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.

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.

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.

Abnormal patterns of regional cerebral blood flow in schizophrenia with primary negative symptoms during an effortful auditory recognition task.

OBJECTIVE: Using functional brain imaging, the authors sought to replicate their earlier finding of low metabolism in the middle frontal and inferior parietal cortices of schizophrenic patients with primary negative symptoms. METHOD: According to the presence or absence of enduring negative symptoms, patients with schizophrenia were classified as having deficit or nondeficit schizophrenia, respectively. Twelve normal volunteers and 18 drug-free schizophrenic volunteers (deficit, N=8; nondeficit, N=10) were trained in a tone discrimination task. They were trained to perform with 70%-80% accuracy and were then scanned with positron emission tomography with [(15)O]H(2)O during three conditions: rest, sensory-motor control task, and decision task. RESULTS: Levels of performance of the auditory recognition task were similar in the three groups. An initial hypothesis-driven analysis revealed that across tasks the deficit group failed to show significant activation in the middle frontal cortex. This was in contrast to both the normal volunteers and nondeficit patients. When the patient groups were contrasted, the deficit patients showed significantly less activation in the middle frontal cortex bilaterally during the control task and in the right middle frontal cortex and inferior parietal cortex during the decision task. An exploratory analysis contrasting deficit and nondeficit patients across conditions did not reveal further differences between groups. CONCLUSIONS: This study replicated the finding of low activation in the middle frontal cortex and inferior parietal cortex in deficit schizophrenia. This deficit was observed without performance confound and may provide a marker of primary negative symptoms and a target for new therapies.

A comparison of symptom provocation procedures in psychiatry and other areas of medicine: implications for their ethical use in research.

BACKGROUND: Symptom provocation is used to study a wide variety of medical disorders. In contrast to other areas of medicine, the application of these procedures to the study of mental disease has generated significant scientific, political, and public debate. Purported differences include an overabundance of these procedures in psychiatry and a lack of diagnostic and therapeutic utility. Accurate appraisal of these research designs is needed to address scientific merit and ethical concerns. This article provides a general review of challenge studies in several areas of medical research, compares purposes and methods to those used in psychiatry, and ascertains whether fundamental differences exist. METHODS: In total, 655 challenge studies were identified using MEDLINE and PsychInfo Boolean key word searches. Information was collected from each study including the year of publication, whether subjects were healthy or patient volunteers, the disease being studied, and the study purpose (e.g., to study pathophysiology, test treatment efficacy, or diagnosis of a disorder). RESULTS: Differences in study design, purpose, and frequency of studies across time were similar for medical and psychiatric diseases. CONCLUSIONS: Given extensive similarity in purpose and procedures, why are psychiatric challenge studies being subjected to public criticism and special review and approval procedures? Several relevant issues are addressed including risk, scientific merit, and clinical application.

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.

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.

Mazindol treatment of negative symptoms.

Hypodopaminergic and hyponoradrenergic pathophysiology may be a basis for primary and/or secondary negative symptoms in schizophrenia. The hypothesis that enhanced neurotransmission in these systems would be therapeutic for negative symptoms was tested by comparing mazindol and placebo in a double-blind, cross-over design trial. Outcome following mazindol supplementation was comparable to placebo supplementation (F(1,30) = 0.9; p = .57). Results for deficit and non-deficit schizophrenia subjects were similar, and were not affected by whether concurrent the antipsychotic drug treatment was clozapine, fluphenazine, or haloperidol. The efficacy hypothesis was not supported for either primary or secondary negative symptoms.

Decisional capacity for informed consent in schizophrenia research.

BACKGROUND: The adequacy of subjects' informed consent to research is the focus of an important public and professional debate. The potential impairment of decisional capacity in persons with schizophrenia is central to the discussions. This study ascertains the decisional capacity for informed consent in schizophrenic research subjects, to determine if reduced capacity relates to specific aspects of psychopathologic features and to test the hypothesis that reduced capacity can be remediated with an educational informed consent process. METHODS: Decisional capacity was assessed for 30 research subjects with schizophrenia and 24 nonill (normal) comparison subjects. Measures of psychopathologic features and cognition were obtained for the subjects with schizophrenia. Subjects who performed poorly on the decisional capacity measure received an educational intervention designed to improve their ability to provide informed consent and were then retested. RESULTS: The patient group did not perform as well as the controls on initial decisional capacity assessment. Poor performance was modestly related to the extent of symptoms but robustly related to cognitive impairments. Following the educational intervention, the performance of subjects with schizophrenia was equal to that of the nonill comparison group. CONCLUSIONS: Many persons with schizophrenia may be challenged by the cognitive demands of an informed consent process for research participation. In many cases, their reduced capacity can be compensated by a more intensive educational intervention as part of the informed consent process.

Assessing the efficacy of treatments for the deficit syndrome of schizophrenia.

The primary, enduring negative symptoms found in some patients with schizophrenia have become the focus of clinical treatment trials, but there has been no consensus on the best methods for approaching this area. In future trials, a number of issues need to be considered, including analytic strategies, the limitations in instruments used to measure negative symptoms, and study design. An appropriate design for establishing the efficacy of treatments for the deficit syndrome is proposed.

Risk factors for the deficit syndrome of schizophrenia.

Previous studies have found two risk factors associated with the deficit syndrome of schizophrenia: an increase in summer births, compared to others with schizophrenia; and a higher risk of schizophrenia in relatives. In data from the Camberwell Register Psychosis Series, a population-based sample that approximated a treated-incidence sample, the deficit/nondeficit categorization was made using a previously validated proxy method. Associations were found between the deficit syndrome and both summer birth and a family history of schizophrenia. In contrast, nondeficit schizophrenia was associated with a family history of psychiatric problems other than schizophrenia. The deficit group also had poorer insight. An early age of onset was associated with disorganization, but not with the deficit or nondeficit group. The deficit/nondeficit differences could not be attributed to confounding by demographic features or the severity of hallucinations, delusions, or formal thought disorder.

The schizophrenia ketamine challenge study debate.

Protection of subjects in psychiatric research is an issue of considerable public and professional interest. Perhaps the most hotly debated issue concerns challenge study protocols where symptoms of illness are increased in a bioassay designed to gain knowledge of pathophysiology. Although widely used in biomedical research, the ethics of this application in mental illness research are contested. At issue is whether acute distress and lasting harm are caused without direct benefit in vulnerable subjects without valid informed consent. The ketamine challenge study in schizophrenia subjects is at the vortex of the current debate. This report presents background data on ketamine safety and a qualitative and quantitative analysis of data from all schizophrenia subjects in North American ketamine studies. Duration and severity of change in psychosis and anxiety, "worst case" experiences, and information on prolonged adverse effects are detailed. The vulnerable population and informed consent issue is discussed. Group results show that psychosis increase is mild to moderate and brief, anxiety is mild and brief, and no evidence of prolonged adverse effects is found. Few "worst case" incidents were identified, and these were clinically managed successfully in a short time period. Although more difficult to evaluate, informed consent procedures seem adequate, and consent was voluntary in subjects judged to have decisional capacity for this purpose and in circumstances where alternative clinical care could be freely chosen. The author concludes that ketamine challenge studies meet ethical standards, have been conducted without lasting adverse effects, that discomfort is modest and brief, and important new knowledge has been gained of potential benefit to the class from which subjects were drawn.