Russell E. Poland

CSF testosterone and 5-HIAA correlate with different types of aggressive behaviors

We studied the potential roles of testosterone and serotonin in various forms of aggressive and violent behaviors by measuring each biochemical and behaviour in free-ranging adolescent male nonhuman primates. Our results showed that (1) CSF free testosterone concentrations were positively correlated with overall aggressiveness, but not with measures of impulsivity. (2) CSF 5-HIAA concentrations were negatively correlated with impulsive behavior, and severe, unrestrained aggression, but not with overall rates of aggression. High rates of impulsive behavior were positively correlated with severe, unrestrained aggression, but not overall rates of aggression. (3) Dimensional analyses showed that while subjects with low CSF 5-HIAA exhibited high rates of aggression, high CSF testosterone further augmented rates and intensity of aggression in subjects with low CSF 5-HIAA. We conclude that high CSF free testosterone concentrations are associated with competitive aggression, while low CSF 5-HIAA concentrations are associated with severe aggression which results from impaired impulse control, and perseverance.

In vivo proton magnetic resonance spectroscopy of the normal aging human brain

The effect of age on brain metabolite concentrations was evaluated using localized proton magnetic resonance spectroscopy. This technique allows in vivo measurements of N-acetyl compounds (NA), total creatine (CR), choline-containing compounds (CHO), myo-inositol (MI), glutamate and glutamine (GLX), as well as the percentage of cerebrospinal fluid (CSF) and the brain water content within the brain region studied. Frontal gray matter and frontal white matter brain regions were examined in 36 normal healthy volunteers (19-78 years of age). Using a rigorous absolute quantitation method, with an external reference and atrophy correction, we found relatively stable concentrations of NA, a neuronal marker. In contrast, CR, CHO, MI, and the percentage of CSF increased in the gray matter with age. However, the brain water content decreased significantly with age (r = -0.72; p < 0.0001). No significant age-related changes in metabolite concentrations, CSF or brain water content were observed in the white matter regions. These findings demonstrate that biochemical alterations are associated with aging in the frontal gray matter. There might be an increase in the brain density as indicated by increased metabolite concentrations and decreased brain water content with aging.

EFFECTS OF EARLY AND RECENT ADVERSE EXPERIENCES ON ADRENAL RESPONSE TO PSYCHOSOCIAL STRESS IN DEPRESSED ADOLESCENTS

BACKGROUND As observed in depressed adults, there is considerable variability in the degree and direction of hypothalamic-pituitary-adrenal (HPA) dysfunction in depressed adolescents. The variability in HPA findings may be attributed to experiential factors. METHODS A modified version of a standard psychosocial stressor used in adults, the Trier Social Stress Test (TSST), was administered to 30 adolescents with major depressive disorder and 25 healthy adolescent volunteers. Cortisol concentrations were measured in saliva samples collected before and after the stressor. Information was also gathered on early and recent adverse experiences with standard interviews. RESULTS Participants from both groups had increased cortisol secretion in response to TSST. Compared with control subjects, depressed subjects showed more elevated and prolonged cortisol secretion in response to TSST. The combination of early-life adversity and high levels of chronic stress during adolescence was the most powerful predictor of enhanced adrenal response to the TSST. CONCLUSIONS These results support previous findings on the role of experiential factors on HPA response to stress and in the development of mood disorders. Dissection of the heterogeneous pathophysiology of adolescent depression will assist in developing more specific interventions for different subgroups of patients.

Psychobiologic effects of 3,4-methylenedioxymethamphetamine in humans: methodological considerations and preliminary observations

3,4-Methylenedioxymethamphetamine (MDMA) is a phenethylamine with potent effects on serotonergic neurotransmission which has been the object of controversy over its potential as a therapeutic adjunct versus its possible risks for causing neurotoxic injury. This paper discusses the background, methodology and preliminary findings of the first FDA approved Phase I study prospectively evaluating the effects of MDMA administration in humans. Six subjects with prior experience with MDMA were administered two different dosages of MDMA and an inactive placebo utilizing a randomized, double-blind methodologic design. Dosages from 0.25 to 1.0 mg/kg, p.o., were administered. All subjects tolerated the procedures without any overt evidence of physical discomfort or psychological distress. MDMA produced a modest increase in heart rate and blood pressure. The threshold dose for the stimulation of ACTH and prolactin appeared to be between 0.5 and 0.75 mg/kg, with the two higher doses clearly stimulating both ACTH and prolactin. Methodology for assessing MDMAs effects on serotonergic neurotransmission is discussed.

Genetic polymorphism of cytochrome P450 2C19 in Mexican Americans: A cross‐ethnic comparative study

Our objectives were to investigate cytochrome P450 (CYP) 2C19 polymorphism in Mexican Americans and compare the findings with those in 4 other ethnic groups.

Omega-3 Fatty Acid Augmentation of Citalopram Treatment for Patients with Major Depressive Disorder

Objective The objective of this study was to explore the efficacy of combination therapy with citalopram plus omega-3 fatty acids versus citalopram plus placebo (olive oil) in the initial treatment of individuals with major depressive disorder (MDD). We hypothesized that combination therapy would lead not only to greater efficacy but also to a more rapid onset of therapeutic response. Methods Forty-two subjects participated in this 9-week randomized, masked, placebo-controlled study of combination therapy (two 1 g capsules containing a blend of 900 mg of eicosapentaenoic acid, 200 mg of and docosahexaenoic acid, and 100 mg of other omega-3 fatty acids twice daily plus citalopram) versus monotherapy (two 1 g capsules of olive oil per day plus citalopram) treatment of MDD. Results The combination therapy demonstrated significantly greater improvement in Hamilton Depression Rating scale scores over time (F = 7.32; df 1,177; P = 0.008) beginning at week 4 (t = −2.48; df 177; P = 0.014). Conclusions Combination therapy was more effective than monotherapy in decreasing signs and symptoms of MDD during the 8 weeks of active treatment; however, combination therapy did not seem to enhance the speed of the initial antidepressant response. These findings suggest that there may be an advantage to combining omega-3 fatty acids with a selective serotonin uptake inhibitor in the initial treatment of individuals with MDD. A larger definitive study is warranted.

Effect of ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] on cerebral blood flow: a co-registered SPECT and MRI study

3,4-methylenedioxymethamphetamine (MDMA), an illicit recreational drug, damages serotonergic nerve endings. Since the cerebrovasculature is regulated partly by the serotonergic system, MDMA may affect cerebral blood flow (CBF) in humans. We evaluated 21 abstinent recreational MDMA users and 21 age- and gender-matched healthy subjects with brain SPECT and MRI. Ten of the MDMA subjects also had repeat SPECT and MRI after receiving two doses of MDMA. Abstinent MDMA users showed no significantly different global or regional CBF (rCBF) compared to the control subjects. However, within 3 weeks after MDMA administration, rCBF remained decreased in the visual cortex, the caudate, the superior parietal and dorsolateral frontal regions compared to baseline rCBF. The decreased rCBF tended to be more pronounced in subjects who received the higher dosage of MDMA. Two subjects who were scanned at 2-3 months after MDMA administration showed increased rather than decreased rCBF. Low-dose recreational MDMA use does not cause detectable persistent rCBF changes in humans. The lack of long-term rCBF changes may be due to a non-significant effect of serotonergic deficits on rCBF, or regeneration of serotonergic nerve terminals. The subacute decrease in rCBF after MDMA administration may be due to the direct effect of MDMA on the serotonergic system or the indirect effects of its metabolites on the dopaminergic system; the preliminary data suggest these effects may be transient.

Nocturnal Increase of Plasma Testosterone in Men: Relation to Gonadotropins and Prolactin

The nocturnal increase of plasma testosterone (T) in adult men has been well established. Luteinizing hormone (LH) does not show a similar increase throughout the night, whereas prolactin (PRL) does, suggesting the possibility of other hormone influence on T secretion. To investigate this possibility, 8 young adult men were studied for 4 consecutive nights in the sleep laboratory (2 nights adaptation, 2 nights blood sampling), by blood samples taken every 30 min during the 8-h sleep period, for measurement of LH, follicle stimulating hormone (FSH), PRL, and T. LH and FSH were secreted episodically, with little or no change in baseline levels during the night. PRL and T also were secreted episodically, but their baseline levels increased as the night progressed. Both LH and PRL had maximum within-subject correlations (averages equal +0.35 and +0.48 respectively) with T when they led T by 60 min. Within-subject correlations done on first differences (to remove the effect of slow trends) were near zero. LH and PRL had larger correlations with T than did FSH, for both calculations. These data suggest that both LH and PRL levels precede T levels by about 60 min. PRL thus may participate in the regulation of nocturnal T secretion in adult men.

Haloperidol and prolactin concentrations in Asians and Caucasians.

Serum haloperidol and prolactin concentrations were measured in 34 normal male volunteers (12 Caucasians, 11 American-born Asians, and 11 foreign-born Asians) over a 7-hour period after haloperidol administration (0.5 mg given intramuscularly or 1.0 mg given orally). The results were similar between the two Asian groups but significantly different between Caucasians and Asians. After controlling for body surface area, Caucasians still had lower serum haloperidol concentrations and less prominent prolactin responses than did Asians. Furthermore, the ethnic difference in prolactin responses could not be fully accounted for by the differences in serum haloperidol concentrations between the two ethnic groups. These results indicate that both pharmacokinetic factors, including absorption and hepatic first-pass metabolism, and pharmacodynamic factors (dopamine receptor-mediated responses) contribute to the difference in responses between Caucasians and Asians.

Cerebral 1H MRS alterations in recreational 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) users

3,4‐Methylenedioxymethamphetamine (MDMA) is an illicit drug that has been associated with serotonergic axonal degeneration in animals. This study evaluates neurochemical abnormalities in recreational MDMA users. Twenty‐two MDMA users and 37 normal subjects were evaluated with magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) in the mid‐frontal, mid‐occipital, and parietal brain regions. 1H MRS showed normal N‐acetyl (NA) compounds in all brain regions. The myo‐inositol (MI) concentration (+16.3%, P = 0.04) and the MI to creatine (CR) ratio (+14.1%, P = 0.01) were increased in the parietal white matter of MDMA users. The cumulative lifetime MDMA dose showed significant effects on [MI] in the parietal white matter and the occipital cortex. The normal NA concentration suggests a lack of significant neuronal injury in recreational MDMA users. However, the usage‐related increase in MI suggests that exposure to MDMA, even at recreational doses, may cause increased glial content. J. Magn. Reson. Imaging 1999;10:521–526.