The relationship between folate and docosahexaenoic acid in men.

OBJECTIVE: Docosahexaenoic acid (DHA, 22:6n-3), an essential omega 3 fatty acid, may protect against disorders of emotional regulation as well as cardiovascular disease. Animal studies demonstrate that dietary folate can increase tissue concentrations of DHA, although the literature, to date, includes no human studies examining the possibility that folate status may affect plasma DHA concentrations. The objective of this study is to determine if the blood concentrations of folate and DHA are correlated in humans. DESIGN: Retrospective study. SETTING: An American research hospital. SUBJECTS: A total of 15 normal and 22 hostile and aggressive subjects, with a mean age of 38 years. METHODS: Concentrations of plasma polyunsaturated essential fatty acids and red blood cell folate (RBC folate) were obtained prior to 1996, before American flour was enriched with folate. RESULTS: RBC folate was significantly correlated with plasma DHA, r=0.57, P=0.005 in the aggressive group. Age, smoking and alcohol consumption did not alter the results. No other essential fatty acids were significantly associated with RBC folate in either group. CONCLUSIONS: The positive relationship between plasma DHA and RBC folate concentrations suggests that these two nutrients should be examined together in order to make the most accurate inferences about their relative contributions to disease pathogenesis. Our findings present one explanation why some conditions associated with hostility and low DHA status, such as cardiovascular disease and emotional disorders, are also associated with low folate status. SPONSORSHIP: National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism.

A prospective follow-up study of alcoholic violent offenders and fire setters.

BACKGROUND: This study investigated biochemical and family variables and predictors of recidivism among forensic psychiatric patients who had committed violent offenses or set fires. METHODS: One hundred fourteen male alcoholic violent offenders and fire setters were followed up for an average of 4.5 years after release from prison. At the beginning of their incarceration, the first half of the offenders were administered clinical diagnostic interviews, whereas the latter half received the Structured Clinical Interview for DSM-III (SCID) that was blind rated. A structured family history questionnaire was administered to all available first-degree relatives of offenders. The offenders also received lumbar punctures for monoamine metabolites, an oral glucose tolerance test, and a measurement of fasting plasma cholesterol level. At the end of the follow-up, the Finnish criminal registry was searched for recidivist crimes. RESULTS: Among all offenders, low cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) concentrations were associated with a family history positive for paternal alcoholism with violence. Low plasma cholesterol concentration was associated with a family history positive for paternal alcoholism without violence. The recidivists, who committed violent offenses or set fires during the follow-up period, had low CSF 5-HIAA and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations compared with those in nonrecidivists. Early family environments of the recidivists, compared with those of the nonrecidivists, were characterized by common paternal absence from and presence of brothers at home. CONCLUSION: Among male alcoholic violent offenders and fire setters, low CSF 5-HIAA and HVA concentrations are strongly associated with a family history positive for paternal violence and alcoholism, while low fasting plasma cholesterol concentration is associated with a family history positive for paternal alcoholism. Recidivist violent offenders and fire setters are predicted by low CSF 5-HIAA and MHPG concentrations and a developmental history positive for early paternal absence from and presence of brothers in the family of origin.

Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism.

BACKGROUND: To examine whether the tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme in the biosynthesis of serotonin, may be a factor influencing serotonin turnover and behaviors controlled by serotonin. METHODS: Using a polymerase chain reaction-based method, TPH genotype was determined in DNA samples from 56 impulsive and 14 nonimpulsive, alcoholic, violent offenders and 20 healthy volunteers. RESULTS: In the behaviorally extreme impulsive group, we observed a significant association between TPH genotype and cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) concentration. No association of TPH genotype with impulsive behavior was detected. The polymorphism was also associated with a history of suicide attempts in all violent offenders, independent of impulsivity status and cerebrospinal fluid 5-HIAA concentration. CONCLUSION: In some individuals, a genetic variant of the TPH gene may influence 5-HIAA concentration in the cerebrospinal fluid and predisposition to suicidal behavior.

Hippocampal volume in patients with alcohol dependence.

BACKGROUND: Smaller hippocampal volumes have been reported in the brains of alcoholic patients than in those of healthy subjects, although it is unclear if the hippocampus is disproportionally smaller than the brain as a whole. There is evidence that alcoholic women are more susceptible than alcoholic men to liver and cardiac damage from alcohol. It is not known whether the hippocampi of the female brain are more vulnerable to alcohol. METHODS: We compared the hippocampal volumes in 52 hospitalized alcoholic men and women with those of 36 healthy nonalcoholic men and women. All subjects were between 27 and 53 years of age. The hippocampal volumes were measured from sagittal T-weighted high-resolution magnetic resonance images. RESULTS: The alcoholic women had less lifetime drinking and a later age at onset of heavy drinking than alcoholic men. Both alcoholic men and women had significantly smaller right hippocampi and larger cerebrospinal fluid volumes than healthy subjects of the same sex. Only among women were the left hippocampus and the nonhippocampal brain volume also significantly smaller. The proportion of hippocampal volume relative to the rest of the brain volume was the same in alcoholic patients and healthy subjects, in both men and women. The right hippocampus was larger than the left among all subjects. Women demonstrated larger hippocampal volumes relative to total brain volume than men. Psychiatric comorbidity, including posttraumatic stress disorder, did not affect hippocampal volume. CONCLUSIONS: In chronic alcoholism, the reduction of hippocampal volume is proportional to the reduction of the brain volume. Alcohol consumption should be accounted for in studies of hippocampal damage.

A quantitative investigation of hippocampal pyramidal cell size, shape, and variability of orientation in schizophrenia.

Hippocampal abnormalities have been described in patients with schizophrenia, with disarray of pyramidal cells being one of the more intriguing findings. Controversy exists regarding whether disarray is present in the brains from schizophrenics in the Yakovlev collection at the Armed Forces Institute of Pathology, Washington, DC. We examined for disarray the CA1 region of the midhippocampus of 17 schizophrenics and 32 controls from this collection using computerized determination of neuronal angle and directional statistical analysis of the variability of neuronal angle. Neuronal area and shape were also assessed. We found no differences between patients and controls in these measures. Possible methodological reasons for the discrepancy between our and others' findings are discussed, as well as directions for further research into possible pathological study of the hippocampus and related structures in schizophrenia.

Personality profiles and state aggressiveness in Finnish alcoholic, violent offenders, fire setters, and healthy volunteers.

BACKGROUND: Based on clinical observations in a series of studies on Finnish alcoholic, violent offenders, we asserted that the impulsive offenders represented an extreme group of type 2 alcoholics. We also observed that these subjects were vulnerable to hypoglycemia after the administration of oral glucose load. Furthermore, we believe that while being hypoglycemic, the impulsive offenders are particularly irritable and aggressive. In the present study, we addressed these issues by studying psychological trait and state variables in a new group of violent offenders and fire setters, and age- and sex-matched healthy volunteers. METHODS: Fifty-eight alcoholic, violent offenders and impulsive fire setters and 21 healthy volunteers were administered the Karolinska scales of personality and the Rosenzweig picture frustration test after an oral aspartame and glucose challenge. RESULTS: The psychological test results and the criminal histories of the offenders, together with biochemical measurements, suggest that a low 5-hydroxyindoleacetic acid concentration in cerebrospinal fluid in the alcoholic offenders is associated with irritability and impaired impulse control, and a high free testosterone concentration in cerebrospinal fluid is associated with increased aggressiveness, monotony avoidance, sensation seeking, suspiciousness, and reduced socialization. CONCLUSION: Finnish alcoholic, impulsive offenders have personality profiles characteristic of Scandinavian early-onset male alcoholics with antisocial traits, who have been also referred to as type 2 alcoholics.

CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers.

BACKGROUND: There is an extensive literature describing a central serotonin deficit in alcoholic, impulsive, violent offenders and fire setters. In the present study, we investigated biochemical concomitants of impulsivity and aggressiveness, and the physiological consequences of reduced central serotonin turnover. METHODS: Forty-three impulsive and 15 nonimpulsive alcoholic offenders and 21 healthy volunteers were studied in the forensic psychiatry ward of a university psychiatric department. The subjects underwent lumbar punctures and oral glucose and aspartame challenges, and their diurnal activity rhythm was measured with physical activity monitors. Discriminant function analyses were used to investigate psychophysiological and biochemical concomitants of aggressive and impulsive behaviors. RESULTS: Alcoholic, impulsive offenders with antisocial personality disorder had low mean cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and corticotropin levels and high mean CSF testosterone concentrations. Compared with healthy volunteers, they showed increased physical activity during the daytime. Alcoholic, impulsive offenders with intermittent explosive disorder had a low mean CSF 5-HIAA concentration and blood glucose nadir after an oral glucose challenge, and desynchronized diurnal activity rhythm. Healthy volunteers had mean CSF 5-HIAA concentrations that were intermediate between those of alcoholic, impulsive and nonimpulsive offenders. Alcoholic, nonimpulsive offenders had a significantly higher mean CSF 5-HIAA concentration than all the other groups, including healthy volunteers. CONCLUSIONS: In the present sample, a low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence.

Negative association of neuroticism with brain volume ratio in healthy humans.

BACKGROUND: Brain volume decreases with normal aging. We sought to determine whether, in addition to age, individual differences in stress reactivity (i.e., neuroticism) would also predict reductions in brain volume. METHODS: Brain volume ratios were calculated for a sample of 86 healthy volunteers, based on segmented brain volumes taken from T(1)-weighted magnetic resonance imaging and corrected for intracranial volume. Standardized self-reported measures of dispositional neuroticism were concurrently obtained by administering the Revised NEO Personality Inventory. RESULTS: After statistically controlling for age and sex, neuroticism showed a significant negative association with the ratio of brain to the remainder of the intracranial volume, but was not related to intracranial volume itself. In particular, subfactors of neuroticism related to the chronic experience of arousing negative emotions were associated with reduced brain ratio. CONCLUSIONS: These results suggest that individual differences in stress reactivity contribute to reductions in brain volume observed during adulthood.

Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics.

BACKGROUND: Impulsive violence, suicide, and depression are strongly associated with low concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA). Increased suicide and trauma reported in some cholesterol-lowering trials may be related to altered concentrations of polyunsaturated fatty acids rather than cholesterol, a possible surrogate marker. METHODS: CSF 5-HIAA and homovanillic acid (HVA), total cholesterol, and plasma fatty acid concentrations were examined in 176 subjects, including 49 healthy volunteers, and 88 early- and 39 late-onset alcoholics. RESULTS: Among each group, polyunsaturated fatty acids predicted both CSF 5-HIAA and CSF HVA concentrations, but total cholesterol was unrelated to either neurotransmitter metabolite. The relationships between plasma 22: 6n3 and CSF 5-HIAA were significantly different when healthy volunteers (r = .35) were compared to early-onset alcoholics (r = -.38) (p < .0002). CONCLUSIONS: Dietary studies are indicated to determine if essential fatty acid supplementation can influence central nervous system serotonin and dopamine metabolism and modify impulsive behaviors related to these neurotransmitters.

Lactate-induced rage and panic in a select group of subjects who perpetrate acts of domestic violence.

BACKGROUND: Perpetrators of domestic violence frequently report symptoms of autonomic arousal and a sense of fear and/or loss of control at the time of the violence. Since many of these symptoms are also associated with panic attacks, we hypothesized that perpetrators of domestic violence and patients with panic attacks may share similar exaggerated fear-related behaviors. To test this hypothesis, we employed the panicogenic agent sodium lactate to examine the response of perpetrators to anxiety fear induced by a chemical agent. METHODS: Using a double-blind, placebo-controlled design, we infused 0.5 mol/L sodium lactate or placebo over 20 min on separate days to a select group of subjects who perpetrate acts of domestic violence and two nonviolent comparison groups. We compared their behavioral, neuroendocrine, and physiologic responses. RESULTS: Lactate administration elicited intense emotional responses in the perpetrators of domestic violence. Perpetrators evidenced more lactate-induced rage and panic and showed greater changes in speech, breathing, and motor activity than did nonviolent control subjects. There were no significant differences between the groups for any neuroendocrine or physiologic measure. CONCLUSIONS: These results are consistent with our hypothesis that some perpetrators of domestic violence have exaggerated fear-related behavioral responses.

Behavioral and endocrine responses to clomipramine in panic disorder patients with or without alcoholism.

Central nervous system serotonin functions may differ between certain subgroups of alcoholics, patients with panic disorder, and healthy volunteers. To investigate these possibilities we administered the serotonin uptake inhibitor, clomipramine (12.5 mg, i.v.), to patients with alcohol dependence, patients with panic disorder with or without alcohol dependence, and healthy volunteers. Alcoholics did not differ from healthy volunteers in their neuroendocrine or behavioral responses. In contrast, patients with panic disorder exhibited marked dysphoric reactions and/or panic attacks following low-dose i.v. clomipramine, whereas their neuroendocrine responses were similar to the other two groups. Patients with panic disorder may have super-sensitive postsynaptic serotonin receptors in areas of their central nervous system, which are important for mood regulation.

Monitoring the source of memory in detoxified alcoholics.

The ability to monitor the source of remembered information and related reflective cognitive processes was examined in normal volunteers and detoxified alcoholics. Normal volunteers were very accurate judges of whether remembered events were presented as stimuli or were self-generated, even when memory was tested 2 days later. In contrast, a subgroup of otherwise cognitively unimpaired alcoholics demonstrated impairments in the ability to track the source of remembered knowledge and were also less able to inhibit intrusion errors in recalling information from memory. These findings provide preliminary evidence of an impairment in cognitive control functions in certain alcoholics. This conclusion is supported by associated findings indicating that, among alcoholics, performance on explicit memory tasks that required reflective cognitive operations were positively correlated with glucose utilization rates in left prefrontal, temporal, and posterior orbital frontal cortical regions.

Relative risk for cognitive impairments in siblings of patients with schizophrenia.

BACKGROUND: Patients with schizophrenia have impairments in several domains of cognition, including working memory/executive function, verbal memory, language, oculomotor scanning/psychomotor speed, and general intelligence. Impairments have also been found in unaffected siblings, suggesting they could be heritable. To assess the suitability of cognitive dysfunction for use in genetic studies, we estimated relative risk (lambda) in a large cohort of siblings. METHODS: One hundred forty-seven patients with schizophrenia, 193 of their siblings, and 47 control subjects were studied using a neuropsychological test battery, which included intelligence quotient (IQ), Wide Range Achievement Test, Wisconsin Card Sort, Wechsler Memory Scale (revised), California Verbal List Test, Trails A and B, and Letter and Category Fluency. Relative risk was estimated using a cutoff score of 1 SD below the control mean. RESULTS: As expected, patients performed markedly worse than control subjects on all tests except the Wide Range Achievement Test. Siblings had impaired performance on the Wisconsin Card Sort and Trails B, with trends for reduction (p = .01-.05) on the California Verbal List Test and Letter Fluency. Relative risk to siblings was elevated on the Trails B (lambda = 4.0) and California Verbal List Test (lambda = 2.8). Trends (p = .01-.05) for increased lambda were also seen for Wisconsin Card Sort, Letter Fluency, Wechsler Memory Scale and decline in IQ (lambda = 1.74-2.4). Correlations between tests of different cognitive functions were weak, indicating they measure relatively independent processes. CONCLUSION: Unselected siblings of patients with schizophrenia have impairments in several cognitive domains. Relative risk scores were in the moderate range, suggesting a significant genetic component. Impairments on one test only weakly predicted impairments on other tests. Thus, cognitive phenotypes identify distinct, familial traits associated with schizophrenia. Using this dimensional approach to subdividing schizophrenia may reduce the clinical and genetic heterogeneity of schizophrenia and improve the power of genetic studies.

A replication study of violent and nonviolent subjects: cerebrospinal fluid metabolites of serotonin and dopamine are predicted by plasma essential fatty acids.

BACKGROUND: Among an independent group of subjects selected for their history of violent, impulsive behaviors and nonviolent control subjects, we attempted to replicate the finding that plasma docosahexaenoic acid concentrations were negatively correlated with cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations. METHODS: CSF 5-HIAA and homovanillic acid (HVA), fasting total cholesterol, and plasma fatty acid concentrations were examined in violent and nonviolent subjects matched for their severity of alcohol dependence. RESULTS: Violent subjects had significantly higher lifetime violence and hostility ratings and lower concentrations of CSF 5-HIAA than nonviolent subjects. Plasma docosahexaenoic acid was negatively correlated with CSF 5-HIAA only among violent subjects. CONCLUSIONS: This observational study suggests that dietary essential fatty acids may change neurotransmitter concentrations. Prospective dietary intervention trials will be required to determine if increasing dietary intake of docosahexaenoic acid will increase or decrease either CSF 5-HIAA concentrations or impulsive and violent behaviors.

Pharmacologic maintenance of abstinence in patients with alcoholism: no efficacy of 5-hydroxytryptophan or levodopa.

Pharmacologic enhancement of central nervous system serotonin and dopamine functions has been postulated to improve maintenance of abstinence in patients with alcoholism. To test this hypothesis, patients with alcoholism who completed a 42-day inpatient treatment program were randomized to be administered, in a double-blind fashion, either 5-hydroxytryptophan and carbidopa, levodopa and carbidopa, or placebo for 1 year. Eight of 31 patients who entered the analysis remained abstinent from alcohol for 1 year; however, there was no significant effect of the treatment condition on maintenance of abstinence. Baseline psychologic measures showed that patients who abstained from alcohol had more education and higher scores on memory function tests. Measures of cerebrospinal fluid obtained before the start of the study indicated that all patients who had higher concentrations of the dopamine metabolite homovanillic acid relapsed, suggesting that further research is needed to elucidate the role of dopamine in alcoholism.

Evidence for a gender-related effect of alcoholism on brain volumes.

OBJECTIVE: The goal of this study was to compare brain volumes of alcoholic and nonalcoholic men and women and determine if the magnitudes of differences in brain volumes between alcoholic women and nonalcoholic women are greater than the magnitudes of the differences between alcoholic men and nonalcoholic men. METHOD: The study group included 118 subjects: 79 inpatients 30-60 years of age who were alcohol dependent but had no clinically apparent cognitive impairment or medical illness (43 men and 36 women) and 39 healthy comparison subjects of similar age who were not alcoholic (20 men and 19 women). The volume of intracranial contents was segmented into gray matter, white matter, sulcal CSF, and ventricular CSF from a T(1)-weighted magnetic resonance image obtained after the alcoholic subjects had attained 3 weeks of sobriety. RESULTS: Alcoholic women had significantly smaller volumes of gray and white matter as well as greater volumes of sulcal and ventricular CSF than nonalcoholic women. The differences in gray and white matter volumes between alcoholic and nonalcoholic men were significant, but the significance of these differences was of a smaller magnitude than the significance of the differences between alcoholic and nonalcoholic women. Direct comparisons of alcoholic men and women showed that the proportion of intracranial contents occupied by gray matter was smaller in alcoholic women than in alcoholic men. The magnitudes of differences in brain volumes adjusted for intracranial size between alcoholic women and nonalcoholic women were greater than the magnitudes of the adjusted differences between alcoholic men and nonalcoholic men. CONCLUSIONS: These results are consistent with greater sensitivity to alcohol neurotoxicity among women.

Neuropsychological functioning in detoxified alcoholics between 18 and 35 years of age.

OBJECTIVE: The authors determined 1) cognitive functioning in detoxified alcoholics who had alcohol-related problems for a relatively brief time and 2) relationships between neuropsychological test scores and recent and chronic alcohol consumption patterns, childhood symptoms of hyperactivity/minimal brain dysfunction, and extent of familial alcoholism. METHOD: The subjects were 101 detoxified, drug-free alcoholics between 18 and 35 years of age who had consumed excessive amounts of alcohol (average of 114 g four to five times per week) for an average of 6 years. An average of 39 days after the last drink each alcoholic was given an extensive battery of neuropsychological tests assessing language skills, attention, motor skills, intelligence, memory, and cognitive functioning related to the frontal regions of the brain. RESULTS: Only four individuals evidenced mild cognitive dysfunction. Current psychiatric condition, anxiety and depressive states, and liver dysfunction were not related to cognition. Relationships of cognition of lifetime estimates of alcohol consumption (average of 189 kg) and number of days from last drink to testing were determined to be nonlinear and suggested that greater lifetime consumption predicted worse performance and that longer abstinence predicted better performance. Neither extent of familial alcoholism nor number of childhood signs and symptoms of hyperactivity/minimal brain dysfunction was predictive of cognition except that more antisocial behavior predicted poorer cognitive functioning. CONCLUSIONS: Cognition in young alcoholics, averaging 6 years of excessive alcohol consumption, was within normal limits, even though greater lifetime consumption predicted lower test scores and longer abstinence predicted higher scores.

Link between pregnancy complications and minor physical anomalies in monozygotic twins discordant for schizophrenia.

OBJECTIVE: The aim of the current study was to explore the relevancy of early pregnancy complications for the development of minor physical anomalies in monozygotic twins discordant and concordant for schizophrenia. METHOD: Pregnancy complications and minor physical anomalies were independently assessed in 22 discordant, 10 concordant, and six normal comparison monozygotic twin pairs. RESULTS: Complications occurring during early pregnancy were associated with a higher frequency of minor physical anomalies in the total group and in the discordant twin pairs particularly. While no significant differences in anomaly rates were observed among the discordant, concordant, and normal comparison groups, the discordant ill twins showed a trend toward having more anomalies than their well co-twins. CONCLUSIONS: Complications occurring early in pregnancy are relevant for the development of minor physical anomalies and may be of particular importance for the development of these anomalies in twin pairs discordant for schizophrenia.

Are neurological abnormalities in well discordant monozygotic co-twins of schizophrenic subjects the result of perinatal trauma?

OBJECTIVE: Neurological abnormalities found in schizophrenic subjects and their healthy relatives have raised questions concerning etiology. The aim of the present study was to investigate the genetic and environmental antecedents of neurological impairment in monozygotic twins discordant for schizophrenia, with particular focus on the well discordant twins. The etiological factors of interest were history of obstetric complications, family history of psychosis, history of substance abuse, and history of postnatal cerebral trauma. METHOD: History of obstetric complications, including information from pregnancy through the neonatal period, and data on neurological "hard" and "soft" signs were obtained blindly and separately for each member of 22 monozygotic twin pairs discordant for schizophrenia and seven normal comparison monozygotic twin pairs. Clinical and family interviews provided information about background factors. RESULTS: Degree of neurological impairment in the well discordant monozygotic twins was significantly positively related to history of both neonatal and total obstetric complications. None of the three other background factors investigated was related to degree of neurological impairment in the ill or well co-twins. CONCLUSIONS: The contribution of obstetric complications to the current level of neurological impairment in well discordant co-twins suggests that the spectrum of neuroabnormality, ranging from neurological signs to schizophrenia, in monozygotic discordant twins may be the result of subtle gene-environment interaction.