Stephen H. Koslow

Specificity of mixed affective states: clinical comparison of dysphoric mania and agitated depression

To investigate the clinical specificity of mixed affective states, we compared clinical characteristics of mixed (dysphoric) manics to those of agitated depressed patients. The subjects were inpatients studied in the NIMH Clinical Research Branch Collaborative Study on the Psychobiology of Depression, Biological Studies. Behavior and symptom ratings for depressive and manic symptoms were obtained during a 15-day placebo washout period. Patients with agitated depression were compared to those in acute manic episodes with and without prominent depressive symptoms. Mania ratings clearly distinguished agitated depressed from mixed manic patients. Concerning depression and general psychopathology, mixed manics had more severe agitation, hostility and cognitive impairment than did agitated depressed patients. Depressed mood and anxiety did not differ significantly between the two groups. Nurse ratings for depression and anxiety, based on ward behavior, were similar for mixed manics and agitated depressed patients, while physician-interview rated depression and anxiety were higher in agitated depressed patients. These data support the existence of superimposed depressive and manic syndromes in mixed manics.

Should the neuroscience community make a paradigm shift to sharing primary data

The author outlines the pros and cons of data sharing for neuroscientists and argues that continued progress in the field will depend on a cultural shift toward making primary data freely available. He argues in favor of distributed databases to maximize the efficient use of data.

Lithium treatment of mania: Clinical characteristics, specify of symptom change, and outcome

The effects of lithium treatment and prediction of response in 18 manic patients were studied as part of the National Institute of Mental Health Collaborative Study of the Psychobiology of Depression. Patients were rated using the Mania Diagnostic and Severity Scale (MADS) and an additional battery of behavioral constructs developed for measurement of state and drug response in depressed patients. About 67% of the patients had good treatment outcome after 26 days of lithium treatment. Responders did not differ from nonresponders before treatment with respect to delusions, hallucinations, or irritable-paranoid symptoms. Nonresponders were rated as more anxious than responders before treatment and had higher scores on the Hamilton Rating Scale for Depression. Improvement on the MADS, however, did not correlate with pretreatment behavioral ratings. Patients with relatively high ratings for aspects of behavior not specific to mania tended to improve in these regardless of change in MADS score. Manic patients who were also depressed (44%) had higher mania ratings than manic patients who were not depressed. Patients with concomitant depression and mania had significantly worse overall treatment outcome, although their depression ratings improved during lithium treatment.

NEUROINFORMATICS: THE INTEGRATION OF SHARED DATABASES AND TOOLS TOWARDS INTEGRATIVE NEUROSCIENCE

There is significant interest amongst neuroscientists in sharing neuroscience data and analytical tools. The exchange of neuroscience data and tools between groups affords the opportunity to differently re-analyze previously collected data, encourage new neuroscience interpretations and foster otherwise uninitiated collaborations, and provide a framework for the further development of theoretically based models of brain function. Data sharing will ultimately reduce experimental and analytical error. Many small Internet accessible database initiatives have been developed and specialized analytical software and modeling tools are distributed within different fields of neuroscience. However, in addition large-scale international collaborations are required which involve new mechanisms of coordination and funding. Provided sufficient government support is given to such international initiatives, sharing of neuroscience data and tools can play a pivotal role in human brain research and lead to innovations in neuroscience, informatics and treatment of brain disorders. These innovations will enable application of theoretical modeling techniques to enhance our understanding of the integrative aspects of neuroscience. This article, authored by a multinational working group on neuroinformatics established by the Organization for Economic Co-operation and Development (OECD), articulates some of the challenges and lessons learned to date in efforts to achieve international collaborative neuroscience.

Biochemistry and suicidal behavior in depressed patients

The present study was undertaken in order to further explore the relationship between monoamine levels and hypothalamic-pituitary-adrenocortical (HYPAC) functioning and suicidal behavior in depressed patients. One hundred and thirty-two depressed inpatients participated in the NIMH Collaborative Study on the Psychobiology of Depression. Similar to previous reports, our suicide attempters were younger, more likely to be bipolar, had an earlier age at onset, and displayed more psychotic features. No correlation between cortisol hypersecretion or Dexamethasone Suppression Test (DST) nonsuppression and suicide attempts were found. Only the pre-DST evening plasma cortisol distinguished the groups, being lower in the attempter group. We were unable to confirm the previously reported correlation between cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and suicide attempts. Of the monoamines examined, only urinary and plasma 3-methoxy-4-hydroxphenylglycol (MHPG) differed between suicide attempters and nonattempters, showing lower levels in the attempter group. There was a trend for CSF MHPG in the same direction. This latter reduction was restricted to the bipolar group.

Biological component of the NIMH clinical research branch collaborative program on the psychobiology of depression: I. Background and theoretical considerations.

There are many reports which suggest that patients with effective illness (mania and/or depression) have abnormalities in the functioning of one or more neurobiological systems. At a conference convened by the Clinical Research Branch, Division of Extramural Research Programs, National Institute of Mental Health, these findings were reviewed and some of the factors impeding movement towards a more complete and integrated view of the functioning of neurobiological systems in patients with mania or depression were identified. As a result, a multi-research centre, collaborative approach to the study of the psychobiology of affective disorders was developed. In this collaborative programme, which has now been underway for several years, the focus has been upon: (a) the assessment of the functioning of several different types of biological systems in the same patient, both before and during treatment; (b) obtaining a reasonably large number of patients and comparison subjects; and (c) the use within and across centres of standardized diagnostic categories and behavioural rating methodologies. In this paper the history, background, and rationale for this collaborative effort are reviewed. Those biological systems chosen for study are noted, and issues such as reliability and validity of diagnoses, measurement of state variables, assessment of change with treatment, and logistical and coordinating problems are discussed.

A Multi-Vantaged Approach to Measurement of Behavioral and Affect States for Clinical and Psychobiological Research:

The development of methods based on the “multivantaged” assessment of behavioral, affect, and cognitive constructs in patients with affective disorders, is reponed. The state and outcome constructs were derived for application in clinical and psychobiological studies, particularly those aimed at testing biobehavioral hypotheses and the evaluation of the effects of drugs. The development of the constructs is based on the combining of scales from established measures which assess the patient in the interview, on the ward, from his self-report, and from a new vantage, through video methodology. Psychometric analyses primarily from data from the NIMH Collaborative Study of the Psychobiology of Depression describe the assembling of the 11 state constructs, and the estimation of their reliabilities, their interrelationships, and their validities. The methods are shown to be capable of characterizing pathologic and “normal” affects, social and expressive behaviors, and impairments in the cognitive and somatic spheres. They differentiated such diverse groups as depressives, manics, and normals, and such behaviorally similar depressive types as the unipolar and bipolar. Preliminary evidence is reported which indicates differential sensitivity to the effects of tricyclic drugs

Sharing primary data: a threat or asset to discovery?

The degree of complexity of neuroscience data is a sufficient reason both for sharing and for not sharing primary data. Sharing data should make research more efficient and greatly facilitate our understanding of brain function. The intellectual challenges are identical with or without data sharing. Sharing increases the value of the data and provides new knowledge and understanding.

Onset of antidepressant activity: reexamining the structure of depression and multiple actions of drugs.

The question of when antidepressant drugs (AD) initiate significant clinical actions in depressed patients is still unsettled. Findings from early studies on whether there is a lag in the onset of therapeutic actions were in disagreement. More recent results with the selective serotonin reuptake inhibitors (SSRIs) and other new Ads indicate that clinical actions occur within the first 2 weeks. In this paper, evidence from efficacy studies with the Ads is reviewed and the methodologic and conceptual obstacles to achieving definitive results about the onset issue are analyzed. Depression, formerly viewed as a homogenous disorder, is now seen as heterogenous and multifaceted in structure. Such major structural components as anxiety and disturbed psychomotor functioning can be as significant to the core of the disorder as depressed mood itself. Further, the Ads have been shown to act initially on different facets of the clinical disorder which then result in multiple clinical actions, e.g., an initial reduction in anxiety followed by stimulation of motor activity. Data from the NIMH Collaborative Study of the Psychobiology of Depression are used to illustrate: (1) the componential structure of severe depressive disorder; (2) the sequence of change in the major behavioral components of the disorder associated with the tricyclic drugs; (3) the consequent ‘multiple’ onsets of clinical actions; and (4) measurement of the clinical significance and visibility of the early behavioral changes. Recent results describing new behavioral and methodological approaches, the use of early clinical changes to predict outcome, and strategies for designing sound studies of onset are discussed. Depression and Anxiety 4:257–267, 1996/1997.© 1997 Wiley‐Liss, Inc.

Neuroscience data and tool sharing: a legal and policy framework for neuroinformatics.

The requirements for neuroinformatics to make a significant impact on neuroscience are not simply technical—the hardware, software, and protocols for collaborative research—they also include the legal and policy frameworks within which projects operate. This is not least because the creation of large collaborative scientific databases amplifies the complicated interactions between proprietary, for-profit R&D and public “open science.” In this paper, we draw on experiences from the field of genomics to examine some of the likely consequences of these interactions in neuroscience.Facilitating the widespread sharing of data and tools for neuroscientific research will accelerate the development of neuroinformatics. We propose approaches to overcome the cultural and legal barriers that have slowed these developments to date. We also draw on legal strategies employed by the Free Software community, in suggesting frame-works neuroinformatics might adopt to reinforce the role of public-science databases, and propose a mechanism for identifying and allowing “open science” uses for data whilst still permitting flexible licensing for secondary commercial research.