Martin M. Katz

Onset and Early Behavioral Effects of Pharmacologically Different Antidepressants and Placebo in Depression

This study was aimed at resolving the time course of clinical action of antidepressants (ADs) and the type of early behavioral changes that precede recovery in treatment-responsive depressed patients. The first goal was to identify, during the first 2 weeks of treatment, the onset of clinical actions of the selective serotonin reuptake inhibitor (SSRI), paroxetine, and the selective noradrenergic reuptake inhibitor, desipramine (DMI). The second aim was to test the hypothesis that the two pharmacologic subtypes would induce different early behavioral changes in treatment-responsive patients. The design was a randomized, parallel group, placebo-controlled, double-blind study for 6 weeks of treatment following a 1-week washout period. The study utilized measures of the major behavioral components of the depressive disorder as well as overall severity. The results indicated that the onset of clinical actions of DMI ranged from 3 to 13 days, averaged 13 days for paroxetine, and was 16–42 days for placebo. Furthermore, as hypothesized, the different types of ADs initially impacted different behavioral aspects of the disorder. After 1 week of treatment, DMI produced greater reductions in motor retardation and depressed mood than did paroxetine and placebo, and this difference persisted at the second week of treatment. Early improvement in depressed mood–motor retardation differentiated patients who responded to DMI after 6 weeks of treatment from those that did not. Paroxetine initially reduced anxiety more in responders than in nonresponders, and by the second week, significantly improved depressed mood and distressed expression in responders to a greater extent. Depressed patients who responded to placebo showed no consistent early pattern of behavior improvement. Early drug-specific behavioral changes were highly predictive of ultimate clinical response to the different ADs, results that could eventually be applied directly to clinical practice.

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.

Development of the Bipolar Inventory of Symptoms Scale

Objective:  Most rating scales for bipolar disorders (BDs) do not encompass the spectrum of symptomatology now established as characterizing the illness. We report the rationale, format, reliability and initial validity studies of the Bipolar Inventory of Symptoms Scale (BISS), a 44‐item scale designed to encompass the spectrum of behavioral disturbances in BDs.

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.

Behavioural measurement and drug response characteristics of unipolar and bipolar depression

This research is part of the NIMH--CRB Collaborative Study on the psychobiology of depression. The main objective of the research programme is to test hypotheses concerning the interaction of neurobiological mechanisms and behaviour in the depressive disorders. Part I of the report describes the rationale and the overall approach to measuring behavioural state and outcome in the research programme. Part II reports on the results of applying the behavioural methods to a comparison of the clinical phenomenology of unipolar and bipolar depression. The behavioural patterns expressed during the episode by the two groups are different. Further, the two types are shown to react differently to treatment with tricyclic drugs, reinforcing the thesis that they are qualitatively distinct forms of the depressive disorders.

Principal domains of behavioral psychopathology identified by the Bipolar Inventory of Signs and Symptoms Scale (BISS)

Current symptom rating scales and diagnostic categories for bipolar disorder (BD) do not provide dimensional profiles of the types of behavior disturbed in this complex disorder. To overcome these limitations we identified the principal domains of behavioral symptomatology in bipolar individuals, including all mood states, and used a more comprehensive rating scale for BD: the Bipolar Inventory of Signs and Symptoms Scale (BISS). A total of 246 patients with BD (196 with BD type I, and 50 with BD type II) were interviewed using the BISS. Exploratory factor analysis was performed on the BISS results using the maximum likelihood factor extraction method, followed by oblique rotation of the extracted factor loadings. We determined the strength of relationships between factor scores using the Pearson correlation coefficient. The following five factors were extracted: mania, depression, irritability, anxiety and psychosis. Anxiety was significantly correlated with depression and irritability. The mania factor score was only weakly associated with the other four factors. The domains of the BISS capture both the historical categories of depression and mania, plus irritability, psychosis, and an additional principal domain, anxiety. Despite the common occurrence of anxiety in BD, it has not been identified in most prior factor analyses, in part due to limited coverage of anxiety symptoms in the source scales.

Development of the Bipolar Inventory of Symptoms Scale: concurrent validity, discriminant validity and retest reliability

Scales used in studies of bipolar disorder have generally been standardized with major depressive or hospitalized manic patients. A clinician rated scale based on a semi‐structured interview for persons with bipolar disorder, with comprehensive coverage of bipolar symptomatology, is needed. We report concurrent, divergent and convergent psychometric reliability, discriminant validity and relationship to a measure of overall function for a new psychometric rating instrument. A primarily outpatient sample of 224 subjects was assessed using the Bipolar Inventory of Symptoms Scale (BISS). The BISS total score and depression and mania subscales were compared to the Young Mania Rating Scale (YMRS), the Montgomery Asberg Depression Rating Scale (MADRS) and the Global Assessment of Functioning Scale (GAF). Clinical mood states were also compared using the BISS. The BISS scores demonstrated good concurrent validity, with estimates (Pearson correlations) ranging from 0.74 to 0.94 for YMRS and MADRS and test–retest reliability from 0.95 to 0.98. BISS concurrent validity with the GAF was significant for four clinical states, but not mixed states. The BISS discriminated primary bipolar mood states as well as subjects recovered for eight weeks compared to healthy controls. In conclusion, the BISS is a reliable and valid instrument broadly applicable in clinical research to assess the comprehensive domains of bipolar disorder. Future directions include factor analysis and sensitivity to change from treatment studies. Copyright

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.

Weight loss, cortisol levels, and dexamethasone suppression in major depressive disorder

ABSTRACT— Appetite and/or weight loss are integral, albeit not necessary, symptoms of depression. We explored the contribution of diminished appetite and/or weight loss ascertained by history to the hypothalamic‐pituitary‐adrenocortical (HPA) axis dysregulation in 120 patients with primary major depressive disorder. Significant positive relationship for both appetite and weight loss with cortisol levels in plasma and cerebrospinal fluid (CSF) were observed. Plasma cortisol levels were consistently higher in patients who noted both appetite and weight loss as opposed to patients without appetite or weight loss. Depressed patients with weight loss showed higher rates of dexamethasone‐nonsuppression. Age and severity of depression influenced but did not eliminate the significance of the findings, suggesting that weight loss accounts in part for the HPA‐axis function changes observed in depression.

Enhancing the Technology of Clinical Trials and the Trials Model to Evaluate Newly Developed, Targeted Antidepressants☆

Concern about disappointing results from recent multi-center trials of new antidepressants prompted several ACNP workshops on “improving the technology of clinical trials.” The workshops focused on technical problems, such as patient screening, reliability of clinical ratings, and the role of the placebo control. They aimed to determine how to more effectively apply the current clinical trials model for evaluating antidepressant drugs. The problems confronting the field of clinical trials, however, extend beyond technology. They also included conceptual issues concerning changes in the understanding of depressive disorders and of the multiple actions of antidepressant drugs. Such problems have been further complicated by the rapidly changing field of drug development itself, which is continually refining the targeting of new antidepressant agents. Drugs are increasingly being developed to try to change specific behavioral facets more rapidly and may be less likely, therefore, to act initially on “whole” disorders. To address such issues, a symposium was held in Rhodes in 2000 that focused on such conceptual changes with the goal of developing recommendations to revise the clinical evaluation model. Its purpose was to integrate new knowledge on depression and the mechanisms of action of antidepressant drugs toward developing more efficient methods of drug development. Since the evaluation process will eventually require changes in governmental policy, senior staff from the National Institute of Mental Health (NIMH) and Food and Drug Administration (FDA) participated as well as members of academia, industry and clinical practice. Recommendations for altering clinical trial methodology were made in four areas: patient selection, methodology of evaluation, measuring onset of action, and FDA and NIMH perspectives on current practice. This article discusses these four areas and presents the consensus of the panel participants.