Increased hippocampal tail volume predicts depression status and remission to anti-depressant medications in major depression.

Studies of patients with major depressive disorder (MDD) have consistently reported reduced hippocampal volumes; however, the exact pattern of these volume changes in specific anatomical subfields and their functional significance is unclear. We sought to clarify the relationship between hippocampal tail volumes and (i) a diagnosis of MDD, and (ii) clinical remission to anti-depressant medications (ADMs). Outpatients with nonpsychotic MDD (n=202) based on DSM-IV criteria and a 17-item Hamilton Rating Scale for Depression (HRSD17) score ⩾16 underwent pretreatment magnetic resonance imaging as part of the international Study to Predict Optimized Treatment for Depression (iSPOT-D). Gender-matched healthy controls (n=68) also underwent MRI scanning. An automated pipeline was used to objectively measure hippocampal subfield and whole brain volumes. Remission was defined as an HRSD17 of ⩽7 following 8 weeks of randomized open-label treatment ADMs: escitalopram, sertraline or venlafaxine-extended release. After controlling for age and total brain volume, hippocampal tail volume was larger in the MDD cohort compared to control subjects. Larger hippocampal tail volume was positively related to clinical remission, independent of total hippocampal volume, total brain volume and age. These data provide convergent evidence of the importance of the hippocampus in the development or treatment of MDD. Hippocampal tail volume is proposed as a potentially useful biomarker of sensitivity to ADM treatment.

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.

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.

Animal models recapitulate aspects of HIV/CNS disease.

Neurobehavioral and pathological data indicate that the central nervous system (CNS) becomes infected with HIV-1 soon after the virus enters the body. However, neuropathogenesis of HIV-1 infection is difficult to investigate because the brain parenchyma is not accessible to sampling during the course of AIDS. The second compartment of the CNS, cerebrospinal fluid (CSF), is accessible to sampling but how changes in the CSF relate to the changes in the parenchyma is poorly understood. Thus, knowledge of the neuropathogenesis of HIV-1 infection predominantly stems from either postmortem or in vitro studies. This raises the need for animal models of HIV infection of the CNS. Such models have been developed and are briefly reviewed here. The models faithfully recapitulate some aspects of the HIV/CNS disease. Appropriate neuropathological changes and neurobehavioral dysfunction (e.g., cognitive and motor deficits) occur in SIV-infected macaques. Central sensory electrophysiological changes and sleep disturbances occur in FIV-infected cats. Infection of the brain and behavioral changes comparable to some of the changes seen in humans occur in mice infected with a mixture of murine leukemia viruses. Genetically immunodeficient mice (e.g., SCID) accept HIV-infected human organs and or cell grafts. Evidence summarized here indicates that these HuSCID animals undergo neuropathological changes similar to those observed in brains of individuals who died with AIDS. Thus, presently available animal models provide an opportunity to investigate HIV/CNS disease, and to develop and test therapeutic interventions to prevent or cure the disease.

Drug-induced actions on brain neurotransmitter systems and changes in the behaviors and emotions of depressed patients.

Despite cumulative evidence that the tricyclic drugs result in significant changes in the functioning of brain serotonergic (5-HT) and nordrenergic (NE) systems, such changes have not been found to be associated with recovery from depression. Based upon evidence that the 5-HT and NE systems were associated with different emotions, it was hypothesized that changes in these systems were associated with different components of behavior in drug-responsive patients and not with changes in the "whole" disorder. Findings from this multihospital study of 104 unipolar and bipolar depressed patients showed early drug-associated reductions in anxiety and hostility in treatment responders to precede changes in motor retardation and depressed mood. Adopting this approach of looking for relationships between changes in components of major depression and changes in neurotransmitter system function, decreases in 5-HT and NE metabolite concentrations in cerebrospinal fluid (CSF) in patients treated with tricyclics, were found to be correlated with changes in specific behaviors. Results indicated the following: (1) drug-induced changes in the 5-HT system to be associated with mood aspects, notably anxiety, and depressed mood; changes in NE primarily with the psychomotor, secondarily with the mood components of the depressed state; (2) the pattern of relationships between changes in 5-HT and in mood in the unipolar was different than that in the bipolar subtype. The results indicate that in determining the relationships of biochemical changes to behavioral ones, that it is important to take into account the type of depression (bipolar or unipolar), as well as examining individually and over time those components that make up the disorder of depression. These results support evidence that tricyclics have multiple behavioral actions, that response is mediated through changes in specific behaviors and that this approach warrants further application in prospective studies of antidepressant drug mechanisms and their therapeutic actions.

Neurotechnology: expanding opportunities for funding at the National Institute of Mental Health.

The National Institute of Mental Health recognizes the importance that creative development of technology and methodology play in brain and behavioral science research. This institute is making major efforts to support such development through specific initiatives, like the Human Brain Project. In addition, this Institute is actively building bridges between business and academic research communities to make optical use of funds for the research and development of commercially viable technologies relevant to all aspects of the Institute's mission through the Small Business Innovation Research and Small Business Technology Transfer Programs. Together, these efforts will culminate in a more vigorous scientific enterprise, and ultimately benefit the entire mental health community and society.

Adrenomedullary function in depressed patients.

In this paper from the Collaborative Depression Study (CDS)--Biological, a set of data analyses are presented which indicate that depressed states and perhaps depressed mood are associated with a greater activation of the adrenomedullary system than the sympathetic nervous system [as measured by norepinephrine (NE) and normetanephrine excretion]. For the most part this finding of predominant activation of the adrenomedullary system is seen in unipolar and not bipolar patients.

The pattern of physical symptom changes in major depressive disorder following treatment with amitriptyline or imipramine.

The study describes a sequential analysis of depression-related physical symptoms and their relationship to imipramine and amitriptyline plasma levels over 4 weeks of treatment in 79 unipolar and bipolar patients hospitalized for major depressive disorder. Insomnia diminished in all patients after 2 weeks of drug administration. After 4 weeks, the sleep of patients whose depressive disorder has significantly improved was nearly normal, whereas patients who remained depressed showed continued sleep impairment. Reductions in loss of appetite, weight and sexual interest paralleled mood improvement. Tricyclic plasma levels significantly correlated with improved sleep. The findings suggest a close link between depressed mood and physical symptoms during recovery from major depressive disorder.

Depressive mania versus agitated depression: biogenic amine and hypothalamic-pituitary-adrenocortical function.

The existence of mixed affective states challenges the idea of specific biological abnormalities in depression and mania. We compared biogenic amines and hypothalamic-pituitary-adrenocortical (HPA) function in mixed manic (n = 8), pure manic (n = 11), agitated bipolar depressed (n = 20), and nonagitated bipolar depressed (n = 27) inpatients (Research Diagnostic Criteria). Mixed manics met Research Diagnostic Criteria for primary manic episodes and also met criteria for major depressive episodes except for duration. The norepinephrine metabolite methoxyhydroxy phenthylene glycol (MHPG) was higher in cerebrospinal fluid from mixed manic than from agitated depressed patients, consistent with differences previously reported between the overall samples of depressed and manic patients. Similarly, patients in a mixed state had higher urinary excretion of norepinephrine (NE) and elevated output of NE relative to its metabolites. HPA activity was similar in mixed manic and agitated depressed patients. These data suggest that mixed manics combine certain biological abnormalities considered to be characteristic of mania and of depression.

The Human Brain Project: an international resource.

As the amount of basic neuroscientific information increases dramatically, its day-to-day integration and application becomes an increasing difficulty. Technological advances, particularly in computer and information sciences, should allow this information 'explosion' to become more manageable. To this end, the Human Brain Project, an initiative of several NIH Institutes and other United States Government agencies, is being developed to provide a computer database that will allow neuroscientists access to information at all levels of integration, from genes to behavior. In this article Michael Huerta, Stephen Koslow and Alan Leshner outline the genesis and ideas behind the initiative and discuss its future development.

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.

Gliomatosis cerebri: a case report with autopsy correlation.

MRI-autopsy correlation in a case of gliomatosis cerebri suggests that poor gray-white matter demarcation on MRI may be sign of neoplastic infiltration. The extent of infiltration is imperfectly assessed by current imaging modalities.