVA in nonresponding ADHD patients. This replicated the findings of two smaller studies in "hyperactive" children (Shetty and Chase) and of children with minimal brain dysfunction (Shaywitz and others). The second technique was to administer pharmacological doses of the precursor amines of dopamine, namely phenylalanine, l-tyrosine, and l-dopa (Reimherr and others; Wood and others 1982, 1985). Our principal finding was that approximately half the patients receiving tyrosine experienced a moderate-to-marked improvement of their ADHD symptoms; phenylalanine and l-dopa did not have such an effect. These findings are post facto interpretable. Increasing phenylalanine or tyrosine should not increase dopamine. The primary metabolic chain is phenylala-nine(r)tyrosine(r)l-dopa(r)dopamine; and the conversion of tyrosine to l-dopa, which is catalyzed by the enzyme tyrosine hydroxylase, is the rate-limiting step in the formation of dopamine. On the basis of the enzyme kinetics, the observed clinical effectiveness of tyrosine could be explained by increasing tyramine, which would increase dopamine by an alternative metabolic pathway. The response to l-dopa was increased fatigue and a decreased ability to concentrate. This can be attributed to its acting as a false neurotransmitter (i.e., it could have been taken up by nondopaminergic neurons and might have displaced their transmitters and inactivated them). The third approach was to administer drugs with a comparatively specific action to patients with ADHD. The hypothesized relevant neurotransmitter dopamine is metabolized in the brain by monoamine oxidase B (MAO-A metabolizes predominantly serotonin and norepinephrine). In low doses two MAO inhibitors, pargyline (no longer marketed) and l-deprenyl (selegiline [Eldepryl]), are specific MAO-B inhibitors. We found that in low doses both drugs produced moderate-to-marked improvement in about 60 percent of ADHD adults (Wender and colleagues 1983; Wood and colleagues 1983). Since at low levels these drugs presumably increase the availability of dopamine and do not increase levels of serotonin and norepinephrine, the results are compatible with the dopaminergic hypothesis. Further trials of selegiline (now available as an orphan drug) are warranted.
Pages: 1  2  3  4