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A letter to the editor is presented in response to an article by Thomas L. Walsh and colleagues about the usefulness of verapamil and nifedipine in treating patients with Tourette's disorder.

Objective: A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the alpha5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study was to replicate these findings in an independent data set and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking., Method: Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid variant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influences receptor function., Results: A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across nonhuman species, but its frequency varied across human populations (0% in African populations to 37% in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown., Conclusions: This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.

Objective: Panic attacks are a common complication of affective disorder, although the etiologic relationship of panic and affective symptoms has not been determined. Evidence from a family study suggests that panic attacks and panic disorder may be related genetically to bipolar disorder. This study used diagnostic data from the NIMH Bipolar Disorder Genetics Initiative to assess in a separate, larger family set the familiality of panic combined with bipolar disorder., Method: First-degree relatives (N=966) of probands with bipolar I disorder (N=192) and schizoaffective disorder, bipolar type, (N=11) were included in the study. All subjects were interviewed directly and were assigned best-estimate diagnoses for major affective and other psychiatric disorders. The risk of a family member being diagnosed with panic disorder if the proband with bipolar disorder had panic attacks or panic disorder was calculated with logistic regression analysis with generalized estimating equations that controlled for sex and affective disorder subdiagnosis., Results: More than 90% of the probands and first-degree relatives with panic disorder also had an affective disorder diagnosis. Panic disorder was present in 17% of the relatives with recurrent major affective disorder and in 3% of the relatives without recurrent major affective disorder. Risk of panic disorder in relatives with bipolar disorder was increased significantly if the proband had panic attacks or panic disorder., Conclusions: Risk for panic disorder with familial bipolar disorder appears to be inherited. Inherited risk for panic disorder with bipolar disorder may indicate a shared genetic etiology for both disorders in some families. The patterns of bipolar disorder and panic disorder comorbidity observed in families imply a complex genetic etiology, which may be elucidated by using endophenotypes.

Objective: Depression (major depression or depressive syndrome) is more prevalent in alcoholic than in nonalcoholic subjects in families with multiple members with alcoholism studied as part of the Collaborative Study on the Genetics of Alcoholism (National Institute on Alcohol Abuse and Alcoholism). First-degree relatives of probands with comorbid alcoholism and depression have a higher prevalence of both disorders than relatives of probands with alcoholism alone, and both groups have a higher prevalence than the relatives of comparison subjects selected without regard to psychopathology. Data from the collaborative study were used to test three phenotypes (comorbid alcoholism and depression, alcoholism or depression, and depression) for genetic linkage., Method: Genome-wide sibling-pair linkage analyses were performed with the phenotypes comorbid alcoholism and depression, alcoholism or depression, and depression (major depression or depressive syndrome). Analyses were performed in two data sets (initial and replication data sets) from subject groups ascertained with identical criteria, as well as in the combined data set., Results: Peak lod scores on chromosome 1 (near 120 centimorgan) for the alcoholism or depression phenotype were 5.12, 1.52, and 4.66 in the initial, replication, and combined data sets, respectively. The corresponding lod scores on chromosome 2 were 2.79, 0.20, and 3.26; on chromosome 6, they were 3.39, 0.00, and 0.92; and on chromosome 16, they were 3.13, 0.00, and 2.06. Lod scores on chromosome 2 for the comorbid alcoholism and depression phenotype in the three data sets were 0.00, 4.12, and 2.16, respectively., Conclusions: The results suggest that a gene or genes on chromosome 1 may predispose some individuals to alcoholism and others to depression (which may be alcohol induced). Loci on other chromosomes may also be of interest.

Objective: Schizophrenia following a traumatic brain injury could be a phenocopy of genetic schizophrenia or the consequence of a gene-environment interaction. Alternatively, traumatic brain injury and schizophrenia could be spuriously associated if those who are predisposed to develop schizophrenia have greater amounts of trauma for other reasons. The authors investigated the relationship between traumatic brain injury and psychiatric diagnoses in a large group of subjects from families with at least two biologically related first-degree relatives with schizophrenia, schizoaffective disorder, or bipolar disorder., Method: The Diagnostic Interview for Genetic Studies was used to determine history of traumatic brain injury and diagnosis for 1,275 members of multiplex bipolar disorder pedigrees and 565 members of multiplex schizophrenia pedigrees., Results: Rates of traumatic brain injury were significantly higher for those with a diagnosis of schizophrenia, bipolar disorder, and depression than for those with no mental illness. However, multivariate analysis of within-pedigree data showed that mental illness was related to traumatic brain injury only in the schizophrenia pedigrees. Independent of diagnoses, family members of those with schizophrenia were more likely to have had traumatic brain injury than were members of the bipolar disorder pedigrees. The members of the schizophrenia pedigrees also failed to show the gender difference for traumatic brain injury (more common in men than in women) that was expected and was present in the bipolar disorder pedigrees. Subjects with a schizophrenia diagnosis who were members of the bipolar disorder pedigrees (and thus had less genetic vulnerability to schizophrenia) were less likely to have had traumatic brain injury (4.5%) than were subjects with schizophrenia who were members of the schizophrenia pedigrees (and who had greater genetic vulnerability to schizophrenia) (19.6%)., Conclusions: Members of the schizophrenia pedigrees, even those without a schizophrenia diagnosis, had greater exposure to traumatic brain injury compared to members of the bipolar disorder pedigrees. Within the schizophrenia pedigrees, traumatic brain injury was associated with a greater risk of schizophrenia, consistent with synergistic effects between genetic vulnerability for schizophrenia and traumatic brain injury. Posttraumatic-brain-injury schizophrenia in multiplex schizophrenia pedigrees does not appear to be a phenocopy of the genetic disorder.

Objective: DSM-IV indicates that diagnoses of substance dependence should be further characterized with regard to the presence of a physiological component, defined by tolerance or withdrawal. This study evaluated the possible meaning of this distinction in alcohol-dependent men and women., Method: As part of the Collaborative Study on the Genetics of Alcoholism, structured interviews were carried out with 3,395 DSM-III-R-defined alcohol-dependent individuals divided into 2,949 subjects (86.9%) with evidence of tolerance and/or withdrawal (group 1), 51.3% of whom evidenced withdrawal symptoms, and 446 subjects (13.1%) without a physiological component (group 2). Data were evaluated to determine differences between the two groups., Results: Group 1 reported greater severity of alcohol dependence as demonstrated by a larger maximum number of drinks in 24 hours, more persons reporting binges, more alcohol-related life problems, more relevant DSM-III-R criteria endorsed, more physiological complications, and more alcohol-related emotional/psychiatric symptoms such as depression and anxiety. Each of these severity indicators for problems in group 1 was significant in the presence of the others in a logistic regression, and similar items remained significant when tolerance alone, withdrawal alone, or their combination was used as the criterion for group 1 membership; however, for withdrawal a larger proportion of the variance was explained by the predictor variables. The regression results were independent of gender, proband status, and history of antisocial personality disorder., Conclusions: The results support the clinical relevance of distinguishing between alcohol-dependent patients with and without a physiological component. The data indicate a potential advantage to limiting that definition to withdrawal only.

Objective: Many of the studies linking anorexia nervosa and bulimia nervosa to substance use disorders suffer from problems with small samples; some lack rigorous definitions of the syndromes, and it is difficult to determine whether eating problems were primarily temporary consequences of heavy substance use or drugs were temporarily used in an effort to control appetite. The goal of this study was to evaluate the relationship between alcohol dependence and eating disorders., Method: Structured interviews were carried out with 2,283 women and 1,982 men as part of the Collaborative Study on the Genetics of Alcoholism. Data on drug abuse and dependence, psychiatric disorders, and symptoms of anorexia and bulimia were evaluated among alcohol-dependent probands, their relatives, comparison probands, and their relatives., Results: Lifetime rates for anorexia and bulimia were 1.41% and 6.17%, respectively, for the alcohol-dependent women, and bulimia was observed in 1.35% of the alcoholic men. However, once the impact of additional primary diagnoses was controlled for, anorexia was seen in only 1.26% of the women with primary alcohol dependence and none of the alcohol-dependent men; the rates for bulimia were 3.46% and 0.72%, respectively. There was no evidence of a strong familial crossover between alcohol dependence and anorexia or bulimia., Conclusions: While the rate of anorexia was not elevated in alcoholics after controlling for other disorders, bulimia did occur at a greater than expected rate. However, both eating disorders were relatively rare, and much of the association with alcoholism occurred in the context of additional preexisting or secondary psychiatric disorders.

Of the 241 lithium clinic patients at the New York State Psychiatric Institute with bipolar I affective disorder, 38 (15.7%) had never been hospitalized or somatically treated for depression. These "unipolar manic" patients had a significantly lower incidence of rapid cycling and suicide attempts than other bipolar I patients. No differences were found, however, in risk of illness in first-degree relatives. Lithium was an effective prophylactic agent in these patients. Some patients originally classified as "unipolar manic" were found to have depressive episodes with additional information and clinical observation. "Unipolar mania" appears to be a subgroup of bipolar I illness, but there are no data to support the hypothesis that it is a separate entity.

Lithium treatment has been associated with a wide range of cardiac complications. The authors report three additional cases of cardiac sinus node dysfunction due to lithium. Two of the three cases were documented to be lithium dependent by the use of Holter monitoring of cardiac rhythm. On the basis of this finding as well as other reports in the literature the authors recommend careful monitoring of the pulse of patients taking lithium as well as ECG monitoring of patients who are over the age of 50 or who have a history of cardiac disease.

Four patients with major depression who were unresponsive to antidepressant medications rapidly improved and remained euthymic after an advance of the sleep-wake cycle. Phase advance of the sleep-wake cycle and antidepressant treatment may have complementary effects on the circadian system. The authors suggest that the combination may be useful in treating drug nonresponders and in hastening response to antidepressant drugs.

The most prevalent psychiatric disorders in the families of patients with anorexia nervosa are bipolar and unipolar major affective disorder. The presence of affective disorder, self-induced vomiting, or bulimia in the patient is not predictive of affective illness in the relatives. Thus these features do not define genetic heterogeneity within anorexia nervosa. There may be genetic factors shared between anorexia nervosa and affective disorders.

To test the hypothesis that depression and REM sleep share common cholinergic mechanisms the authors administered arecoline 25 min after completion of the first REM period to 14 patients with remitted bipolar affective disorder, 15 normal controls, and 5 subjects with a personal or family history of affective disorder. The second REM period occurred significantly sooner in the remitted patients than in the normal controls. The patients also had a significantly higher density of eye movements during the first REM period and a higher percentage of REM sleep. The authors believe that increased cholinergic sensitivity and REM density may be biological markers of increased vulnerability to bipolar affective illness.

Exposure to light during the night reduces plasma melatonin levels. A previous study showed that, in response to light, nighttime plasma melatonin levels fell twice as much in a group of acutely ill manic-depressive patients as in a group of normal subjects. The present study compares 11 euthymic manic-depressive patients not taking medications with 24 age- and sex-matched normal subjects. Melatonin levels in these patients also fell twice as much as the levels of the normal subjects, suggesting that supersensitivity to light may be a trait marker for bipolar affective disorder.