All the world's a (clinical) stage: rethinking bipolar disorder from a longitudinal perspective.

Psychiatric disorders have traditionally been classified using a static, categorical approach. However, this approach falls short in facilitating understanding of the development, common comorbid diagnoses, prognosis and treatment of these disorders. We propose a 'staging' model of bipolar disorder that integrates genetic and neural information with mood and activity symptoms to describe how the disease progresses over time. From an early, asymptomatic, but 'at-risk' stage to severe, chronic illness, each stage is described with associated neuroimaging findings as well as strategies for mapping genetic risk factors. Integrating more biologic information relating to cardiovascular and endocrine systems, refining methodology for modeling dimensional approaches to disease and developing outcome measures will all be crucial in examining the validity of this model. Ultimately, this approach should aid in developing targeted interventions for each group that will reduce the significant morbidity and mortality associated with bipolar disorder.

The association between meal timing and frequency with cardiometabolic profile in patients with bipolar disorder.

OBJECTIVE: The goal of this study was to explore the association of timing of and frequency of meals with markers of cardiometabolic risk in patients with bipolar disorder in out-patient maintenance treatment. METHODS: We used Pittsburgh Sleep Diary and actigraphy measures for individuals with bipolar I disorder. Linear and logistic regression analyses were used to determine whether dinnertime, instability of dinnertime, and/or interval between meals were associated with metabolic syndrome and its components. RESULTS: Later dinnertime was associated with greater waist circumference (ß = 0.25, P = 0.02) after adjusting for age, sex, dinner-to-bed interval, and sleep duration. Longer breakfast-to-lunch intervals were also associated with greater waist circumferences (ß =-.35, P = .002) after adjusting for age, sex, and sleep duration. Neither instability of dinnertime nor number of meals per day was associated with the metabolic syndrome or its components. CONCLUSION: Weight gain is often perceived as inevitable side-effect of medications. While patients often need to be on medication to function, a more careful lifestyle assessment with attention to social rhythms and timing of activities may be critical not only for mood stability, but also to reduce cardiovascular risk.

Elevated serum measures of lipid peroxidation and abnormal prefrontal white matter in euthymic bipolar adults: toward peripheral biomarkers of bipolar disorder.

Diffusion tensor imaging (DTI) studies consistently reported abnormalities in fractional anisotropy (FA) and radial diffusivity (RD), measures of the integrity of white matter (WM), in bipolar disorder (BD), that may reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD. We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA (and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE) and 19 age- and gender-matched healthy adults (CONT). There was a significant effect of group upon FA in these a priori WM tracts (BDECONT: F[1,41]=10.3; P=0.003), and a significant between-group difference in LPH (BDE>CONT: t[40]=2.4; P=0.022), but not in 4-HNE. Multivariate multiple regression analyses revealed that LPH variance explained, respectively, 59 and 51% of the variance of FA and RD across all study participants. This is the first study to examine relationships between measures of WM integrity and peripheral measures of lipid peroxidation. Our findings suggest that serum LPH may be useful in the development of a clinically relevant, yet easily obtainable and inexpensive, peripheral biomarkers of BD.

Pattern recognition analysis of anterior cingulate cortex blood flow to classify depression polarity.

Differentiating bipolar from recurrent unipolar depression is a major clinical challenge. In 18 healthy females and 36 females in a depressive episode--18 with bipolar disorder type I, 18 with recurrent unipolar depression--we applied pattern recognition analysis using subdivisions of anterior cingulate cortex (ACC) blood flow at rest, measured with arterial spin labelling. Subgenual ACC blood flow classified unipolar v. bipolar depression with 81% accuracy (83% sensitivity, 78% specificity).

Simultaneous evaluation of the harms and benefits of treatments in randomized clinical trials: demonstration of a new approach.

BACKGROUND: One aim of personalized medicine is to determine which treatment is to be preferred for an individual patient, given all patient information available. Particularly in mental health, however, there is a lack of a single objective, reliable measure of outcome that is sensitive to crucial individual differences among patients. METHOD: We examined the feasibility of quantifying the total clinical value provided by a treatment (measured by both harms and benefits) in a single metric. An expert panel was asked to compare 100 pairs of patients, one from each treatment group, who had participated in a randomized clinical trial (RCT) involving interpersonal psychotherapy (IPT) and escitalopram, selecting the patient with the preferred outcome considering both benefits and harms. RESULTS: From these results, an integrated preference score (IPS) was derived, such that the differences between any two patients' IPSs would predict the clinicians' preferences. This IPS was then computed for all patients in the RCT. A second set of 100 pairs was rated by the panel. Their preferences were highly correlated with the IPS differences (r=0.84). Finally, the IPS was used as the outcome measure comparing IPT and escitalopram. The 95% confidence interval (CI) for the effect size comparing treatments indicated clinical equivalence of the treatments. CONCLUSIONS: A metric that combines benefits and harms of treatments could increase the value of RCTs by making clearer which treatments are preferable and, ultimately, for whom. Such methods result in more precise estimation of effect sizes, without increasing the required sample size.

Predictors and moderators of time to remission of major depression with interpersonal psychotherapy and SSRI pharmacotherapy.

BACKGROUND: Although many studies suggest that, on average, depression-specific psychotherapy and antidepressant pharmacotherapy are efficacious, we know relatively little about which patients are more likely to respond to one versus the other. We sought to determine whether measures of spectrum psychopathology are useful in deciding which patients with unipolar depression should receive pharmacotherapy versus depression-specific psychotherapy. METHOD: A total of 318 adult out-patients with major depression were randomly assigned to escitalopram pharmacotherapy or interpersonal psychotherapy (IPT) at academic medical centers at Pittsburgh, Pennsylvania and Pisa, Italy. Our main focus was on predictors and moderators of time to remission on monotherapy at 12 weeks. RESULTS: Participants with higher scores on the need for medical reassurance factor of the Panic-Agoraphobic Spectrum Self-Report (PAS-SR) had more rapid remission with IPT and those with lower scores on the psychomotor activation factor of the Mood Spectrum Self-Report (MOODS-SR) experienced more rapid remission with selective serotonin reuptake inhibitor (SSRI) pharmacotherapy. Non-specific predictors of longer time to remission with monotherapy included several panic spectrum and mood spectrum factors and the Social Phobia Spectrum (SHY) total score. Higher baseline scores on the 17- and 25-item Hamilton Depression Rating Scales (HAMD-17 and HAMD-25) and the Work and Social Adjustment Scale (WSAS) also predicted a longer time to remission, whereas being married predicted a shorter time to remission. CONCLUSIONS: This exploratory study identified several non-specific predictors but few moderators of psychotherapy versus pharmacotherapy outcome. It offers useful indicators of the characteristics of patients that are generally difficult to treat, but only limited guidance as to who benefits from IPT versus SSRI pharmacotherapy.

The structure of lifetime manic-hypomanic spectrum.

BACKGROUND: The observation that bipolar disorders frequently go unrecognized has prompted the development of screening instruments designed to improve the identification of bipolarity in clinical and non-clinical samples. Starting from a lifetime approach, researchers of the Spectrum Project developed the Mood Spectrum Self-Report (MOODS-SR) that assesses threshold-level manifestations of unipolar and bipolar mood psychopathology, but also atypical symptoms, behavioral traits and temperamental features. The aim of the present study is to examine the structure of mania/hypomania using 68 items of the MOODS-SR that explore cognitive, mood and energy/activity features associated with mania/hypomania. METHODS: A data pool of 617 patients with bipolar disorders, recruited at Pittsburgh and Pisa, Italy was used for this purpose. Classical exploratory factor analysis, based on a tetrachoric matrix, was carried out on the 68 items, followed by an Item Response Theory (IRT)-based factor analytic approach. RESULTS: Nine factors were initially identified, that include Psychomotor Activation, Creativity, Mixed Instability, Sociability/Extraversion, Spirituality/Mysticism/Psychoticism, Mixed Irritability, Inflated Self-esteem, Euphoria, Wastefulness/Recklessness, and account overall for 56.4% of the variance of items. In a subsequent IRT-based bi-factor analysis, only five of them (Psychomotor Activation, Mixed Instability, Spirituality/Mysticism/Psychoticism, Mixed Irritability, Euphoria) were retained. CONCLUSIONS: Our data confirm the central role of Psychomotor Activation in mania/hypomania and support the definitions of pure manic (Psychomotor Activation and Euphoria) and mixed manic (Mixed Instability and Mixed Irritability) components, bearing the opportunity to identify patients with specific profiles for a better clinical and neurobiological definition.

Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophrenia.

We hypothesize that circadian dysfunction could underlie, at least partially, the liability for bipolar 1 disorder (BD1). Our hypothesis motivated tests for the association between the polymorphisms of genes that mediate circadian function and liability for BD1. The US Caucasian patients with BD1 (DSM-IV criteria) and available parents were recruited from Pittsburgh and surrounding areas (n = 138 cases, 196 parents) and also selected from the NIMH Genetics Collaborative Initiative (n = 96 cases, 192 parents). We assayed 44 informative single-nucleotide polymorphisms (SNPs) from eight circadian genes in the BD1 samples. A population-based sample, specifically cord blood samples from local live births, served as community-based controls (n = 180). It was used as a contrast for genotype and haplotype distributions with those of patients. US patients with schizophrenia/schizoaffective disorder (SZ/SZA, n = 331) and available parents from Pittsburgh (n = 344) were assayed for a smaller set of SNPs based on the results from the BD1 samples. Modest associations with SNPs at ARNTL (BmaL1) and TIMELESS genes were observed in the BD1 samples. The associations were detected using family-based and case-control analyses, albeit with different SNPs. Associations with TIMELESS and PERIOD3 were also detected in the Pittsburgh SZ/SZA group. Thus far, evidence for association between specific SNPs at the circadian gene loci and BD1 is tentative. Additional studies using larger samples are required to evaluate the associations reported here.

The psychotic spectrum: validity and reliability of the Structured Clinical Interview for the Psychotic Spectrum.

This study evaluates the validity and the reliability of a new instrument developed to assess the psychotic spectrum: the Structured Clinical Interview for the Psychotic Spectrum (SCI-PSY). The instrument is based on a spectrum model that emphasizes soft signs, low-grade symptoms, subthreshold syndromes, as well as temperamental and personality traits comprising the clinical and subsyndromal psychotic manifestations. The items of the interview include, in addition to a subset of the DSM-IV criteria for psychotic syndromes, a number of features derived from clinical experience and from a review of the phenomenological descriptions of psychoses. Study participants were enrolled at 11 Italian Departments of Psychiatry located at 9 sites and included 77 consecutive patients with schizophrenia or schizoaffective disorder, 66 with borderline personality disorder, 59 with psychotic mood disorders, 98 with non-psychotic mood disorders and 57 with panic disorder. A comparison group of 102 unselected controls was enrolled at the same sites. The SCI-PSY significantly discriminated subjects with any psychiatric diagnosis from controls and subjects with from those without psychotic disorders. The hypothesized structure of the instrument was confirmed empirically.

Two roads to rapid eye movement latency.

Although considerable attention has been paid to the accumulated body of data on sleep-related "markers" of affective illness, there has been ongoing controversy with respect to the application of these sleep measures. This report attempts to reexamine the data on the electroencephalographic sleep features of individuals with depressive illness from a different theoretical perspective. Our focus on rapid eye movement latency is intended to provide both a new interpretation of the available data and directions for future research.

Electroencephalographic sleep in young, never-medicated schizophrenics. A comparison with delusional and nondelusional depressives and with healthy controls.

Electroencephalographic (EEG) sleep characteristics of young, never-medicated, nonschizoaffective schizophrenics were compared with the EEG sleep of patients with major depressive disorders (delusional and nondelusional) and with that of healthy controls. Schizophrenics had decreased sleep continuity comparable to delusional depressives. Slow-wave sleep percent was similar to that seen in healthy controls, as was the intranight temporal distribution of EEG delta activity. However, schizophrenics showed diminished delta counts per minute of non-rapid eye movement (NREM) sleep and a decreased total delta wave count. In contrast, depressives showed diminished slow-wave sleep percent compared with controls, greatly decreased delta activity (more so than did the schizophrenics), and an altered temporal distribution of delta activity, as evidenced by a shift of delta activity from the first to the second NREM period. Minutes of slow-wave sleep in the schizophrenics was inversely correlated with the severity of negative symptoms independent of the effects of age and the presence of depression. The schizophrenics showed normal REM latency and first REM period duration, in contrast to the depressives. These findings, reviewed in the historical context of sleep physiologic studies of schizophrenia over the past 30 years, suggest that young, never-medicated schizophrenics do not show the characteristic constellation of abnormalities in the first NREM-REM cycle seen in patients with major depression. However, decreased slow-wave sleep should be investigated as a possible marker for negative symptoms in schizophrenia.

Social zeitgebers and biological rhythms. A unified approach to understanding the etiology of depression.

Results of biological and psychosocial studies of depression completed in the last decade have stimulated the need for new hypotheses that synthesize these findings in a unified etiologic theory. The importance of disruption of biological rhythms on the one hand, and psychosocial losses on the other, in the causation of depressive episodes suggest one possible unifying hypothesis. The concept of loss of "social zeitgebers," ie, persons, social demands, or tasks that set the biological clock, may provide the link between biological and psychosocial theories of etiology. We suggest that a disruption of social rhythms, which may result in instability in biological rhythms, could be responsible for triggering the onset of a major depressive episode in vulnerable individuals.

Electroencephalographic sleep diagnosis of primary depression.

Studies of severely depressed hospitalized patients suggest a shortened rapid eye movement (REM) latency as a specific biological marker for primary affective disease. To assess the validity of these findings, 40 outpatients referred to our Electroencephalographic Sleep Center for evaluation of depressive symptoms were studied. Concurrent with the all night EEG sleep studies, all patients received a brief clinical interview and a battery of self-rating scales. The entire sample was then subdivided into primary and secondary depressives on the basis of follow-up diagnoses. While there were no significant differences between groups on self-ratings of depressive symptoms, the group of primary depressives had significantly shorter REM latencies and higher measures of phasic REM than the secondary depressives. Furthermore, in this patient group, the delineation of primary vs secondary depression was greater than 80% on the basis of only two nights of EEG sleep. Such objective biological measures, if replicated, could provide a method for increasing the accuracy of differential diagnosis among depressed populations in clinical research.

The advantage of early treatment intervention in recurrent depression.

Two key questions regarding the treatment of depression remain unanswered: whether early treatment intervention will shorten the length of the episode and whether a previously successful treatment will be associated with a more rapid response when administered during the subsequent episode. A group of 45 patients with recurrent major depression treated with combined pharmacotherapy and psychotherapy in a similar fashion for two consecutive episodes showed comparable mean times to stabilization of between 11 and 12 weeks. However, the early intervention in the second treatment episode significantly shortened the overall length of the depressive episode by approximately 4 to 5 months.

Early recurrence in unipolar depression.

While some advances have occurred in the maintenance treatment of unipolar depression, empirical data on recurrences of illness following the discontinuation of medication are sparse. We examined survival time during the first 18 months after discontinuation of medication in 74 patients with recurrent unipolar depression. Although demographic characteristics, clinical characteristics, and pharmacologic treatment variables failed to predict time to recurrence, continued interpersonal psychotherapy was significantly related to longer survival time.

The definition and operational criteria for treatment outcome of major depressive disorder. A review of the current research literature.

A review of research articles published in nine journals over a 2-year period was conducted to determine how critical changes in the clinical course of depressive disorder are defined in the research literature. These change points, labeled by terms such as response, recovery, and relapse, are critical for evaluation and communication of study results. The review focused on studies of unipolar depression that used a criterion-based diagnostic system and involved some form of therapeutic maneuver. The review showed significant inconsistency in the labeling and definition of change points and indicated the need for more precise conceptual definitions and operational criteria to enhance comparison, generalization, and application of results from clinical studies of depression.

Methodologic issues in maintenance therapy clinical trials.

In the early 1980s, the National Institute of Mental Health supported a multicenter, randomized, controlled, clinical trial on unipolar and bipolar disorder to evaluate the comparative efficacies of lithium carbonate, imipramine hydrochloride, a lithium-imipramine combination, and placebo in preventing the recurrence of affective disorders. The objective of this report is to present a reanalysis of the relative efficacies of these treatments in patients with unipolar disorder to focus attention on general issues related to the design and conduct of maintenance therapy trials. We show that the earlier conclusions of that study that imipramine and the combination therapy are more effective than lithium and placebo in preventing the recurrence of depression in unipolar patients can be accounted for by alternative explanations that are a consequence of the design of the study. Our findings have important implications for the design, conduct, and interpretation of results of maintenance therapy clinical trials in general.

Electroencephalographic sleep in psychotic depression. A valid subtype?

Electroencephalographic (EEG) sleep patterns were examined in 27 psychotic and 79 nonpsychotic subjects with major depression to evaluate the validity of the psychotic-nonpsychotic subtype dichotomy. Sleep in psychotic depression was characterized by increased wakefulness, decreased rapid eye movement (REM) sleep percentage, and decreased REM activity even after controlling for clinical differences in age, severity, and agitation. Psychotic depressive subjects also were more likely to have extremely short sleep-onset REM latencies. In psychotic depression EEG sleep varied as a function of total illness duration. Patients with recent-onset syndromes had profiles characterized by marked initial insomnia, increased stage 1 sleep percentage, and long REM latency; patients with illnesses of longer duration had extremely short REM latencies. Demonstration of selected EEG sleep variables discriminating between psychotic and nonpsychotic depression further supports psychotic depression as a distinct subtype of major affective disorder.

Linkage studies of bipolar disorder: methodologic and analytic issues. Report of MacArthur Foundation Workshop on Linkage and Clinical Features in Affective Disorders.

To review the findings of the linkage studies of affective disorders, a workshop, "Linkage and Clinical Features in Affective Disorders," was organized by the MacArthur Foundation Mental Health Research Network I on the Psychobiology of Depression meeting in Alexandria, Va, April 13 to 15, 1989. The major goals of the workshop for affective disorders were to explore the relationship between genetic and clinical heterogeneity, to identify major impediments to linkage studies, and to develop recommendations for the application of standardized methods of conducting linkage studies. The participants in the conference presented detailed demographic and clinical data from most of the published linkage studies of affective disorders. No systematic correspondence between genetic and clinical subtypes of bipolar disorder pedigrees was evident. The major problems hampering the linkage analyses of psychiatric disorders that were identified follow: (1) the major psychiatric disorders--the affective disorders in particular--constituting complex human disorders; (2) the lack of valid definitions of affective disorders; (3) comorbidity between the affective disorders with other disorders; (4) nonrandom mating; (5) a cohort effect, with younger birth cohorts exhibiting higher rates of affective disorders; and (6) the lack of replication of current linkage studies. The recommendations that were made for linkage study designs that incorporate some of the complexities of the affective disorders are reported.

Reduced cortisol latency in depressive illness.

Depressed patients commonly have disturbances in their sleep and cortisol secretory patterns. When the sleep-related changes in plasma cortisol concentration were measured in 14 patients with a primary major depressive illness, they differed significantly from the changes measured in 14 age- and sex-matched healthy control subjects. The nadir of the nocturnal plasma cortisol concentration was significantly greater in the group of depressed patients, and the nocturnal increase in the plasma cortisol concentration occurred significantly closer to sleep onset in these patients. The circadian activity within the hypothalamic-pituitary-adrenal axis of these depressed patients showed a subtle but significantly disturbed temporal relationship to sleep onset. This reduced time between sleep onset and the nocturnal increase in cortisol secretion suggests a possible biologic correlate of a depressive illness that might be useful as an illness marker in depressed patients.