Biological correlates of impulsive disruptive behavior disorders: attention deficit hyperactivity disorder, conduct disorder, and borderline personality disorder.
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Biomedical subjects
Publications and source records attributed to D M Stoff.
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We examined the intraindividual stability of plasma prolactin (PRL) and cortisol responses to D,L-fenfluramine challenges (1.0 mg/kg, p.o.), at a 1-week interval, in boys with disruptive behavior disorders. Two acute administrations of fenfluramine produced consistent and predictable effects on net prolactin responses (peak delta PRL, area under the curve delta PRL), but variable and unpredictable effects on net cortisol responses. The time course and magnitude of fenfluramine blood levels, not nor-fenfluramine, paralleled net PRL responses to fenfluramine. These data indicate that the PRL response to fenfluramine shows continuity within individuals over the course of 1 week, providing a reliable index to reflect the overall function of the serotonin system in the limbic-hypothalamus.
Prolactin (PRL) and cortisol (CORT) responses to a single oral administration (1.0 mg/kg) of the indirect serotonin agonist dl-fenfluramine were assessed in unmedicated prepubertal and adolescent males with disruptive behavior disorders (DBD). Neuroendocrine responses were correlated with scores on aggression rating scales in prepubertal and adolescent DBD patients and compared with those of matched adolescent normal control subjects. Net dl-fenfluramine-induced PRL and CORT release was not correlated with aggression rating scores in prepubertal and adolescent DBD patients and did not differ significantly between adolescent DBD patients and normal control subjects. Although the present study does not demonstrate a serotonergic abnormality in aggression or DBD, this may be more a reflection of limitations of the neuroendocrine challenge test procedures or the methods used than evidence that serotonergic function in the central nervous system is normal in aggression.
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Reliability and stability of neurological "subtle" ("soft") signs were assessed in 54 psychiatric patients and 25 normal children, aged 5-17 years, using the revised Neurological Examination for Subtle Signs (NESS). Acceptable interrater reliability (kappa greater than or equal to 0.50, or intraclass correlation coefficient greater than or equal to 0.70) was found for 40 of the 64 items tested. Test-retest reliability at 2 weeks was unsatisfactory for most of the categorically scored items, including some "classic" subtle signs such as overflows or dysrhythmias. Continuous items, such as time needed to perform 20 consecutive movements, remained mostly stable at retest. A practicing effect was evident only in the graphesthesia test. Overall internal consistency was good (Cronbach's alpha = 0.74). Given the poor stability of overflows and dysrhythmias, researchers and clinicians should rely more on subtle signs that can be assessed on continuous scales.
Platelet monoamine oxidase (MAO) activity was measured in 32 drug-free prepubertal boys with externalizing symptoms of disruptive behavior disorders and 47 boys with no DSM-III-R diagnoses, and correlated to questionnaire and laboratory performance measures of impulsivity. A subgroup of boys with high MAO activity exhibited significantly poorer performance (i.e., more impulsivity) than a subgroup of low MAO activity on laboratory tasks requiring response inhibition. High MAO patients were more impulsive than high MAO controls on some performance tasks and elevated platelet MAO was unrelated to personality questionnaire measures of impulsivity or to patient status. These data suggest that biological markers such as MAO activity may correlate better with performance than clinical questionnaire measures. Abnormally high platelet MAO activity may not be sufficient to produce externalizing symptoms in children, perhaps interacting with an underlying behavioral dimension of impulsivity.
Male healthy subjects, fasting 12 hours, ingested increasing amounts of a mixture containing a fixed proportion of seven essential amino acids (L-isoleucine 11.5%, L-leucine 18.0%, L-lysine 13.1%, L-methionine 18.0%, L-phenylalanine 18.0%, L-threonine 8.2%, L-valine 13.1%) and lacking tryptophan. The diets produced a rapid fall in plasma tryptophan which was proportional to the total amount of the amino acids ingested. Following the highest dose administered (36.6 g) plasma tryptophan fell to a minimum of about 35% the initial level and remained markedly reduced at 6 hours after treatment. The mechanism of this decrease and its potential clinical relevance are discussed.
Binding characteristics of tritiated imipramine on blood platelets were determined in daytime hospitalized prepubertal children who had mixed diagnoses of conduct disorder (CD) plus attention deficit disorder hyperactivity (ADDH) and in inpatient adolescents who had a history of aggressive behavior. The number of (3H)-imipramine maximal binding sites (Bmax) was significantly lower in the prepubertal patient group of CD plus ADDH; the dissociation constant (Kd) was not significantly different. There were significant negative correlations between Bmax and the Externalizing or Aggressive factors of the Child Behavior Checklist when the CD plus ADDH prepubertal patients were combined with their matched controls and within the adolescent inpatient group. We propose that a decreased platelet imipramine binding Bmax value, as an index of disturbed presynaptic serotonergic activity, is not specific to depression and may be used as a biologic marker for the lack of behavioral constraint in heterogeneous. populations of psychiatric patients.
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Testosterone pretreatment (1.0-4.0 mg/kg) attenuated, in a dose-response fashion, the induction of stereotyped behavior and hyperactivity by pargyline (0.25, 4.0 mg/kg) and beta-phenylethylamine (8.0, 16.0 mg/kg) in preubertal, male rats. The dyskinetic movements induced by pargyline and beta-phenylethylamine were proposed as a possible animal model for tardive dyskinesias. Attenuation by testosterone of these effects suggested an hormonal involvement consistent with the reported predominant occurrence of tardive dyskinesias in women and in the elderly.
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N,N-Dimethyltryptamine (DMT) was given (ip) in different doses (0.25, 0.5, 1.0, 2.0, 4.0, 8.0 mg/kg) in a randomized order to a group of ten rats (Fisher 344/Mai) who were trained to a high, stable base line of conditioned avoidance responding in the shuttlebox. DMT produced dose-dependent disruptive effects, as a sigmoid function, with 1.0 mg/kg the minimal dose causing disruption and progressively more disruption with increasing doses, reaching a plateau at the highest dose. The disruptive effects were time-related, with onset and peak 8 min after injection, gradual decline thereafter, and disappearance by about 25-30 min. Both the threshold dose and time course for the disruptive effects correspond closely to what has been previously reported for DMT's psychological effects in humans.
Acute parachlorophenylalanine (pCPA) pretreatment (150 mg/kg, i.p., 24 h beforehand) potentiated facilitatory effects of mescaline (39.6 mg/kg i.p.) on shuttlebox escape/avoidance in hooded rats, tested in two different situations: 1. during aquisition of avoidance behavior (Experiment 1); and 2. in stable pretrained poor avoiders (Experiment 2). pCPA alone did not influence avoidance behavior in either situation. Mescaline, with pCPA pretreatment, may be associated with long-term behavioral effects; all rats treated with this combination were later found to be poor avoiders, unable to achieve a stable baseline of good avoidance. pCPA significantly depleted brain norepinephrine and dopamine, as well as serotonin, measured after testing in the second situation.