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Objective: Genetic variation influences differential vulnerability to addiction within populations. However, it remains unclear whether differences in frequencies of vulnerability alleles contribute to disparities between populations and to what extent ancestry correlates with differential exposure to environmental risk factors, including poverty and trauma. Method: The authors used 186 ancestry-informative markers to measure African ancestry in 407 addicts and 457 comparison subjects self-identified as African Americans. The reference group was 1,051 individuals from the Human Genome Diversity Cell Line Panel, which includes 51 diverse populations representing most worldwide genetic diversity. Results: African Americans varied in degrees of African, European, Middle Eastern, and Central Asian genetic heritage. The overall level of African ancestry was actually smaller among cocaine, opiate, and alcohol addicts (proportion=0.76-0.78) than nonaddicted African American comparison subjects (proportion=0.81). African ancestry was associated with living in impoverished neighborhoods, a factor previously associated with risk. There was no association between African ancestry and exposure to childhood abuse or neglect, a factor that strongly predicted all types of addictions. Conclusions: These results suggest that African genetic heritage does not increase the likelihood of genetic risk for addictions. They highlight the complex interrelation between genetic ancestry and social, economic, and environmental conditions and the strong relation of those factors to addiction. Studies of epidemiological samples characterized for genetic ancestry and social, psychological, demographic, economic, cultural, and historical factors are needed to better disentangle the effects of genetic and environmental factors underlying interpopulation differences in vulnerability to addiction and other health disparities.

OBJECTIVE--We sought to report the 6-year incidence of proteinuria and associated risk factors in African Americans with type 1 diabetes. RESEARCH DESIGN AND METHODS--African Americans (n = 483) with type [...]

Norepinephrine is one of the catecholamines, which are biologically active compounds that affect the nervous and cardiovascular systems, the metabolic rate, smooth muscle, and body temperature. Disturbances in the norepinephrine metabolism of the brain have been associated with mood disorders. Research has also implicated disturbances in noradrenergic function in schizophrenia. Autopsies of schizophrenics have detected excessive levels of norepinephrine and related metabolites in various brain tissues. Other studies have reported elevated levels of norepinephrine or its metabolites in blood plasma and in the cerebrospinal fluid (CSF). To further investigate this issue, blood plasma levels of norepinephrine were measured in 14 subjects diagnosed with chronic schizophrenia or schizoaffective disorder; levels were measured while the subjects were standing and while they were at rest, and the difference between these two values was determined. The extent of schizophrenic psychopathology in the patients was noted, and observations were also made of CSF levels of norepinephrine and homovanillic acid, a dopamine metabolite. Dopamine is also a catecholamine associated with some mental disorders. Thirty-three control subjects who were matched for sex and age to the patients were also tested, and all subjects were not taking any drugs during the testing. Significantly higher levels of norepinephrine, both resting and standing, were found in the schizophrenic patients. Correlations were also found between plasma norepinephrine levels and clinical symptoms, which suggests a relationship between abnormally high norepinephrine and the disease process. A positive correlation was found between CSF and resting plasma norepinephrine levels, while negative correlations were found between homovanillic acid and both resting and standing plasma norepinephrine levels. Further research is recommended to investigate the role of norepinephrine levels in schizophrenia. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objective: The authors examined an index of dopaminergic neurotransmission in recently abstinent cocaine-dependent patients. Method: CSF concentrations of the dopamine metabolite homovanillic acid (HVA) were determined in 30 recently abstinent cocaine-dependent patients and 69 healthy comparison subjects. Results: The cocaine-dependent patients had a significantly higher mean concentration of CSF HVA than did the healthy comparison group. Conclusions: Recently abstinent cocaine-dependent patients may show dysregulation of the central dopaminergic system.

Since there have been reports of elevated CSF concentrations of thyrotropin-releasing hormone (TRH) in depression, the authors compared the TRH levels of 17 depressed patients and 19 normal subjects. All subjects underwent lumbar punctures after fasting overnight, and CSF concentrations of TRH were determined by radioimmunoassay. CSF concentrations of norepinephrine and monoamine metabolites were also measured. There was no significant difference between the two groups on any measure, and in the depressed patients there was no significant relation between CSF concentrations of TRH and thyrotropin-stimulating hormone responses to TRH infusion.

The effect of alcohol on gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter that is found in the brain and nervous system, has not been fully explored. This GABA system is thought to have a role in anxiety. Previous research indicates that alcohol has nonspecific effects on the cell membranes, and also affects the binding site in the complex which involves GABA, benzodiazepine (a tranquilizer), and chloride. Alcoholics are known to have a higher incidence of anxiety disorders. It was hypothesized that alcoholic patients and control subjects would have significantly different levels of GABA in their cerebrospinal fluid (CSF). Levels of GABA were determined by using an ion-exchange chromatography test combined with fluorometric detection methods. The subjects consisted of 53 alcoholics and 22 nonalcoholic controls. The alcoholics had been withdrawn from alcohol for a minimum of three weeks prior to the collection of data. When the two groups were compared, no significant differences were observed in GABA levels in the CSF. Within the alcoholic group, there were no differences in the GABA levels between those patients who had histories of withdrawal seizures and those who did not. Statistical analysis indicated that a larger sampling would be required to obtain more than a preliminary conclusion from the data. Also, results obtained for CSF GABA in alcoholics in various phases, such as during withdrawal or intoxication, may be different. (Consumer Summary produced by Reliance Medical Information, Inc.)

Up to 60 percent of depressed patients have been found to have an imbalance in the hormonal regulation in the hypothalamus, pituitary and adrenal system. Recent studies have suggested that excessive secretion of the corticotropin-releasing hormone (CRH) from the hypothalamus may be the primary dysfunction in this cycle observed with depression. The cognitive theory of depression is that it originates in negative beliefs about oneself, the world, and the future. This study was done to evaluate correlations between cognition and CRH levels. Cerebrospinal fluid (CSF) was obtained from 17 depressed patients who were also given the Beck Depression Inventory, which elicits information about pessimism, sense of failure, guilt, expectation of punishment, self-dislike, self-accusation, suicidal wishes, sadness and crying. No significant correlations were found between CRH levels in the CSF and total scores on the Beck inventory. Two items, self-accusation and crying, were related to decreased CRH levels, but independently of each other. The authors suggest that the biological and cognitive factors in depression possibly interact and should be studied further, both during and after recovery from depression. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objective: Although suicidal behavior is frequent among cocaine-dependent patients, it has been little studied. Therefore, the author examined the characteristics of cocaine-dependent patients who had attempted suicide. Method: Cocaine-dependent patients who had attempted suicide (N=84) were compared with cocaine-dependent patients who had never attempted suicide (N=130) on clinical, personality, psychiatric, and physical variables. Results: Significantly more of the patients who had attempted suicide were female and had a family history of suicidal behavior; they reported significantly more childhood trauma and were significantly more introverted, neurotic, and hostile. They had also had significantly more comorbidity with alcohol and/or opiate dependence, major depression, and physical disorders. Conclusions: The clinical implications are that family, childhood, personality, psychiatric, and physical risk factors contribute to suicidal behavior in cocaine-dependent patients. Comorbidity appears to be an important determinant of suicidal behavior. (Am J Psychiatry 2001; 158:1215-1219)

Objective: This study was an examination of whether a family history of suicide is associated with attempts at suicide among alcoholics. Method: A consecutive series of 333 alcoholics were interviewed about whether or not they had ever attempted suicide and about their family history of suicide. Results: Compared with alcoholics who had never attempted suicide, significantly more of the alcoholics who had attempted suicide reported that a first- or second-degree relative had committed suicide. Conclusions: A family history of suicide may indicate that an alcoholic has a higher risk of attempting suicide. (Am J Psychiatry 2000; 157:2050-2051)

Objective: The authors hypothesized that significantly more living monozygotic than dizygotic co-twins of twin suicide victims would themselves have attempted suicide. Method: They determined the absence or presence of an attempt at suicide at any time among 26 living monozygotic co-twins and nine living dizygotic co-twins of twins who had committed suicide. Results: They found that 10 of the 26 surviving monozygotic co-twins but none of the nine surviving dizygotic co-twins had themselves attempted suicide. Conclusions: Although monozygotic and dizygotic twins may have some differing developmental experiences, these results contribute to findings of previous studies of suicide in twins in suggesting that genetic factors may play a role in suicidal behavior.

Animal and human studies indicate that GABBR1, encoding the GABAB1 receptor subunit, and SLC6A1,encoding the neuronal gamma‐aminobutyric acid (GABA) transporter GAT1, play a role in addiction by modulating synaptic GABA. Therefore, variants in these genes might predict risk/resilience for alcoholism. This study included 3 populations that differed by ethnicity and alcoholism phenotype: African American (AA) men: 401 treatment‐seeking inpatients with single/comorbid diagnoses of alcohol and drug dependence, 193 controls; Finnish Caucasian men: 159 incarcerated alcoholics, half with comorbid antisocial personality disorder, 181 controls; and a community sample of Plains Indian (PI) men and women: 239 alcoholics, 178 controls. Seven GABBR1tag single nucleotide polymorphisms were genotyped in the AAand Finnish samples; rs29220 was genotyped in the PIfor replication. Also, a uniquely African, functional SLC6A1insertion promoter polymorphism (IND) was genotyped in the AAs. We found a significant and congruent association between GABBR1rs29220 and alcoholism in all 3 populations. The major genotype (heterozygotes in AAs, Finns) and the major allele in PIs were significantly more common in alcoholics. Moreover, SLC6A1 INDwas more abundant in controls, that is, the major genotype predicted alcoholism. An analysis of combined GABBR1rs29220 and SLC6A1 INDgenotypes showed that rs29220 heterozygotes, irrespective of their INDstatus, had an increased risk for alcoholism, whereas carriers of the INDallele and either rs29220 homozygote were more resilient. Our results show that with both GABBR1and SLC6A1,the minor genotypes/alleles were protective against risk for alcoholism. Finally, GABBR1rs29220 might predict treatment response/adverse effects for baclofen, a GABABreceptor agonist. The GABBR1gene, encoding the GABAB1 receptor subunit, modulates synaptic GABA thereby playing a role in addiction. We found a congruent association between a GABBR1SNP rs29220 and alcoholism in three populations that differed by alcoholism phenotype and by ethnicity: African Americans (AA), Finnish Caucasians and Plains American Indians (PI). The major genotype (heterozygotes in AAs, Finns) and the major allele in PIs were significantly more common in alcoholics. In contrast, the minor genotypes/allele were protective against risk for alcoholism.

AbstractIntroductionSelf-harm is a direct, socially unacceptable,repetitive behavior that causes minor to moderate physical injury without suicidal intent. It is also a significant and growing concern among prison inmates, although it has been rarely studied. In the present study, we aimed to investigate demographic, psychosocial, and clinical variables associated to this critical bahaviour in a high risk sample of 1,555 male prisoners.MethodsPrisoners were interviewed about their history of self-mutilation, psychiatric history,and forensic history. The prisoners completed the Barratt Impulsivity Scale, Buss-Durkee Hostility Inventory, Eysenck Personality Questionnaire, and Childhood Trauma Questionnaire.ResultsEighteen percent of prisoners had a history of self-harm. They more frequently reported childhood traumas, were more likely to be unmarried, previously imprisoned, tested positive for substance abuse, had a history of suicide attempt, and more likely showed violent tendencies.DiscussionSelf-harm among prisoners is common, being found in almost 20% of the subjects in our sample. Self-mutilation among prisoners appears to be multi-factorial with developmental, socio-demographic, psychiatric, and personality determinants.ConclusionSelf-harm is associated with critical behaviors such as violence, substance abuse and suicide attempts, which represent major critical problems in contention environments.

Background: Ethanol is metabolized by 2 rate‐limiting reactions: alcohol dehydrogenases (ADH) convert ethanol to acetaldehyde that is subsequently metabolized to acetate by aldehyde dehydrogenases (ALDH). Approximately 50% of East Asians have genetic variants that significantly impair this pathway and influence alcohol dependence (AD) vulnerability. We investigated whether variation in alcohol metabolism genes might alter the AD risk in four non‐East Asian populations by performing systematic haplotype association analyses to maximize the chances of capturing functional variation.

To examine the relationship between childhood trauma and prevalence of cardiovascular disease (CVD) (either coronary disease or stroke) in Type 1diabetes (DM).

Studies have increasingly shown that gene-environment interactions are important in psychiatry. Suicidal behavior is a major public health problem. Suicide is generally considered to be a multi-determined act involving various areas of proximal and distal risk. Genetic risk factors are estimated to account for approximately 30 to 40 of the variance in suicidal behavior. In this article, the authors review relevant studies concerning the interaction between the serotonin transporter gene and environmental variables as a model of gene-environment interactions that may have an impact on suicidal behavior. The findings reviewed here suggest that there may be meaningful interactions between distal and proximal suicide risk factors that may amplify the risk of suicidal behavior. Future studies of suicidal behavior should examine both genetic and environmental variables and examine for gene-environment interactions.

Objective: A high percentage of suicide victims have seen a primary care physician in the months before committing suicide. Thus, primary care physicians may play an important role in suicide prevention. Method: The authors mailed a survey to directors of training programs in family practice, internal medicine, and pediatrics, and 50.5% responded. Data obtained were analyzed with WebStat. Results: Training directors reported deficiencies in training in suicide and depression. Notably, less than half of the internal medicine and pediatrics training directors who replied reported that teaching about suicide was adequate. The majority of them indicated a need for standardized curricular materials on suicide and depression. Conclusions: Experts could provide standardized curricula to primary care residencies in the recognition and management of suicide and depression. More robust training about these vital mental health concerns in primary care could reduce morbidity and mortality.

To examine longitudinal data about depression in relationship to glycemic control and as a risk factor for diabetic retinopathy (DR). Depression is a common psychiatric disorder among diabetic persons and has been shown in cross-sectional studies to be associated with the vascular complications of diabetes.

In a matched controlled study manic depressive patients who suicided were compared with those who did not suicide. Significantly more of those who suicided lived alone, had early parental loss, had attempted suicide in the past, and were depressed and suicidal at their last admission. The period after discharge was found to be a time of increased risk.

A follow-up study was carried out of suicidal behavior among 127 chronic schizophrenic patients. We were able to obtain follow-up information for 100 of the 127 patients (78.7%). Over the mean follow-up time of 4½ years, 6 of these 100 patients (6%) had committed suicide and 16 other patients (16%) had attempted suicide. Chronic schizophrenic patients who attempted suicide during the follow-up period, compared with those who did not, had had significantly more psychiatric admissions. Using the data obtained at the time of the index admission we were unable to accurately predict the 6 schizophrenic patients who were known to have subsequently committed suicide.

BACKGROUND: The main reinforcing effect of cocaine is alteration of dopaminergic neurotransmission in the brain reward systems. Since dopamine is found in high concentrations in the retina, we investigated whether cocaine dependence may be associated with abnormalities of the electroretinogram. METHODS: We compared recently withdrawn cocainedependent patients (n=20) with age-, sex-, and racematched normal subjects (n=20) for responses of cone photoreceptors to light flashes on full-field electroretinograms. RESULTS: Cocaine-dependent patients had significantly reduced blue cone electroretinogram responses compared with matched normal subjects. CONCLUSIONS: This result suggests that cocainewithdrawn patients have a dysregulation of blue cone function. The electroretinogram may be useful in future studies of cocaine-dependent patients.

• Alcoholics as a group have been consistently reported to show differences from controls on various personality-inventories. Moreover, neurobiologic substrates have been postulated to underlie personality dimensions. Therefore, we compared alcoholics with controls on measures of personality and investigated relationships between measures of personality and cerebrospinal fluid monoamine metabolite concentrations. The alcoholics were significantly different from controls on many personality measurements. There were significant, negative correlations between interview-derived lifetime aggression scores and cerebrospinal fluid concentrations of both the serotonin metabolite 5-hydroxyindoleacetic acid and the dopamine metabolite homovanillic acid. However, there were no significant correlations between any cerebrospinal fluid monoamine metabolite concentrations and scores on personality inventories.

• Although depression is common among alcoholics, its determinants are poorly understood. Among 339 alcoholics, 111 (33%) had a history of major depression. Depressed, compared with never-depressed alcoholics, had a higher daily alcohol intake, more lifetime diagnoses of other anxiety and affective disorders and drug abuse, more had attempted suicide, and more reported alcoholism in both parents. Depressed alcoholics also had significantly lower cerebrospinal fluid levels of the dopamine metabolite homovanillic acid and of γ-aminobutyric acid. Among subgroups of depressed alcoholics, secondary compared with primary depressives were more often divorced, of lower social status, with an earlier onset of alcoholism, and higher Michigan Alcohol Screening Test scores. Secondary depressives also had significantly lower cerebrospinal fluid concentrations of homovanillic acid than never depressed alcoholics. These results suggest that certain psychosocial variables, alcohol consumption, and neurochemical variables may be specifically associated with depression in alcoholics.

• Eighty-one percent of 339 alcoholics participating in a research program were found to have associated mental disorders. Alcoholics with onset of heavy drinking before 20 years of age had significantly more antisocial personality traits, drug abuse, bipolar disorder, panic disorder, suicide attempts, and paternal alcoholism than alcoholics with onset after age 20 years. Alcoholics with onset before and after 20 years of age also differed significantly from each other for cerebrospinal fluid concentrations of diazepam-binding inhibitor and somatostatin. These results support the notion that age of onset may delineate subgroups of alcoholics with significant clinical and neurochemical differences.

• Suicide appears to cluster in fanmilies, suggesting that genetic factors may play a role in this behavior. We studied 176 twin pairs in which one or both twins had committed suicide. Seven of the 62 monozygotic twin pairs were concordant for suicide compared with two of the 114 dizygotic twin pairs (11.3% vs 1.8%). The presence of psychiatric disorder in the twins and their families was examined in a subsample of 11 twin pairs, two of whom were concordant for suicide. Eleven of these 13 twin suicide victims had been treated for psychiatric disorder, as had eight of their nine surviving cotwins. In addition, twins in 10 pairs had other first- or second-degree relatives who had been treated for psychiatric disorder. Thus, these twin data suggest that genetic factors related to suicide may largely represent a genetic predisposition for the psychiatric disorders associated with suicide. However, they leave open the question of whether there may be an independent genetic component for suicide.

• Plasma homovanillic acid (HVA) levels were measured hourly for a 24-hour period in 10 patients with schizophrenia during treatment with placebo and fluphenazine. Ten age- and sex-matched normal volunteers were similarly studied. Diet and activity were carefully controlled and monitored in both patients and controls. A circadian rhythm of the plasma HVA level was found in controls with a nadir in the afternoon and peak values in the early morning hours; when the patients were free from drugs, they showed a similar rhythm with lower amplitudes. Fluphenazine treatment significantly reduced the plasma concentrations of HVA and abolished the 24-hour rhythm. These data suggest that a 24-hour rhythm of the plasma HVA level exists in humans and that the amplitude of this rhythm may be less pronounced in patients with schizophrenia. Treatment with neuroleptic drugs reduces both the absolute levels and the normal circadian rhythm of the plasma HVA level.

• We carried out a 5-year follow-up study of suicidal behavior among depressed patients who earlier had determinations of cerebrospinal fluid levels of monoamine metabolites. Patients who reattempted suicide during the follow-up had significantly lower cerebrospinal fluid levels of both the serotonin metabolite 5-hydroxyindoleacetic acid and the dopamine metabolite homovanillic acid. The findings were most striking among melancholic patients. These follow-up results suggest that reduced central turnover of serotonin and dopamine may be associated with further suicidal behavior among depressed patients who have previously attempted suicide.

• Diazepam-binding inhibitor is a novel peptide purified to homogeneity from rat and human brain. Diazepam-binding inhibitor is present, though not exclusively, in γ-aminobutyric acid (GABA)—containing neurons where it is believed to inhibit GABAergic neurotransmission mediated by GABA by binding to the benzodiazepine-GABA receptor complex. Since an impairment of central GABAergic tone has been postulated to be associated with a number of neuropsychiatric disorders, we measured human diazepam-binding inhibitor immunoreactivity in the cerebrospinal fluid (CSF) of patients suffering from endogenous depression, schizophrenia, and dementia of the Alzheimer's type. Patients with major depression had significantly higher concentrations of human diazepam-binding inhibitor immunoreactivity in CSF when compared with age- and sex-matched normal volunteers, while no difference in CSF diazepam-binding inhibitor immunoreactivity was found in schizophrenics or patients with dementia of the Alzheimer's type when compared with controls. The possibility is discussed that the increased CSF human diazepam-binding inhibitor immunoreactivity observed in depressed patients may represent a functional disinhibition of GABAergic neurotransmission associated with depression.

• The cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 23 patients meeting DSM-III criteria for major depressive episode, 15 of whom also met criteria for melancholia. Life events during the six-month period before the onset of depression were recorded using Paykel's method. There was no difference in Hamilton depression ratings between patients with life events and those without. However, depressed patients who did not have a life event in the six months before the onset of depression had significantly lower levels of the dopamine metabolite homovanillic acid and the serotonin metabolite 5-hydroxyindoleacetic acid than those with life events. The incidence of nonsuppression on the dexamethasone suppression test was also greater in patients with a major depressive episode who did not have an undesirable life event than in those who did. Thus, the presence or absence of life events led to a separation into biologically distinct groups.

• The plasma levels of homovanillic acid (HVA), a major circulating dopamine (DA) metabolite, were measured in schizophrenic patients during five weeks each of double-blind placebo-controlled neuroleptic treatment (N =16) and withdrawal (N =11). Both neuroleptic treatment and withdrawal were associated with time-dependent changes in the plasma levels of HVA; treatment was associated with decreases and withdrawal with increases. The levels of plasma HVA measured longitudinally during both conditions were highly correlated with psychosis ratings. Moreover, changes in individual mean weekly levels of plasma HVA were predictive of treatment response, including changes in both positive and negative symptoms of schizophrenia. These data are consistent with the suggestion that the mechanisms of action of antipsychotic drugs involve, in addition to short-term DA receptor blockade, a slowly developing decrease in presynaptic DA activity.

• Low levels of cerebrospinal fluid (CSF) somatostatin and abnormal response to dexamethasone are two neuroendocrine disturbances reported to appear in depression and other neuropsychiatric disorders. We measured the levels of CSF somatostatin in patients with schizophrenia (n = 44) and depression (n=19). In view of in vitro and animal evidence of the ability of somatostatin to inhibit stimulated corticotropin secretion, we also administered the dexamethasone suppression test to a subgroup of the patients with schizophrenia (n =16) and the total depressed group. Lower levels of CSF somatostatin were found in dexamethasone nonsuppressors regardless of diagnosis and were negatively correlated with maximum postdexamethasone cortisol level in the total and depressed patient groups. These data suggest a functional relationship between hypothalamic-pituitary-adrenal axis hyperactivity and reduced CSF somatostatin level.

• The plasma norepinephrine (NE) level was measured in 45 depressed patients and in 41 normal control subjects. Patients who met DSM-III criteria for a major depressive episode with melancholia (MDE-MEL; N=16), and those with MDE but with melancholia in a previous episode (MDE-PMEL; N =8), had significantly higher levels of plasma NE than normal control subjects while lying and standing and a greater change in the levels; whereas, patients with MDE alone (N =10) and patients with dysthymic disorder (N =11) had levels of NE comparable with control levels. Bipolar patients (N = 7), all with current melancholia or a history of it, had significantly lower levels of NE while lying down or standing than depressed unipolar patients with similar histories of melancholia. Among unipolar patients with melancholia, nonsuppressors on the dexamethasone suppression test had significantly higher lying-down NE values than did suppressors, suggesting that dysregulation of both the hypothalamic-pituitary-adrenal axis and the peripheral sympathetic nervous system occur together in this subgroup of depressed patients.

• In a comparison with 300 matched controls, significantly more of 300 patients with nonendogenous depression had experienced permanent separation (not due to death) from their mother before both 11 and 17 years of age and significantly more had experienced permanent separation from their father (not due to death) before both 11 and 17 years of age. The results suggest that (1) early permanent separation from mother is a risk factor for nonendogenous depression but occurs in only about 6.7% of these patients before 11 years of age and in about 10% before 17 years of age and (2) early permanent separation from father is also a risk factor for nonendogenous depression and occurs in about 9.3% of these patients before 11 years of age and in about 16.7% before 17 years of age.

• Computed tomographic scans of 30 chronic schizophrenic patients and 26 matched medical controls were blindly assessed for ventricular brain ratio, cortical atrophy, thirdventricle diameter, and cerebellar atrophy. Schizophrenic tients had significantly larger third ventricles than the medical controls. There was no difference in the other brain morphologic variables. Phenomenology, drug response, CSF levels of 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, and a wide variety of clinical variables did not correlate with any measure of brain morphology. Clinicopathologic correlates of brain morphology may be limited to those patients with significant atrophy.

In a consecutive series of 28 depressed women, pre-menopausal (n = 13) and post-menopausal (n = 15) patients were compared. Post-menopausal women had significantly higher levels of plasma norepinephrine, plasma 3-methoxy-4-hydroxyphenylglycol, post-dexamethasone plasma cortisol, cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol and corticotropin-releasing hormone. However, when biologic measures were adjusted for age by analyses of covariance there were no significant differences. Pre-menopausal women had had significantly more life events before the onset of depression than post-menopausal women. The implications of these findings are discussed.

The evidence is reviewed that violent and suicidal behavior is associated with a deficiency of the serotonin system and that individuals with poor impulse control tend to become hypoglycemic during an oral glucose tolerance test, and have low levels of 5-hydroxyindole acetic acid in the cerebrospinal fluid. It is postulated that serotonergic deficits may predispose individuals to poor impulse control, disturbance of glucose metabolism, alcohol abuse, violent behavior and suicide.

Suicidal behavior, like so much else in psychiatry, tends to cluster in families. Clinical studies show that a family history of suicide is associated with a raised risk of both attempts at suicide and completed suicide. Twin studies show that monozygotic twins have a greater concordance for suicidal behavior than dizygotic twins. Adoption studies also suggest that there may be genetic factors in suicide. Most recently, molecular genetic studies report that polymorphisms of the tryptophan hydroxylase gene are associated with suicidal behavior.

Over the last few years data have accumulated suggesting that there may be genetic and biologic risk factors for suicide. This paper reviews studies from clinical populations, twins, the Amish, as well as data from the Iowa-500 and Danish-American adoption studies which suggest that there may be a genetic factor predisposing to suicide. The paper also reviews neurochemical data from cerebrospinal fluid, urine and postmortem studies which suggest that diminished central serotonin and dopamine may be implicated in suicidal behavior.

There are generally considered to be five lines of evidence about the possibility that there may be genetic factors in suicide. This paper will review the clinical, Iowa-500, Amish, twin and adoption studies which provide evidence about this possibility.

Alcoholism is a psychiatric disorder with an increased risk of suicide. Knowledge about risk factors for suicide among alcoholics is briefly reviewed.

Approximately 10% of schizophrenics die by committing suicide. The schizophrenic who commits suicide tends to be male, young, unmarried, vulnerable to develop depression, is in the first few years of illness and has made a past suicide attempt. The postdischarge period is a time of increased risk.

Depressed patients (n = 46) were compared with normal controls (n = 42) for their scores on 7 personality variables measured on 4 personality questionnaires. The scores of the depressed patients obtained during the index depressive episode were significantly higher for introversion, neuroticism, and hostility, and significantly lower for self-esteem, than those of controls. Similarly, a subset of the female depressed patients studied when in remission and euthymic also had significantly higher socres than female controls for neuroticism and hostility, with a trend for significantly lower self-esteem scores. There were no significant differences on any of the 7 personality variables measured between depressed patients, with and without melancholia, or between patients with either unipolar or bipolar depression.

• Cerebrospinal fluid studies have reported that low concentrations of the dopamine metabolite homovanillic acid are associated with suicidal behavior in depression. Although only a small proportion of homovanillic acid in the urine derives from the brain, we decided to examine 24-hour urinary outputs of homovanillic acid in relation to suicidal behavior in depression. Patients with depression who had attempted suicide had significantly smaller urinary outputs of homovanillic acid, dihydroxyphenylacetic acid, and total body output of dopamine (sum dopamine) than did patients with depression who had not attempted suicide. Patients with depression who reattempted suicide during 5-year follow-up had significantly smaller urinary outputs of homovanillic acid and sum dopamine than did patients who did not reattempt suicide, patients who never attempted suicide, and normal control subjects, and had significantly smaller outputs of dihydroxyphenylacetic acid than patients who never attempted suicide or control subjects. These data suggest that urinary outputs of homovanillic acid may be peripheral correlates of suicidalithomovanillicion. These data add to data on the low levels of homovanillic acid in cerebrospinal fluid in suggesting that diminished dopaminergic neurotransmission may play a part in suicidal behavior in depression.

• Among 140 depressed and control subjects, there were significant positive correlations between indexes of noradrenergic activity in cerebrospinal fluid (CSF), plasma, and urine. Among the depressed patients, CSF levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary outputs of NE and its metabolites normetanephrine, MHPG, and vanillylmandelic acid correlated significantly with plasma cortisol levels in relation to dexamethasone administration. Also, CSF levels of MHPG were significantly higher among patients who were cortisol nonsuppressors than among either patients who were cortisol suppressors or controls. Urinary outputs of NE and normetanephrine were significantly higher among patients who were cortisol nonsuppressors than among controls. Patients who were cortisol suppressors had indexes of NE metabolism similar to those of controls. These results in the depressed patients extend recent observations suggesting that dysregulation of the noradrenergic system and hypothalamic-pituitary-adrenal axis occur together in a subgroup of depressed patients.

• We investigated psychobiological substrates of pathological gambling by measuring levels of norepinephrine, monoamine metabolites, and peptides in cerebrospinal fluid, plasma, and urine. Pathological gamblers had a significantly higher centrally produced fraction of cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol as well as significantly greater urinary outputs of norepinephrine than controls. These results suggest that pathological gamblers may have a functional disturbance of the noradrenergic system. This system has been postulated to underlie sensation-seeking behaviors, aspects of which are thought to be abnormal among pathological gamblers.

• We examined the intercorrelations among urinary outputs of norepinephrine (NE) and its three major metabolites in unipolar depressed patients (n = 28) and normal controls (n = 24). Among the depressed patients, levels of NE correlated with normetanephrine (NM), 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA), and VMA correlated with NM and MHPG. In the total group of depressed and control subjects (n = 52), the sum of NE and its major metabolites correlated with urinary outputs of NE, NM, MHPG, and VMA. These highly significant correlations among urinary outputs of NE and its major metabolites replicate a previous report of strong correlations among these same four urinary substances in a smaller group of depressed patients.

• We investigated the possible interactions between corticosteroids and catecholamines in depression by studying the effects of the synthetic glucocorticoid dexamethasone on plasma levels of homovanillic acid (HVA) and 3-methoxy-4--hydroxyphenylglycol (MHPG) in a group of depressed patients and normal controls. In comparison with metabolite levels on a control day, normal controls showed a significant dexamethasone-induced increase in the plasma HVA level and a trend toward a decrease in the plasma MHPG level at 4 PM following dexamethasone administration (1 mg orally at 11 PM). Conversely, depressed patients, particularly those with psychotic features, showed a significant dexamethasone-induced increase in the plasma MHPG level and a blunting of the plasma HVA response relative to the normal controls. Dexamethasoneinduced increases in the plasma MHPG level were directly correlated with the severity of depressive symptoms and with postdexamethasone cortisol levels in the depressed patients. These data suggest abnormal corticosteroid-catecholamine interactions in depression and, specifically, in depressed patients with psychotic features.

• We measured platelet tritiated imipramine binding and serotonin uptake in 51 depressed patients and 43 normal controls. Although there were no significant differences in platelet 3H-imipramine binding or serotonin uptake when the total group of depressed patients was compared with controls, depressed women (n = 32) had a significantly lower maximal density of 3H-imipramine binding sites (βmax) than control women (n = 25). Moreover, among the total group of depressed patients, there were significant negative correlations between the βmax values and plasma cortisol levels at 4 PM (n = 41) and 11 PM (n = 41) following dexamethasone administration. These negative correlations between βmax and cortisol levels were strongest among melancholic patients both at 4 PM before dexamethasone administration (n =14) and at 11 PM after dexamethasone administration (n =15). These data suggest that the reported decrease in βmax found among depressed patients may be related to and is perhaps secondary to the hypercortisolemia of depression.

• We administered verapamil hydrochloride, a calcium channel antagonist, to seven chronically ill schizophrenic patients for five weeks under double-blind, placebo-controlled conditions. No therapeutic effect was noted. Worsening in hostile and uncooperative behaviors and a syndrome of heightened emotional tone was observed during verapamil treatment and during the postverapamil placebo period. Verapamil produced significant increases in cerebrospinal fluid (CSF) and plasma levels of homovanillic acid and in plasma levels of prolactin, as well as significant decreases in plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol. Verapamil and its active metabolite, norverapamil, were partitioned into CSF with CSF/plasma ratios of 0.06 and 0.04, respectively. The lack of therapeutic effects of verapamil in schizophrenic patients differs from earlier reports of its usefulness in treating manic patients. The biochemical and clinical data from our study suggest the possibility that verapamil exerts behaviorally relevant central nervous system activity in schizophrenic patients.