Conflicting perspectives on neurobehavioral theories of the depressive disorders and drug actions.

OBJECTIVE: A prominent theory of depression focusses on neural plasticity and stress as central issues in seeking to develop a pattern of identifiable biological markers for the depressive disorders. Relative neglect, however, of clinical factors in that theory limits the uncovering of markers and opens to question their methodological approach. A conflicting theory, the 'opposed neurobehavioral states', based on dimensional analysis of monoamine neurotransmitter systems and behavioural factors is presented. This perspectives paper contrasts the two approaches viewing the biomarkers theory as premature at this point in the progress of depression research. METHOD: Studies developed to support the biomarkers theory and the opposed neurobehavioral states theory are examined for their strengths and limitations in explaining the nature of the disorder and the actions of therapeutic drugs. Reference is made to reviews of the many studies on biomarkers and the recent work that supports the opposed neurobehavioral states theory. Discussion Main issue: the biomarkers theory sets important goals, but despite the many advances in the neural investigations of factors underlying depression, is still not successful in specifying markers. Thus, it is believed to be applying the wrong methodologic approach and premature in its claims. PERSPECTIVE: the 'opposed neurobehavioral' theory is limited in its breadth of research. It applies, however, the dimensional approach to the clinical side of the problem, a methodological approach more likely to be effective in selecting the best clinical treatment and open to a more productive path to understanding of the nature of the disorder in future research.

Evidence for shortening the duration of clinical trials of antidepressants and a proposed paradigm for such studies.

The model for the clinical trial of putative antidepressants is older than 50 years. Recent failures resulted in several drug companies, citing excessive costs of lengthy multiweek trials, abandoning new drug development. Collateral problems include patients being maintained on ineffective drugs for 6 to 8 weeks, increasing the pain associated with the disorder. This study proposes an alternative model for testing new drugs that both shortens the clinical trial and broadens its aims to include a profile of the new drug's specific clinical actions. This alternative model makes it possible to uncover the drug's application to treatment of other mental disorders. It is based on recent findings that onset of action and a large proportion of an effective drug's positive effects, contrary to early reports, occur within the first 2 weeks. It uses an index of the 2-week "early improvement" to predict a 6-week outcome. Measuring effects on the dimensions of the disorder determined that effective antidepressants act on mood and behavioral components and that the Hamilton and new "multivantaged" methods can provide a profile of specific drug actions distinguished from nonspecific placebo effects, at 2 weeks. This early improvement is predictive of positive outcome of 6-week trials. Because of the implications of successful 2-week trials for reducing costs, providing data on specific clinical drug actions, potentially stimulating new drug development, and reducing patient suffering from extended treatment with ineffective drugs, a large sample, prospective study designed in accord with this test trial is recommended.

Rethinking depression and the actions of antidepressants: uncovering the links between the neural and behavioral elements.

Despite major strides in the understanding of mechanisms of antidepressant drug action, few, if any, widely applicable drug treatments with new mechanisms have been developed since the selective serotonin reuptake inhibitors in the late 1970's. One factor that may contribute to this lack of advance is reliance on a set of flawed assumptions that have guided most new drug development over the past quarter century. These assumptions have been particularly deleterious to the development of treatments with mechanisms distinctly different from currently approved treatments. One such assumption is that antidepressant actions on clinical aspects are delayed for several weeks. We review the results of studies on time to improvement and describe two collaborative, multidisciplinary studies during this period which employed a behavioral component model for assessment of change, as an alternative to the conventional "diagnostic-specific" research model. These studies incorporated a novel neurobehavioral framework for describing depressive episodes. The studies indicated that (1) depressive states are comprised of relatively independent and somewhat opposed behavioral and emotional components of anxiety-agitation and depression-retardation, coexisting with a third dimension, hostility, all of which might indicate some degree of mixed state phenomenology, (2) drugs selectively targeted at serotonergic and noradrenergic systems have differing profiles of impact on the behavioral dimensions of depressive states and (3) the sequence of behavioral improvements initiated by pharmacodynamically different drugs also differ. In the aggregate these consistent observations provide the basis for a new paradigm on the nature of major depression. The proposition links drug-induced neural and behavioral changes of antidepressants with prediction of clinical outcome based on early response. We submit that the proposed approach may bring about a new paradigm for improving behavioral technology and design of studies capable of identifying drugs with novel properties and rapid onset of improvement, while avoiding some problematic constructs in past biological research on depression.

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.

Early symptom change prediction of remission in depression treatment.

OBJECTIVES: This study investigated hypothesized early symptom changes as differential predictors of long-term remission for duloxetine and escitalopram. EXPERIMENTAL DESIGN: This was a post-hoc analysis from a placebo-controlled, randomized, double-blind study of patients with major depressive disorder treated for 8 weeks with duloxetine 60 mg/day (N = 273) or escitalopram 10 mg/day (N = 274), and for another 6 months with duloxetine up to 120 mg/day or escitalopram up to 20 mg/day. Odds ratios (ORs) for successful treatment (sustained remission), defined as a 17-item Hamilton Depression Rating Scale (HAMD-17) score 2.0. In a follow-up analysis, specific subscale items for psychological anxiety, motor retardation, and suicidality significantly predicted remission for duloxetine, and psychological and somatic anxiety for escitalopram. Notably, high NPVs on the Maier subscale indicated that a lack of 20% improvement on the "core" depression factor by Week 2 was highly predictive of unsuccessful treatment outcome over 8 months. CONCLUSIONS: In accord with hypotheses, early symptom changes were specific to treatment, with early response in the core depression factor (Maier subscale), anxiety, and motor activity for duloxetine, and core factor and anxiety for escitalopram. Lack of early response in depression symptom subscales was highly predictive of lack of sustained remission.

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.

The history and current state of antidepressant clinical trial design: a call to action for proof-of-concept studies.

BACKGROUND: The development of new antidepressant drugs has reached a plateau. There is an unmet need for faster, better, and safer medications, but as placebo-response rates rise, effect sizes shrink, and more studies fail or are negative, pharmaceutical companies are increasingly reluctant to invest in new drug development because of the risk of failure. In the absence of an identifiable human pathophysiology that can be modeled in preclinical studies, the principal point of leverage to move beyond the present dilemma may be improving the information gleaned from well-designed proof-of-concept (POC) studies of new antidepressant drugs with novel central nervous system effects. With this in mind, a group of experts was convened under the auspices of the University of Arizona Department of Psychiatry and Best Practice Project Management, Inc. PARTICIPANTS: Forty-five experts in the study of antidepressant drugs from academia, government (U.S. Food and Drug Administration and National Institute of Mental Health), and industry participated. EVIDENCE/CONSENSUS PROCESS: In order to define the state of clinical trials methodology in the antidepressant area, and to chart a way forward, a 2-day consensus conference was held June 21-22, 2007, in Bethesda, Md., at which careful reviews of the literature were presented for discussion. Following the presentations, participants were divided into 3 workgroups and asked to address a series of separate questions related to methodology in POC studies. The goals were to review the history of antidepressant drug trials, discuss ways to improve study design and data analysis, and plan more informative POC studies. CONCLUSIONS: The participants concluded that the federal government, academic centers, and the pharmaceutical industry need to collaborate on establishing a network of sites at which small, POC studies can be conducted and resulting data can be shared. New technologies to analyze and measure the major affective, cognitive, and behavioral components of depression in relationship to potential biomarkers of response should be incorporated. Standard assessment instruments should be employed across studies to allow for future meta-analyses, but new instruments should be developed to differentiate subtypes and symptom clusters within the disorder that might respond differently to treatment. Better early-stage POC studies are needed and should be able to amplify the signal strength of drug efficacy and enhance the quality of information in clinical trials of new medications with novel pharmacologic profiles.

A video method for the evaluation of antidepressant clinical and behavioural actions.

Measuring efficacy and behavioural actions of new antidepressants (ADs) is greatly enhanced by having videotaped records of assessment interviews. This study describes a revised version of the Video Interview Behaviour Evaluation Scales (VIBES), shortened to make it more applicable to clinical trials. The method focuses on physically expressive, motor and social behavioural aspects of the depressive disorder. The Brief version permits juxtaposing of baseline and outcome interviews during the same viewing session thereby reducing the role of memory in the rater's observations. The method provides measures of behavioural components and four new severity dimensions, Social withdrawal-motor retardation, Anxiety-agitation, Hostility, Depressive mood-cognitive impairment. Viewing a patient's series of baseline, during treatment, and outcome interviews can be conducted in about 1 h. This study compared the VIBES with the Hamilton Depression Rating Scale (HAMD) in (1) assessing the efficacy of the selectively targeted ADs, desipramine and paroxetine, and placebo in depressed in-patients and (2) determining onset and nature of the drugs' early behavioural actions. The findings showed (1) components of the method to be reliable; (2) the VIBES to be more sensitive than the HAMD in measuring efficacy; (3) the methods to be equally sensitive in detecting early clinical actions of the two drugs; (4) the VIBES more informative in identifying discrete behavioural aspects of the disorder that are impacted by the drugs; and (5) that in differentiating the drugs' behavioural actions, desipramine was indicated to initially 'stimulate', i.e. effect motor activity and depressed mood, and paroxetine to reduce global severity and anxiety. The study shows the VIBES to be capable of uncovering behavioural mechanisms underlying AD's capacity to resolve depressive disorder.

A multivantaged behavioural method for measuring onset and sequence of the clinical actions of antidepressants.

An aim in development of new antidepressants (ADs) now includes increasing speed of action. New drugs are tested primarily in outpatients who are less severely depressed than the patients treated in earlier trials of the tricyclic drugs. To determine early efficacy requires measures sensitive to initial changes in components of the illness as well as in the severity of the entire syndrome of depression. This paper describes the development of a brief 'multivantaged' (MV) method for assessing the major behavioural and affective components of depression. The revised Brief MV was significantly reduced from the original to make it more feasible to apply in outpatient studies. In this study we determined the Brief MV's (1) reliability and comparability to the original and (2) its ability to detect the onset of specific behavioural effects in outpatients treated with paroxetine for 6 wk. The latter is compared to the ability of the Hamilton Depression Scale (HAMD) to detect changes in global severity. The constructs derived from the Brief MV were found to be highly similar to those of the original version and as reliable. In depressed patients who responded to paroxetine, the HAMD and MV detected onset of improvement after 7 d of treatment. The Brief MV revealed that the improvement in global severity was due to the drug's action at this time on behaviours such as anxiety and distressed expression, as well as on a severity dimension of anxiety-agitation-somatization. Thus, the Brief MV, in uncovering underlying behavioural actions, represents an important addition to the current unidimensional HAMD approach in drug research.

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.

The contributions of Sam Greenhouse to research on psychiatric diagnosis and psychopharmacology.

Sam Greenhouse began his involvement in mental disorders research in 1954 when appointed chief of the Theoretical Statistics and Mathematics section at the National Institute of Mental Health. He remained with the NIMH until 1966. Despite moving on to several other positions at the NIH and at the university during the ensuing years, he continued as a consultant to NIMH investigators. He also participated actively as an advisor and co-investigator on a number of important collaborative research programmes launched by the Institute in the 1970s and 1980s. His contributions to the design and methodology of the first clinical trials of drugs for the treatment of schizophrenia, to research aimed at revising the national and international classification systems for the mental disorders, and his participation in the planning of the first attempt to use the collaborative research model to test hypotheses about the genesis of a specific mental disorder (depression), are described. Finally, the signal importance of the 'profile analysis of variance' method that he and Seymour Geisser developed, to research on personality and mental disorders, is examined in detail. The authors describe applications of the method in their own research on the classification of the mental disorders, predicting response to drug treatment and the variations in the expression of mental illness across different cultures. Sam worked in mental health during an era of revolutionary changes in the diagnosis and treatment of mental disorders. The field was acutely aware of his many contributions to the progress of research and his colleagues are very grateful to have had the opportunity to work with him.

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) , Unites States and Food and Drug Administration (FDA), Unites States 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.