Attenuated psychosis syndrome: ready for DSM-5.1?

Prodromal features of the schizophrenia syndrome have been described for a century, and work in the past two decades has produced a substantial literature based on these features to identify individuals at increased risk for developing a psychotic disorder. Sometimes conceptualized as a "risk state" and sometimes as early manifestations of a "disorder," the work has been conducted with several related but different constructs. Early in the preparation of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) public comment was sought on the proposal to create a new disorder termed attenuated psychosis syndrome (APS), and a range of issues emerged that generated interesting and important controversies. In this review, these criticisms are fully discussed, the APS concept is explicated; data relating to reliability, validity, and treatment are updated; the heterogeneity of APS is considered; and alternative views of the construct are presented with an emphasis on developmental pattern with timing for primary and secondary prevention and early treatment. Areas of future research are identified, and a potential roadmap for inclusion in DSM-5.1 is traced.

Another view of the history of antipsychotic drug discovery and development.

Chlorpromazine initiated effective pharmacotherapy for schizophrenia 60 years ago. This discovery initiated or stimulated key developments in the field of psychiatry. Nonetheless, advances in pharmacotherapy of schizophrenia have been modest. Psychosis remains the primary aspect of psychopathology addressed, and core pathologies such as cognition and negative symptom remain unmet therapeutic challenges. New clinical and basic neuroscience paradigms may guide the near future and provide a more heuristic construct for novel and innovative discovery.

Advances in schizophrenia.

Recent studies into the etiology of schizophrenia have yielded both promising leads and disappointing dead ends, indicating the multifactored and complex nature of the disorder. The focus has subsequently shifted back to refining the phenotype and identifying clinical and biological subtypes. Recent technological breakthroughs in genomics and proteomics hold promise for advancing our understanding of the molecular pathophysiology of schizophrenia.

Exploring the feasibility of a meta-structure for DSM-V and ICD-11: could it improve utility and validity?

BACKGROUND: The organization of mental disorders into 16 DSM-IV and 10 ICD-10 chapters is complex and based on clinical presentation. We explored the feasibility of a more parsimonious meta-structure based on both risk factors and clinical factors. METHOD: Most DSM-IV disorders were allocated to one of five clusters as a starting premise. Teams of experts then reviewed the literature to determine within-cluster similarities on 11 predetermined validating criteria. Disorders were included and excluded as determined by the available data. These data are intended to inform the grouping of disorders in the DSM-V and ICD-11 processes. RESULTS: The final clusters were neurocognitive (identified principally by neural substrate abnormalities), neurodevelopmental (identified principally by early and continuing cognitive deficits), psychosis (identified principally by clinical features and biomarkers for information processing deficits), emotional (identified principally by the temperamental antecedent of negative emotionality), and externalizing (identified principally by the temperamental antecedent of disinhibition). CONCLUSIONS: Large groups of disorders were found to share risk factors and also clinical picture. There could be advantages for clinical practice, public administration and research from the adoption of such an organizing principle.

The psychoses: cluster 3 of the proposed meta-structure for DSM-V and ICD-11.

BACKGROUND: In an effort to group mental disorders on the basis of etiology, five clusters have been proposed. Here we consider the validity of the cluster comprising selected psychotic and related disorders. METHOD: A group of diagnostic entities classified under schizophrenia and other psychotic disorders in DSM-IV-TR were assigned to this cluster and the bordering disorders, bipolar (BD) and schizotypal personality disorders (SPD), were included. We then reviewed the literature in relation to 11 validating criteria proposed by the DSM-V Task Force Study Group. RESULTS: Relevant comparisons on the 11 spectrum criteria are rare for the included disorders except for schizophrenia and the two border conditions, BD and SPD. The core psychosis group is congruent at the level of shared psychotic psychopathology and response to antipsychotic medication. BD and SPD are exceptions in that psychosis is not typical in BD-II disorder and frank psychosis is excluded in SPD. There is modest similarity between schizophrenia and BD relating to risk factors, neural substrates, cognition and endophenotypes, but key differences are noted. There is greater support for a spectrum relationship of SPD and schizophrenia. Antecedent temperament, an important validator for other groupings, has received little empirical study in the various psychotic disorders. CONCLUSIONS: The DSM-IV-TR grouping of psychotic disorders is supported by tradition and shared psychopathology, but few data exist across these diagnoses relating to the 11 spectrum criteria. The case for including BD is modest, and the relationship of BD to other mood disorders is addressed elsewhere. Evidence is stronger for inclusion of SPD, but the relationship with other personality disorders along the 11 criteria is not addressed and the absence of psychosis presents a conceptual problem. There are no data along the 11 spectrum criteria that are decisive for a cluster based on etiology, and inclusion of BD and SPD is questionable.

Flexible system for the diagnosis of schizophrenia: report from the WHO International Pilot Study of Schizophrenia.

Behavioral data on a large patient group were collected by investigators from nine countries in the International Pilot Study of Schizophrenia, sponsored by the World Health Organization. The data on half the group were analyzed to derive a system of 12 signs and symptoms for the identification of schizophrenia, as this disorder is diagnosed in many centers throughout the world. The findings were replicated with the other half of the patient group. The criteria constitute an operational method for identifying patients who would be commonly considered schizophrenic in many centers.

Remission in schizophrenia: the relationship to baseline symptoms and changes in symptom domains during a one-year study.

The concepts of partial recovery and remission have become increasingly important for the evaluation of the effectiveness of schizophrenia therapeutics. The relationship of baseline symptoms and changes in symptoms to remission of psychosis was evaluated. Fifty-six outpatients with residual schizophrenia completed a double-blind trial of olanzapine versus haloperidol and were then enrolled into a one-year open-label trial of olanzapine. Out of these 56 subjects, 13 (23%) met remission criteria at the beginning of the open-label treatment and were excluded. During the one-year study, 7/43 (16%) subjects met remission criteria. These subjects had significantly lower baseline ratings for tardive dyskinesia (TD) than subjects who did not achieve remission (1.8 +/- 1.5 vs. 4.2 +/- 4.6, P = 0.03). As expected, remitted subjects had significantly greater improvements in Brief Psychiatric Rating Scale total scores, positive subscale scores and scale for the Assessment of Negative Symptoms total scores. Remitted subjects also experienced a significantly greater improvement in depressive symptoms (P = 0.001), activation (P = 0.005), and Clinical Global Impressions scores (P < 0.001), as well as greater improvements in extrapyramidal symptoms (P = 0.007) and TD (P < 0.001). These results suggest that the relationship of depressive symptoms and improved side effects to the construct of remission in schizophrenia may deserve special attention. Future studies should aim to relate remission criteria to functional outcomes, cognition, and other important symptom domains.

Postpsychotic depression in schizophrenia.

Several authors have described a severe depression in patients emerging from psychotic states. The clinical picture usually resembles that of a retarded depression with strong neurasthenic and schizoid components. It frequently emerges after a patient has been discharged from the hospital and may often go unnoticed. When manifest, the syndrome is usually stable phenomenologically, is often lengthy, and may be resistant to all modalities of treatment. Postpsychotic depression is a relatively neglected clinical area despite the risk of suicide and prolonged suffering. Therapeutic perseverence purportedly can improve the patient's long-term prognosis, and the phenomenon itself may be favorable prognostic sign. We present here a review and reformulation of this syndrome.

Prediction of outcome in schizophrenia. III. Five-year outcome and its predictors.

Recent studies of schizophrenia have begun to demonstrate the complex nature of its outcome characteristics and their predictors. However, generalization of findings has been limited by methodological problems such as relatively short-term follow-up the use of retrospective data, or employment of evaluation techniques without demonstrated reliability. This report describes a prospective, five-year follow-up using reliable evaluation techniques to determine whether specific relations between predictors and outcome variables represent behavior patterns persisting over an extended period. Results demonstrate the prognostic importance and specificity of certain predictors over five years. These results support the view that outcome function is comprised of persisting open-linked systems of behavior.

Psychotherapy in hospitalized research patients.

Operations at the clinical-research interface exert a signal influence on the therapy of patients being treated on investigative units. The effect on the treatment milieu has been described but the impact of a research climate on individual psychotheraphy of hospitalized patients has not. We observed research-therapy interaction in 25 acutely schizophrenic patients. Analytically oriented psychotherapy was carried out on a National Institutes of Health clinical research unit where drugs are only occasionally used, and patients are subjects in psychobiological investigation. The subtle, and often neglected, interplay between therapy and research is examined, with emphasis on the shifting meanings of the patient's participation or refusal to participate in therapy, research, or both. A research transference and countertransference are defined, and some special behavioral patterns of research patients receiving dynamic therapy are considered in this framework.

Integration and sealing over. Clinically distinct recovery styles from schizophrenia.

Concepts of integration and sealing over are common clinical psychiatric parlance. Our experience studying and treating acute schizophrenic patients, primarily with psychosocial techniques, has emphasized the meaningfulness of these concepts. By studying the recovered patient's attitude toward his psychotic experiences, we have obtained material from which to formulate definitions and these concepts. Integrators tend to be curious about their symptoms, regard them as part of their life's pattern, and gain information from them, resulting in a more flexible and variable attitude toward illness than patients who seal over. The latter have rather fixed, usually negative, views of their illness, and tend not to strive to understand their psychotic symptoms nor to place their psychotic experiences in perspective with their lives before and after psychosis.

Diagnostic criteria and five-year outcome in schizophrenia. A report from the International Pilot Study of schizophrenia.

Systematic psychiatric assessment was undertaken on 131 patients (the American cohort of the International Pilot Study of Schizophrenia). Nine areas of outcome functioning were assessed five years later at follow-up evaluation on 63% of these patients. An analysis of 66 clinical and demographic variables established that the patients sucessfully followed-up were representatives of the entire cohort. Diagnostic data from initial evaluations and follow-up outcome assessment were used to examine the relationship between diagnostic criteria and outcome in schizophrenia. Applying the criteria for schizophrenic diagnosis defined by Langfeldt, by Schneider, and Carpenter et al failed to define a poor outcome group. No difference in outcome was found when traditional schizophrenic subtypes were contrasted. Overall outcome in 61 patients with conditions diagnosed as schizophrenic was heterogeneous. However, despite overlap, the mean outcome in the schizophrenic cohort was poorer than in the 19 nonschizophrenic patients.

Cerebrospinal fluid amine metabolites in acute schizophrenia.

The metabolites of serotonin, dopamine, and norepinephrine, 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG), respectively, were studied in cerebrospinal fluid of patients with acute schizophrenia. Base line levels of these metabolites were not significantly different from those in normal, neurological, and affectively ill controls. Accumulations of 5HIAA and HVA following probenecid administration, which provide a measure of serotonin and dopamine turnover, were also not significantly different in patients with acute schizophrenia and affective illness. After patients had recovered from their acute schizophrenic illness, HVA accumulations were significantly reduced. We discuss results in relation to amine hypotheses of schizophrenia and the suggestion that altered dopamine metabolism may reflect a biological change predisposing to acute schizophrenia.

The rationale and ethics of medication-free research in schizophrenia.

Schizophrenia research is receiving intense scrutiny from an ethical perspective. Medication-free protocols present a most vexing dilemma in that they greatly enhance the opportunity for advancing knowledge but also raise the prospect of withholding known effective treatment. In this article, we discuss the purpose of medication-free protocols in new drug development and nontreatment research. Potential benefits and risks associated with drug discontinuation are evaluated, and methods for minimizing risk and increasing benefits are proposed as guidelines for the protection of individual subjects. The complex problem of informed consent also is addressed. Medication-free research in schizophrenia is difficult, but it can be conducted relatively, safely with freely consenting, competent subjects. Assurance that studies meet this standard is required. We believe that such investigations can meet high standards of ethics and subject protection, and that a radical revision of procedures for research review and implementation is not indicated.

A separate disease within the syndrome of schizophrenia.

If schizophrenia is a clinical syndrome rather than a single disease, the identification of specific diseases within the syndrome would facilitate the advance of knowledge and the development of more specific treatments. We propose that deficit psychopathology (ie, enduring, idiopathic negative symptoms) defines a group of patients with a disease different from schizophrenia without deficit features, as the deficit and nondeficit groups differ in their signs and symptoms, course, biological correlates, treatment response, and etiologic factors. These differences cannot be attributed to more severe positive psychotic symptoms or a greater duration of illness in the deficit group. The alternative interpretation that patients with deficit schizophrenia are at the severe end of a single disease continuum is not supported by risk factor and biological features data, but there is a need for independent replication of these findings. We suggest a series of studies designed to falsify one of these hypotheses, ie, multiple diseases vs a single disease.

Autonomic nervous system activity in acute schizophrenia: I. method and comparison with normal controls.

Many reports of autonomic dysfunction in schizophrenia may have been influenced by the chronicity or medication status of patients, or both. This study eliminates these sources of variation. Skin conductance (SC) and heart rate (HR) base levels and activity were compared in 118 controls and 46 recently admitted, drug-free, acute schizophrenic patients during rest, 20 mild-tone stimuli, and reaction time (RT) and mental arithmetic tasks. Patients showed higher than normal HR and spontaneous SC responses but lower SC base levels. Schizophrenics showed less SC and HR reactivity to tones and RT stimuli, slow habituation of the SC orienting response, an attenuated tonic response to stress, and disproportionately more spontaneous than elicited SC activity. The findings are similar to previous results for unmedicated, chronic schizophrenics and suggest that autonomic activity in schizophrenics is determined relatively more by endogenous factors than by external stimuli.

Autonomic nervous system activity in acute schizophrenia: II. relationships to short-term prognosis and clinical state.

Autonomic nervous system (ANS) activity in acute schizophrenic patients was assessed to examine predictive relationships to clinical course. Unmedicated patients were rated on global psychopathology and tested on skin conductance, heart rate, and skin temperature during rest, a series of tones, and reaction time and mental arithmetic tasks three weeks after admission and again about three months later. On the admission tests, a pattern of ANS activity found in schizophrenics in general (high resting "arousal," slow habituation, and attenuated ANS reactivity, particularly to demanding stimuli and situations) was found in patients who were to remain clinically ill but not in patients whose recovery was more complete, especially in males. Thus, ANS activity is predictive of short-term outcome in acute schizophrenia. Minimal ANS changes accompanied clinical improvement, which suggests a "'trait" interpretation, but "state" effects cannot be completely ruled out.

Another view of schizophrenia subtypes. A report from the international pilot study of schizophrenia.

Schizophrenia subtypes are defined predominantly my manifest symptoms and behavior. This report, based on sign and symptom data from the International Pilot Study of Schizophrenia, addresses three questions: (1) Are traditional subtype diagnoses applied similarly across cultures? (2) Are the various traditional subtypes symptomatically distinguishable from one another? (3) Can cluster analytic techniques define a more distinctive set of schizophrenic subgroups? Present State Examination data were reduced to 27 psychopathologic signs and symptoms. Profile analysis of variance results indicate that each subtype appears similar, regardless of center of origin. However, this is based on a lack of distinguishing features between different subtypes. On the other hand, when a cluster analytic technique was used, it showed one large and three small subgroups, each readilty distinguishable from the others. These subgroups, labeled "usual," "flagrant," "insightful," and "hypochondriacal," are described clinically. If replicated or validated, such subgroups may prove meaningful in future considerations of subdivisions of the schizophrenia syndrome.

Neuropsychological impairments in deficit vs nondeficit forms of schizophrenia.

BACKGROUND: Previous studies have suggested that functional impairments of the frontal and parietal lobes are related to the deficit symptoms of schizophrenia. The purpose of the current study was to examine whether neuropsychological measures of frontal and parietal lobe function differentiated deficit from nondeficit patients. Neuropsychological measures of temporal lobe function were used as contrast measures. METHODS: The performance of 18 deficit and 21 nondeficit schizophrenic patients was examined on neuropsychological measures of executive, visuospatial, and memory functions, selected on the basis of their association with lesions of either the frontal, parietal, or temporal lobes. The results from the schizophrenic subgroups were compared with the results on the same measures obtained from 30 normal controls. RESULTS: Deficit patients performed more poorly than nondeficit patients on two frontal lobe measures, the Stroop Color-Word Interference and Trails Making B tests, and one parietal lobe measure, the Mooney Faces Closure Test. There were no differences in performance on the temporal lobe measures between the two groups. Both groups performed more poorly on the tests than the normal controls. CONCLUSIONS: The results suggest that deficit patients may have greater performance impairments on neuropsychological measures associated with frontal and parietal neuropsychological abnormalities.