Journal of Autism and Childhood Schizophrenia, 1973, 3, 1, 27-35

Serotonin and Central Nervous System Syndromes of Childhood:

A Review

MARY COLEMAN 1

Children's Brain Research Clinic Washington, D. C.

A brief review is presented of clinical studies of serotonin (5-hydroxytryptamine) (5-HT) and its metabolites in children with diseases of the central nervous system. Evidence of 5-HT abnormalities in the hyperactive syndromes, primary infantile autism, and childhood schizophrenia is reviewed and compared with the many types of mental retardation with documented serotonin abnormalities. The platelet "model" system is postulated to explain the relationship of serotonin abnormalities in blood to clinical evidence of brain dysfunction in these varying patient groups. The nonspecificity of serotonin abnormalities in humans is emphasized.

One of the biogenic amines present in the central and peripheral nervous

systems is serotonin (5-hydroxytryptamine) (5-HT) as depicted in Figure 1.

Measurements of this obscure but intriguing substance and one of its end

products, 5-hydroxyindole acetic acid (5-HIAA), have been made in a large

number of patients with various diseases affecting brain function.

Serotonin is also present in other body tissues such as the enterochromaffin

system of gastrointestinal tract, the spleen, and the platelets in the blood. Thus,

interpretations of serotonin abnormalities in the blood in any patient group with

CNS disease must first exclude the possibilities of gastrointestinal disease

(carcinoid syndrome, malabsorption syndrome, acute gastroenteritis,

gastrointestinal obstruction, congenital anomalies of the gastrointestinal tract,

and the functional gastrointestinal hyperserotonemia syndrome), vascular disease

(collagen vascular disease, migraine, myocardial infarction), thyroid disease

1 Requests for reprints should be sent to Dr. Mary Coleman, 2525 Belmont Road, N.W., Washington, D.C. 20008.

27

Copyright � 9 by V. H. Winston & Sons, Inc.

28 MARY COLEMAN

TRYPTOPHAN

(TRYPTOPHAN- 5- HYDROXYLASE) 1 ( LIVER, KIDNEY, MAST CELLS,INTESTINE )

5-HYDROXYTRYPTOPHAN (5-HTP} /

(AROMATIC L-AMINO ACID DECARBOXYLASE,B6) / (ALMOST ALL TISSUES)

u SEROTONIN,OR

5-HYDROXYTRYPTAMINE(S-HT) ~ N-ACETYL SEROTONIN -..,.> MELATONIN

(MAO) / (MANY TISSUES)

5-HYDROXYINDOL ACE TALDEHYDE

(NAD) / ~ , ~ (NADH)

5-HYDROXYINDOLACETIC ACID (5 -H IAA) 5-HYDROXYTRYPTOPHOL

FIG. 1. Metabolic pathway of 5-hydroxytryptamine.

(hypothyroidism-infant and hyperthyroidism), and diseases affecting platelets (Erspamer, 1966; Warner, 1967; Page, 1968; Coleman, 1970).

Studies by Fuxe, H61~felt, and Ungerstedt (1968) in the brains of rats have shown that 5-HT nerve cell bodies are mainly localized in the raphae nuclei of the lower brainstem; some are also found in the pyramidal tract and the medioventral part of the caudal tegmentum. No 5-HT cell bodies are found in the spinal column, the diencephalon, or the telencephalon. The axon from the 5-HT nerve cell bodies extends throughout the nervous system with 5-HT terminals concentrated in the visceral nucleii of the pons, medulla, reticular formation, hypothalamus, thalamus, amygdala, and septal areas.

In children, abnormal endogenous levels of serotonin in the blood have been reported in patients with psychiatric symptoms as well as in those with evidence of neurological abnormalities. There is evidence of serotonin malfunction in the hyperactivity syndrome, in primary infantile autism, and in childhood schizophrenia, as listed in Table 1.

In the hyperactivity syndrome, low levels of 5-HT in whole blood have been reported in 88% of "functional" hyperactive children with normal intelligence (Coleman, 1971) and in 83% of insitutionalized, retarded patients with clinical hyperactivity (Greenberg & Coleman, 1973). In most hyperactive patients with

SEROTONIN AND CNS SYNDROMES 29

Table 1

Psychiatric Syndromes with Reported Serotonin Abnormalities

Reported 5-HT abnormality

Low level in whole blood Both high and low levels in whole blood Reduced uptake from platelets Increased efflux from platelets

Autism and childhood

schizophrenia

X X X

Syndrome

Hyperactivity- "functional" patients with normal intel-

ligence

X

Hyperactivity- institution-

afized retardates

X

low whole blood serotonin levels, elevation of these levels into the normal range

by drug therapy is associated with calm, nonhyperactive behavior. Removal of supportive drug therapy is accompanied by increase in hyperactive, aggressive behavior and re-depression of the serotonin levels. Even environmental therapy, which is successful in increasing attention span and lowering hyperactivity, is accompanied by higher serotonin levels (Coleman, 1971). This is best illustrated by blind, crossover studies showing a predictable correlation between whole

blood levels of serotonin and hyperactivity patterns in the major patient groups

that suffer from this syndrome (Greenberg & Coleman, 1973). In the case of psychotically disturbed children with autistic and schizophrenic

symptoms, biochemical studies of large overlapping ~Jinical groups of patients have done little to pinpoint specific subgroups with clear-cut disease entities. A number of serotonin abnormalities have been reported in such groups. Schain and Freedman (1961) described elevated levels of blood 5-HT in 6 out of 23 patients with "autism." A more detailed report of the patients is given by Schain and Yannet (1960) who describe what appears to be a group of withdrawn, disturbed children with a variety of neurological and psychiatric diagnoses. The series includes patients with hemiparesis, hydrocephalus, and prematurity. 2

Ritvo, Yuwiler, Geller, Ornitz, Saeger, and Plotkin (1970) also reported

increased 5-HT levels with increased platelet counts in a group of children "variously diagnosed as early infantile autism, atypical ego development, symbiotic psychosis, and certain cases of childhood schizophrenia"; they point

25-hydroxyindole acetic acid is elevated in the cerebrospinal fluid of hydrocephalic patients (Dubowitz & Rogers, 1969).

30 MARY COLEMAN

out that the serotonin per platelet level is not increased in their patient group. Circadian rhythmicity of serotonin and platelets in autistic children did not account for their results (Yuwiler, Ritvo, Bald, Kipper, & Koper, 1971).

Sankar, Cates, Broer, and Sankar (1963) studied the mechanism underlying 5-HT abnormalities reported in the blood of disturbed children. They measured the uptake of 5-HT by the platelets (the cell in the blood containing most of the 5-HT) and found the uptake reduced. Our research group has studied a number of patients with Kanner's "primary" autism as well as retarded and psychotic children with autistic features. Although some patients do have elevated 5-HT levels, it is not consistently seen in any diagnostic category. A patient with the clinical criteria of Kanner's "primary" autism may have high, normal, or low endogenous levels by the whole blood method. However, biochemical identification of a "primary" autistic child may be possible by a study of the binding of 5-HT inside the platelet. In our laboratory, we found increased efflux of 5-HT from platelets compared to controls and other types of psychotic children which we interpreted as a binding defect (Boullin, Coleman, & O'Brien, 1970). In a related study, the efflux ratio was used to distinguish primary autism from other psychiatric diagnoses in a mixed group of disturbed children. There was a 90% correlation in that study between the efflux ratio prediction of autism and the clinical diagnosis of "primary" autism (Boullin, Coleman, O'Brien, & Rimland, 1971). These results have not yet been confirmed by any other laboratory.

One of the problems in interpreting these results in disturbed children is the difficulty in differentiating, in borderline cases, between retarded children with autistic or psychotic features and those patients with primary psychiatric entities. High endogenous levels of serotonin in blood have been reported in a number of forms of retardation in the same range that has been reported for some autistic patients, as shown in Table 2. In patients with four disease entities associated with mental retardation, adequately documented studies have been completed showing abnormal 5-HT blood levels. In addition to Down's syndrome, these entities included phenylketonuria (PKU), histidinemia, and the infantile spasm syndrome. Also, it has been reported that some patients with the congenital organic brain syndromes affecting motor function ("cerebral palsy") have an abnormal 5-HT level (Pare, Sandier, & Stacey, 1960). The remaining reports of abnormal serotonin levels in retarded patients are limited to single series "or, in some cases, to individual case studies. A number of such forms of retardation, in particular the infantile spasm syndrome and the leukodystrophy group, have prominent psychiatric symptoms in addition to neurological manifestations of the disease.

SEROTONIN AND CNS SYNDROMES 3 1

Table 2

R e p o r t s o f A b n o r m a l S e r o t o n i n Levels in Blood o f R e t a r d e d Pa t ien ts

Endogenous 5-HT level in blood

Syndrome I

low high serum platelet ] i

Abnormality reported in 2 or more different studies

Down's syndrome X X Phenylketonuria X X X Histidinemia X X Infantile spasm syndrome X

Abnormality in 2 or more cases reported by one author

Infant hypothyroidism X Maternal rubella X X Kernicterus X X Cornelia de Lange syndrome X

Single case reports

Gargoylism X X Sturge Weber (retarded) X X Cerebral lipidosis X X Schider's disease X

Method used for determination

whole blood

X X

X

X

X

X

Source.-Coleman, Barnet, Lodge, and Cytryn (1973).

It is clear from the studies of all these different patient groups that a causal

relationship between blood serotonin abnormalities and any specific disease state

of the CNS has not been established. In many of these diseases, 5-HT

abnormality is not consistently seen in all patients. Even in the carcinoid syndrome, the disease entity with the most abnormal 5-HT values ever recorded,

the levels in the blood and urine do not correlate directly with the severity of clinical symptoms (Levine & Sjoerdsma, 1963). The mechanism resulting in

5-HT abnormality appears to differ in each group of diseases. One reason for this large number of disease entities with recorded 5-HT abnormalities may be the fact that 5-HT shares enzymes, co-enzymes, transport, and binding mechanisms with a number of other amino acid pathways, is altered by derangement in these

other pathways, and is then conveniently located in the platelets where its fluctuations in endogenous levels and mechanisms can be readily extracted from the blood and measured.

32 MARY COLEMAN

However, it is not possible to dismiss serotonin as irrelevant. One of the most intriguing aspects of 5-HT levels in blood is the close relationship between abnormal levels of 5-HT and decreased CNS function in so many of these patient groups. In the hyperactivity syndrome, a very close relationship exists between blood levels of 5-HT and hyperactivity behavior patterns in patients whose baseline levels show low serotonin. Also, in the retardation syndromes, a pattern of abnormal 5-HT levels/abnormal brain function and normal 5-HT levels/normal brain function is seen in a number of diseases. An example is provided by PKU patients (over 90% are retarded) who have low 5-HT levels (Yarbro & Anderson, 1966) yet hyperphenylalanemia patients (not retarded) have normal blood 5-HT levels (Berman, Justice, & Hsia, 1969). According to Pare et al. (1960), spastics who are retarded may have abnormal serum 5-HT levels while spastic patients with normal intelligence quotients have normal levels. Also, when patients with low 5-HT values are placed on diet therapies designed to improve brain function, the low 5-HT level will rise toward the normal range in the individual patient during treatment. This has been reported in PKU (Pare, Sander, & Stacey, 1958; Baldridge, Borofsky, Baird, Reichle, & Bullock, 1959) and histidinemia (Corner, Holton, Norman, & Williams, 1968). In a fairly recent study of synthetic diets in retarded PKU patients, McKean (1971) reported a simultaneous "abrupt increase in blood serotonin and improved behavior" at phenylalanine levels of 10-12 mg/100 ml. in three patients and 5 rag./100 ml. in a fourth child. These critical levels of phenylalanine that improve behavior differ in each individual patient; it is most interesting that this level coincides with the one that abruptly increases the low blood serotonin levels in each patient. Conversely, when a hypothyroid patient is placed on therapy, his abnormally elevated whole blood 5-HT level drops into the normal range (Coleman, 1970).

Why is the platelet handling of 5-HT so clinically useful? Why does an uptake and binding system in a blood cell appear to reflect abnormalities in CNS function? Paasonen (1968), Pletscher (1968), and Page (1968) have postulated that the platelet may be a partial "model" for the serotonergic neuron.

Much research in the past on biogenic amines has focused on the metabolic pathways-their substrates, enzymes, and co-enzymes-which produce the specific amount of the amine present in the neurone. More recent research has been devoted to measuring the dynamic rate of production of the amines-their turnover times, feedback control systems, etc. However, in the case of 5-HT, this large literature focused on the determinants of the endogenous level of the amine in the CNS has had limited application to actual disease processes. It can be postulated that the endogenous level of 5-HT in the brain is not the critical factor in many diseases because there is data to show that 5-HT synthesis

SEROTONIN AND CNS SYNDROMES 33

generally is well in excess of what is needed, at least in rats (Grahame-Smith,

1971).

It is in the next steps of 5-HT processing-the binding of 5-HT and its delivery to the transmitter sites-that clinically relevant data possibly will be found. Further study is needed of the intraneuronal organization of 5-HT pools, that is, the system that critically determines the amount of 5-HT actually available at the receptor site in the serotonergic neuron. Under normal conditions, this is probably controlled by the amount of 5-HT bound to the 5-HT intraneuronal granule in contrast to the amount of 5-HT unbound in the neuron (Carlsson,

1966; Takatsuka, Segawa, & Takagi, 1971). Ions and other factors that control binding may often control functional levels of 5-HT in the brain.

These same factors may also control 5-HT binding in the platelet in many

physiological states. Both neuronal binding and platelet binding appear to be

highly sensitive to several types of pathological processes. Thus, the easily

extracted platelet in the blood becomes a useful, if limited, tool in the study of the most inaccessible portion of the body- the central nervous system.

The remaining chapters on the value of serotonin studies in diagnosing human diseases of the CNS are still awaiting to be written. As with children, there are a number of adult psychiatric entities where investigators have found apparently nonspecific 5-HT or 5-HIAA abnormalities-one subgroup of depression, some manic patients, and acute schizophrenia. Just as a hemoglobin level outside the normal limits tells us that the patient may have anemia or polycythemia, a 5-HT level outside the normal limits (in the absence of systemic disease or drugs affecting 5-HT) suggests that the patient may have brain dysfunction.

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Berman, J., Justice, P., & Hsia, D. Y. Y. Effect of vitamin B6 on blood 5-hydroxytryptamine concentration. Annals of the New York Academy of Sciences, 1969, 166, 97.

Boullin, D. J., Coleman, M., & O'Brien, R. A. Abnormalities in platelet 5-hydroxytryptamine efflux in patients with infantile autism. Nature, 1970, 226, 371-372.

Boullin, D. J., Coleman, M., O'Brien, R. A., & Rimland, B. Laboratory predictions of infantile autism based on 5-hydroxytryptamine efflux from blood platelets and their correlation with the Rimland E-2 score. Journal of Autism and Childhood Schizophrenia, 1971, 1, 63-71.

34 MARY COLEMAN

Carlsson, A. Physiological and pharmacological release of monoamines in the central nervous system. In U. S. Von Euller, S. Rosell, & B. Uvnas (Eds.), Mechanisms of release of biogenic amines. New York: Pergamon Press, 1966.

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SEROTONIN AND CNS SYNDROMES 35

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