Cytomegalovirus Antibody Elevation in Bipolar Disorder: Relation to Elevated Mood States.

The neurobiology of mood states is complicated by exposure to everyday stressors (e.g., psychosocial, ubiquitous environmental infections like CMV), each fluctuating between latency and reactivation. CMV reactivation induces proinflammatory cytokines (e.g., TNF-α) associated with induction of neurotoxic metabolites and the presence of mood states in bipolar disorder (BD). Whether CMV reactivation is associated with bipolar diagnoses (trait) or specific mood states is unclear. We investigated 139 BD type I and 99 healthy controls to determine if concentrations of IgG antibodies to Herpesviridae (e.g., CMV, HSV-1, and HSV-2) were associated with BD-I diagnosis and specific mood states. We found higher CMV antibody concentration in BD-I than in healthy controls (T234 = 3.1, P uncorr = 0.002; P corr = 0.006) but no difference in HSV-1 (P > 0.10) or HSV-2 (P > 0.10). Compared to euthymic BD-I volunteers, CMV IgG was higher in BD-I volunteers with elevated moods (P < 0.03) but not different in depressed moods (P > 0.10). While relationships presented between BD-I diagnosis, mood states, and CMV antibodies are encouraging, they are limited by the study's cross sectional nature. Nevertheless, further testing is warranted to replicate findings and determine whether reactivation of CMV infection exacerbates elevated mood states in BD-I.

Confirmatory test of two factors and four subtypes of bipolar disorder based on lifetime psychiatric co-morbidity.

BACKGROUND: The first aim was to use confirmatory factor analysis (CFA) to test a hypothesis that two factors (internalizing and externalizing) account for lifetime co-morbid DSM-IV diagnoses among adults with bipolar I (BPI) disorder. The second aim was to use confirmatory latent class analysis (CLCA) to test the hypothesis that four clinical subtypes are detectible: pure BPI; BPI plus internalizing disorders only; BPI plus externalizing disorders only; and BPI plus internalizing and externalizing disorders. METHOD: A cohort of 699 multiplex BPI families was studied, ascertained and assessed (1998-2003) by the National Institute of Mental Health Genetics Initiative Bipolar Consortium: 1156 with BPI disorder (504 adult probands; 594 first-degree relatives; and 58 more distant relatives) and 563 first-degree relatives without BPI. Best-estimate consensus DSM-IV diagnoses were based on structured interviews, family history and medical records. MPLUS software was used for CFA and CLCA. RESULTS: The two-factor CFA model fit the data very well, and could not be improved by adding or removing paths. The four-class CLCA model fit better than exploratory LCA models or post-hoc-modified CLCA models. The two factors and four classes were associated with distinctive clinical course and severity variables, adjusted for proband gender. Co-morbidity, especially more than one internalizing and/or externalizing disorder, was associated with a more severe and complicated course of illness. The four classes demonstrated significant familial aggregation, adjusted for gender and age of relatives. CONCLUSIONS: The BPI two-factor and four-cluster hypotheses demonstrated substantial confirmatory support. These models may be useful for subtyping BPI disorders, predicting course of illness and refining the phenotype in genetic studies.

Antidepressants and risks of suicide and suicide attempts: a 27-year observational study.

OBJECTIVE: The 2007 revision of the black box warning for suicidality with antidepressants states that patients of all ages who initiate antidepressants should be monitored for clinical worsening or suicidality. The objective of this study was to examine the association of antidepressants with suicide attempts and with suicide deaths. METHOD: A longitudinal, observational study of mood disorders with prospective assessments for up to 27 years was conducted at 5 US academic medical centers. The study sample included 757 participants who enrolled from 1979 to 1981 during an episode of mania, depression, or schizoaffective disorder, each based on Research Diagnostic Criteria. Unlike randomized controlled clinical trials of antidepressants, the analyses included participants with psychiatric and other medical comorbidity and those receiving acute or maintenance therapy, polypharmacy, or no psychopharmacologic treatment at all. Over follow-up, these participants had 6,716 time periods that were classified as either exposed to an antidepressant or not exposed. Propensity score-adjusted mixed-effects survival analyses were used to examine risk of suicide attempt or suicide, the primary outcome. RESULTS: The propensity model showed that antidepressant therapy was significantly more likely when participants' symptom severity was greater (odds ratio [OR] = 1.16; 95% CI, 1.12-1.21; z = 8.22; P < .001) or when it was worsening (OR = 1.69; 95% CI, 1.50-1.89; z = 9.02; P < .001). Quintile-stratified, propensity-adjusted safety analyses using mixed-effects grouped-time survival models indicate that the risk of suicide attempts or suicides was reduced by 20% among participants taking antidepressants (hazard ratio, 0.80; 95% CI, 0.68-0.95; z = -2.54; P = .011). CONCLUSIONS: This longitudinal study of a broadly generalizable cohort found that, although those with more severe affective syndromes were more likely to initiate treatment, antidepressants were associated with a significant reduction in the risk of suicidal behavior. Nonetheless, we believe that clinicians must closely monitor patients when an antidepressant is initiated.

Do risk factors for suicidal behavior differ by affective disorder polarity?

BACKGROUND: Suicide is a leading cause of death and has been strongly associated with affective disorders. The influence of affective disorder polarity on subsequent suicide attempts or completions and any differential effect of suicide risk factors by polarity were assessed in a prospective cohort. METHOD: Participants with major affective disorders in the National Institute of Mental Health (NIMH) Collaborative Depression Study (CDS) were followed prospectively for up to 25 years. A total of 909 participants meeting prospective diagnostic criteria for major depressive and bipolar disorders were followed through 4204 mood cycles. Suicidal behavior was defined as suicide attempts or completions. Mixed-effects, grouped-time survival analysis assessed risk of suicidal behavior and differential effects of risk factors for suicidal behavior by polarity. In addition to polarity, the main effects of age, gender, hopelessness, married status, prior suicide attempts and active substance abuse were modeled, with mood cycle as the unit of analysis. RESULTS: After controlling for age of onset, there were no differences in prior suicide attempts by polarity although bipolar participants had more prior severe attempts. During follow-up, 40 cycles ended in suicide and 384 cycles contained at least one suicide attempt. Age, hopelessness and active substance abuse but not polarity predicted suicidal behavior. The effects of risk factors did not differ by polarity. CONCLUSIONS: Bipolarity does not independently influence risk of suicidal behavior or alter the influence of well-established suicide risk factors within affective disorders. Suicide risk assessment strategies may continue to appraise these common risk factors without regard to mood polarity.

Charting patients' course: a comparison of statistics used to summarize patient course in longitudinal and repeated measures studies.

Investigators conducting longitudinal studies of psychiatric illnesses often analyze data based on psychiatric symptom scales that were administered at multiple time points. This study examines the statistical properties of seven indices that summarize patient long-term course. These indices can be used to compare differences between two or more groups or to test for changes in symptoms over time. They may also be treated as outcome measures and correlated with other clinical variables.The performance of each of the seven indices was assessed using data from two large ongoing studies of psychiatric patients: a longitudinal study of affective disorders and a longitudinal study of first-episode psychosis. These two datasets were subjected to bootstrapping techniques in order to calculate both type I error rates and statistical power for each summary statistic. Of the seven indices, Kendall's tau performed the best as a measure of patients' symptom course. Kendall's tau appears to offer more statistical power to detect change in course, yet its average type I error rate was comparable to the other indices.

Cigarette smoking and psychiatric disorder in a community sample.

We examined the lifetime prevalence of psychiatric disorders in cigarette smokers and nonsmokers in a non-patient sample. First-degree relatives of psychiatric patients (n = 697) and normal controls (n = 360) were interviewed with the Diagnostic Interview Schedule and the Structured Interview for DSM-III Personality Disorders. Using these interviews we diagnosed the major mental (Axis I) disorders and personality (Axis II) disorders. A cigarette smoker was defined as someone who smoked daily for a month or more at some time in their lives. We found that smokers more frequently had a lifetime history of major depression, alcohol and drug abuse/dependence, agoraphobia, unstable/acting out and anxious/fearful personality disorders. In a logistic regression analysis, the only significant variables independently associated with smoking status were the alcohol and drug use disorders. Age was an important modifying variable--the smoking-illness relationship was robust in the youngest age cohort and negligible in the oldest cohort. We conclude that cigarette smokers have increased rates of mood, anxiety, substance use, and personality disorders. However, after controlling for the comorbidity among the disorders only alcohol and drug abuse/dependence were independently associated with smoking. Young smokers had particularly high rates of substance use disorders. This age effect may reflect the impact of a quarter century of health education.

Course of treatment received by depressed patients.

Using data from an observational study of affective disorders, we describe the rates of transition among levels of antidepressant treatment for subjects with Major Depressive Disorder (MDD), and relate these changes to changes in clinical status. We report on the treatment received during the first 10 years of follow-up in the Collaborative Depression Study by 555 patients with a diagnosis of MDD of at least one month's duration. This work extends the initial examination of treatment received during the first eight weeks after entry into this study that showed depressed patients to be on low levels of treatment. Multiplicative intensity models which generalize survival analysis models were used to analyse these data. Description of the course of treatment of these depressed patients shows that low levels of treatment persist for these patients across subsequent episodes, and that these episodes, like the index one, are characterized by extended time in a symptomatic subcriterion state after acute symptoms have improved. These long-term descriptions of treatment support the initial hypothesis that these CDS patients were undertreated. The long-term tendency toward undertreatment seems to persist even as newer treatments become available and widely accepted in practice.

Polarity sequence, depression, and chronicity in bipolar I disorder.

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.

Long-term prognosis of bipolar I disorder.

This study examined the contribution of demographic, syndromal and longitudinal course variables to the long-term prognosis of 165 bipolar patients prospectively observed over 10 years as part of the National Institute of Mental Health Collaborative Study of Depression. Although most baseline clinical and demographic variables were not strong prognostic indicators, switching polarity within episodes was. Most episodes among the poor-prognosis patients were polyphasic, while most episodes among the comparison group with a better prognosis were monophasic. There was no evidence of shortening of cycle lengths over follow-up for either the poor-prognosis group or the entire sample. The relevance of these findings to the 'kindling' model is discussed.

Maintenance strategies for unipolar depression: an observational study of levels of treatment and recurrence.

BACKGROUND: This paper analyses data from a large observational study of the course of affective illness to provide insight into the duration and dose of effective maintenance therapies. METHODS: The data are 236 unipolar patients who had received antidepressants during recovery and were followed for affective recurrence for up to 5 years. Using data on the naturally selected somatic treatments, we have conducted analyses that adjust for the potential confounding effects of prognosis and treatment intensity to estimate the causal effect of level of medication on the course of recurrence. RESULTS: The results of these analyses show that it is important for patients to remain on the level of somatotherapy used to treat the acute episode for the initial 8 months after symptoms have abated. After that time, the rate of recurrence for patients with fewer than five previous episodes is approximately 1% per week or less at all levels of medication (including discontinuation). Patients who had experienced more than several recurrences are at greater risk of recurrence and continue to benefit from any level of medication during the first year after recovery. CONCLUSIONS: The CDS analyses reported here suggest that effective maintenance strategies for all but highly recurrent patients may be a middle road, opting for full-dose strategies of limited duration. These results have implications at both the policy and the clinical level, given the need to consider both monetary and nonmonetary costs (side-effects) associated with continued pharmacotherapy during remission. LIMITATIONS: The observational design of the CDS limits the degree to which cause and effect relationships can be inferred from the observed associations.

Major depression and personality disorder.

The authors examined an interview and paper-and-pencil assessment of the DSM-III personality disorders (PDs) in depressed inpatients, and depressed relatives of psychiatric patients and never-ill controls who had a lifetime history of major depression. The rates of PDs according to the Structured Interview for DSM-III Personality Disorders (SIDP) were similar in the two groups, except for borderline PD which was more frequent in the inpatients. Of the individuals with a PD, the patients were more likely than the relatives to have two or more PDs, and the borderline and histrionic patients were more prototypic of these disorders than were the borderline and histrionic relatives. In contrast to the SIDP results, the rates of PDs according to the Personality Disorders Questionnaire (PDQ) were higher in the patient sample. These results thus extend the previously described high rates of PDs in depressed patients to a sample of individuals with a lifetime history of treated or untreated depression, and they suggest that interview assessments of personality may be less sensitive to the state effects of depression than are questionnaires.

DSM-III personality disorder dimensions.

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.

Variability in the application of contemporary diagnostic criteria: endogenous depression as an example.

Specified diagnostic criteria have been credited, in part, with improving diagnostic reliability. The authors hypothesize that nonuniform application of these criteria across different research centers has been one factor responsible for the failure to replicate research findings. For example, researchers using a narrow interpretation of the Research Diagnostic Criteria (RDC) have found a highly significant association between endogenous depression and a positive dexamethasone suppression test result, whereas researchers using a broad interpretation have failed to find the predicted relationship. The authors used two interpretations of the RDC and DSM-III endogenous/melancholia criteria to diagnose 60 depressed patients and found significant difference in rates of diagnoses and symptoms.

Diagnosing personality disorders in the community. A comparison of self-report and interview measures.

The rapidly expanding empirical study of personality disorders is the result of the publication of operational diagnostic criteria in DSM-III and the development of instruments to assess these criteria. Few researchers have examined the comparability of measures of personality disorders, and to our knowledge there are no studies of the factors associated with discordance between measures. In the present study, 697 relatives of psychiatric patients and healthy controls were interviewed with the Structured Interview for Personality Disorders (SIDP) and completed the Personality Disorders Questionnaire (PDQ). Significantly more individuals had a personality disorder according to the SIDP; however, multiple personality disorders were more frequently diagnosed on the PDQ. Schizotypal, compulsive, dependent, and borderline personality disorders were significantly more frequently diagnosed by the PDQ, whereas the SIDP more frequently diagnosed antisocial and passive-aggressive personality disorder. The corresponding dimensional scores of the two measures were all significantly correlated; however, the concordance for categorical diagnoses was poor. Discrepancies between the PDQ and the SIPD dimensional scores were significantly associated with current level of depressive symptoms and PDQ lie scale scores.

Pharmacokinetic protocol for predicting plasma haloperidol concentrations.

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.

Reduced haloperidol plasma concentration and clinical response in acute exacerbations of schizophrenia.

Twenty-nine hospitalized patients suffering acute exacerbations of schizophrenia were treated for 2 weeks with fixed daily oral doses of haloperidol prospectively calculated to achieve a haloperidol plasma concentration of either 8-18 ng/ml or 25-35 ng/ml. Reduced haloperidol as well as haloperidol concentrations were assayed to determine if the former enhanced the predictability of response. Wee 2 haloperidol plasma concentrations were negatively correlated to clinical response as measured by the percentage change in the BPRS score from baseline (r = -0.43, P less than 0.05). In contrast, week 2 plasma concentrations of reduced haloperidol, total haloperidol (haloperidol + reduced haloperidol), and reduced haloperidol/haloperidol ratio did not correlate with the change in the BPRS score. Chi-square analysis concluded that patients with ratios greater than one were no less likely to be treatment responders (less than 25% improvement in BPRS from baseline and week 2 BPRS less than 55) than those with ratios less than one. Although these data lend additional support to reports of a curvilinear relationship between haloperidol plasma concentration and clinical response, they also suggest that reduced haloperidol plasma concentrations are of no value in predicting treatment response.

HPA axis disturbance in obsessive-compulsive disorder.

Twenty nondepressed outpatients with DSM-III obsessive-compulsive disorder entered a 10-week placebo-controlled study of clomipramine and underwent a 1-mg dexamethasone suppression test (DST) at baseline; 11 had a repeat DST at the end of treatment: Nonsuppression was rare. When compared to 82 previously described outpatients with panic disorder studied in a similar fashion, OCD patients had postdexamethasone cortisol values that were substantially lower and more stable over time. Results within the OCD group closely resembled those from a group of never-ill controls.

HPA axis hyperactivity and recovery from functional psychoses.

Some patients with functional psychoses follow a chronic, deteriorating course and others recover; at present clinicians have essentially no established factors beyond diagnosis and chronicity to predict which course a psychotic patient might follow. Because data on diagnostic specificity suggested that the dexamethasone suppression test might provide another, much needed prognostic factor, the authors administered these tests to 98 consecutively admitted patients with nonmanic psychoses. High postdexamethasone cortisol levels (6 micrograms/dl or higher) at baseline predicted recovery from psychosis at 1 year, independent of episode chronicity and diagnosis. Diagnosis did not correspond well to test results but was itself an important predictor.

Personality disorder in the families of depressed, schizophrenic, and never-ill probands.

In a blind family study of 176 probands with nonpsychotic major depression, psychotic major depression, schizophrenia, or no history of DSM-III disorders, only the relatives of depressed probands with mood-incongruent psychotic features had a risk for personality disorders higher than that for the relatives of never-ill probands. The authors did not find a high rate of borderline personality in relatives of depressed probands or of schizotypal personality disorder in relatives of probands with schizophrenia or any psychosis. However, depressed probands with normal dexamethasone test results had a significantly higher familial loading for the DSM-III cluster of histrionic, antisocial, borderline, and narcissistic personality disorders.