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Owing to the clinical relationship between bipolar disorder and nicotine dependence, we investigated two research questions: (i) are genetic associations with nicotine dependence different in individuals with bipolar disorder as compared with individuals without bipolar disorder, and (ii) do loci earlier associated with nicotine dependence have pleiotropic effects on these two diseases.Our study consisted of 916 cases with bipolar disorder and 1028 controls. On the basis of known associations with nicotine dependence, we genotyped eight single-nucleotide polymorphisms (SNPs) on chromosome 8 (three bins) in the regions of CHRNB3 and CHRNA6, and six SNPs on chromosome 15 (three bins) in the regions of CHRNA5 and CHRNA3.To determine whether the genetic associations with nicotine dependence are different in bipolar disorder than in the general population, we compared allele frequencies of candidate SNPs between individuals with nicotine dependence only and individuals with both nicotine dependence and bipolar disorder. There were no statistical differences between these frequencies, indicating that genetic association with nicotine dependence is similar in individuals with bipolar disorder as in the general population. In the investigation of pleiotropic effects of these SNPs on bipolar disorder, two highly correlated synonymous SNPs in CHRNB3, rs4952 and rs4953, were significantly associated with bipolar disorder (odds ratio 1.7, 95% confidence interval: 1.2-2.4, P=0.001). This association remained significant both after adjusting for a smoking covariate and analyzing the association in nonsmokers only.Our results suggest that (i) bipolar disorder does not modify the association between nicotine dependence and nicotinic receptor subunit genes, and (ii) variants in CHRNB3/CHRNA6 are independently associated with bipolar disorder.

Objectives—Bipolar disorder conveys an increased risk of cardiovascular mortality. We compared the risk for cardiovascular mortality between bipolar I and bipolar II subtypes and determined correlates of cardiovascular mortality. Methods—Participants with major affective disorders were recruited for the National Institute of Mental Health Collaborative Depression Study and followed prospectively for up to twenty-five years. A total of 435 participants met diagnostic criteria for bipolar I (N=288) or bipolar II (N=147) disorder based on Research Diagnostic Criteria at intake and measures of psychiatric symptoms during follow-up. Diagnostic subtypes were contrasted by cardiovascular mortality risk using Cox proportional-hazards regression. Affective symptom burden (the proportion of time with clinically significant manic/hypomanic or depressive symptoms) and treatment exposure were additionally included in the models. Results—Thirty-three participants died from cardiovascular causes. Participants with bipolar I disorder had more than double the cardiovascular mortality risk of those with bipolar II disorder, after controlling for age and gender (HR=2.35, 95% C.I. 1.04–5.33, p=0.04). The observed difference in cardiovascular mortality between these subtypes was at least partially confounded by the burden of clinically significant manic/hypomanic symptoms which predicted cardiovascular mortality independent of diagnosis, treatment exposure, age, gender, and cardiovascular risk factors at intake. Selective serotonin uptake inhibitors appeared protective though were introduced late in follow-up. Depressive symptom burden was not related to cardiovascular mortality. Conclusions—Participants with bipolar I disorder may face greater risk of cardiovascular mortality than those with bipolar II disorder. This difference in cardiovascular mortality risk may reflect manic/ hypomanic symptom burden.

Individuals with panic disorder and those at high risk for panic disorder due to a positive family history seem to have elevated sensitivities to the panicogenic effects of carbon dioxide (CO2) inhalation as well as abnormal ventilatory responses to low doses of CO2 exposure. Many reports have described a reduction in anxiety responses in individuals with panic disorder after a brief treatment with a variety of medications effective in the treatment of panic disorder, but few of these have used placebo control.Thirty-two unmedicated individuals who had either a past history of panic attacks or a family history of treated panic disorder and who demonstrated, at baseline, a panic attack after either a single breath of 35% CO2 or 3 minutes of exposure to 5% CO2 or a decline in minute volume during 3 minutes of exposure to 5% CO2 were randomized to 2-week trials of escitalopram at 10 mg daily or placebo and, after a 1-week washout, to a 2-week trial of the alternate condition.Placebo and escitalopram conditions did not differ by changes in anxiety responses to high-dose, single-breath, or low-dose continuous-breathing CO2 exposures. Ventilatory abnormalities were no more likely to resolve with escitalopram than with placebo. Self-ratings of anxiety and depressive symptoms showed little change over time with either escitalopram or placebo.Escitalopram did not produce greater changes than placebo in panic responses or in ventilatory abnormalities seen during CO2 exposure. Future studies concerning the effects of antidepressants on responses to CO2 challenge should use a placebo-controlled design.

OBJECTIVE Studies of both community and clinical samples have associated depressive symptoms with risks for subsequent cardiovascular morbidity and mortality. Because the physiological mechanisms thought to underlie this link would be cumulative in their effects, the following analyses tested the prediction that risks for cardiovascular death would increase in proportion to the persistence of depressive symptoms in a long-term follow-up. METHODS Baseline assessment was performed as patients sought treatment for major depressive disorder, mania, or schizo-affective disorder. Follow-up evaluations occurred semiannually for the next 5 years and annually thereafter. The 903 patients described, observed for a mean of 11.0 years (SD = 5.2 years), were divided into thirds according to the proportion of follow-up weeks in episodes of major depressive disorder, schizoaffective disorder, or intermittent depressive disorder. The resulting groups were then compared by cumulative risks of cardiovascular death. RESULTS Patients whose depressive symptoms were the most persistent were no more likely to die of cardiovascular causes than were those with the fewest weeks ill. A regression analysis showed that older age and the presence of cardiovascular disease at baseline, but not the subsequent chronicity of depressive symptoms, predicted cardiovascular death. CONCLUSIONS The physiological concomitants of depressive illness apparently do not promote cardiovascular mortality in a cumulative manner. Efforts should be directed toward identification of risk factors common to both lifetime depressive symptoms and cardiovascular morbidity.

Five independent studies show that polarity sequence is associated with prognosis in bipolar I disorder. Episodes in which major depression precedes mania (DMI) lead to higher morbidity than biphasic episodes which begin with mania (MDI). However, little is known about the prognostic significance of polarity sequence for long-term outcome. This study examined polarity sequence across multiple episodes among 165 bipolar I patients followed prospectively for up to 15 years as part of the NIMH Collaborative Study of Depression. Episodes beginning with major depression were significantly longer than those beginning with mania for the first three prospectively observed episodes when pooling all episode types-monophasic, biphasic, and polyphasic. Furthermore, affective polarity at onset for the first prospectively observed episode was associated with polarity at onset for the remaining three episodes. Patients whose first prospectively observed episode began with depression had higher overall morbidity during the entire follow-up period.

We explored the course of bipolar I illness in 172 probands who were followed up prospectively for up to 5 years. Probands were grouped into three categories based on whether the symptoms of the index episode were only depressed, only manic, or mixed/cycling. Data were available for recovery from the index episode, subsequent relapse, and rates of recovery from the first prospective episode. Pure manic probands had a significantly faster rate of recovery (median, 6 weeks) than the mixed/cycling probands (median, 17 weeks), and the pure depressive probands had an intermediate rate (median, 11 weeks). After 5 years of follow-up the mixed/cycling patients continue to have the lowest cumulative probability of recovery from the index episode. Mixed/cycling probands also had a substantially faster time to relapse after recovery from the index episode compared with pure manic patients. For those patients who relapsed, the mixed/cycling patients had the lowest cumulative probability of recovery from the first prospectively observed episode. The treatment received by these patients is described and there is a discussion of how this treatment may have influenced the findings on course and outcome.

Dimensional scores were computed for the 11 DSM-III personality disorders (PDs) in 797 relatives of psychiatric patients and never ill control subjects interviewed with the Structured Interview for DSM-III Personality Disorders. The distribution of scores for all 11 PD dimensions was skewed to the right. A principal components analysis with varimax rotation produced three factors that closely corresponded to DSM-III's suggested clustering of the PDs into eccentric, dramatic, and anxious types. Men scored significantly higher on the paranoid, schizoid, compulsive, antisocial, and narcissistic dimensions, whereas women had significantly higher histrionic, dependent, and avoidant scores. Age was negatively correlated with most of the PD dimensions, and the correlations were strongest with the four PDs in cluster 2 (histrionic, antisocial, narcissistic, and borderline). Each of the eight axis I disorders examined was associated with increased axis II pathology.

The accurate prediction of steady-state plasma haloperidol concentrations was successfully accomplished by obtaining two blood samples following a 20 mg test dose (kinetic method). Prediction of steady-state concentrations on the basis of a mg/kg/day dosage (dose method), although equally precise, generated significantly less information concerning the variance between observed and predicted haloperidol plasma concentrations. Both predictive methods were less precise when the daily doses exceeded 0.47 mg/kg/day. Fifty percent (6/12 patients) of the haloperidol plasma concentrations were underpredicted if this threshold was exceeded. This finding may suggest the possibility of dose-dependent pharmacokinetics with haloperidol in some patients.

Consecutively admitted patients with nonmanic psychosis were more likely to meet Research Diagnostic Criteria (RDC) for schizoaffective disorder, depressed type (N = 47), than for psychotic major depression (N = 29) or schizophrenia (N = 21). Although the RDC duration requirements for these three disorders are quite similar, schizophrenics had already experienced much more chronicity as reflected in episode duration, psychosocial impairment during the preceding 5 years, marital status, and low likelihood of prior remission. Schizoaffective patients took intermediate positions in these measures in accord with the majority of follow-up studies comparing these disorders. Although the RDC specify the same array of psychotic symptoms for schizoaffectives and for schizophrenics, these symptoms were significantly more prominent among the schizophrenics. Conversely, although this system also specifies the same list of depressive symptoms for major depression and schizoaffective depression, symptoms of endogenous depression were significantly more prominent in the major depression group. Thus, among functionally psychotic patients, those with schizophrenia-like symptoms have milder and less typical depressive symptoms whereas those with depressive syndromes have fewer and milder schizophrenia-like symptoms.

A search of all multiple admissions to the University of Iowa Psychiatric Hospital yielded 20 bipolar patients first admitted during adolescence and 21 bipolar patients first admitted between the ages of 30 and 40 years. Inclusion required the patient to meet criteria for mania on some admission other than the first. Adolescents were as likely as adults to meet criteria for mania and/or depression during their first admission. There were no group differences in distribution of criteria symptoms or in rates of associated symptoms. Likewise, the groups had similar rates of recovery at discharge and subsequent time spent in hospital. The authors conclude that differences between adolescents and adults need not obscure an appropriate diagnosis of mania.

Twenty-six outpatients with major depression completed a 6-week, fixed dose trial of desipramine and provided plasma samples. Recovery after 6 weeks, defined in either of two ways, corresponded to lower desipramine levels, while clinical status at 4 weeks bore no apparent relationship to plasma levels. Upper limits of 140 or 155 ng/ml emerged depending on the outcome measure used. Patients with endogenous depression, those with primary depression, and those with abnormal dexamethasone suppression test results yielded similar therapeutic thresholds, while the sharpest blood level/response relationship emerged in the subgroup with an abnormal escape from dexamethasone.