Among the noncommunicable diseases, mental ill-health represents the major threat to social and economic progress because it impacts so powerfully on the most critical decades of life. Consequently, mental health reform is increasingly recognized as an urgent priority worldwide. This brings into sharp focus the role of evidence, and more specifically the Cochrane paradigm, in influencing decisions about health system reform. Cochrane clearly still has great value, especially in evidence-based medicine, where the focus is the evaluation of individual treatments. However, it cannot be allowed to be a dominant influence in evidence-based health care (EBHC) policy decisions for health system reform, unless it is modernized or complemented. Health services reform should definitely be as evidence-based as possible; however, the jury should consider its verdict on key reform proposals based on the balance of probabilities and informed by the best “available” evidence from all sources, not only randomized clinical trials, which in many domains may be never be feasible. This is particularly the case when reform is urgent, and the status quo has manifestly failed. So on the one hand, the evidence-based paradigm must not be misused to stifle or paralyze urgent reform. Alternatively, there is a real risk that, if we do not improve the sophistication of EBHC, the whole paradigm will be sidelined and reform will remain reactive, impulsive, and desultory. The recent Cochrane review on early intervention in psychosis provides an opportunity to consider these issues and their wider significance.
early intervention; evidence-based medicine; mental health; psychosis
Little is known about how the biological stress response systems—the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis, and the immune system—function during psychosis. Results of studies on the effect of stress on the immune and autonomic system in patients with schizophrenia are inconsistent. The present study investigates whether the stress response is impaired in medication-naive patients with a first episode of psychosis. Ten male patients with a first episode of psychosis and 15 controls were exposed to the stress of public speaking. Parameters of the ANS (heart rate and catecholamines), the HPA axis (plasma adrenocorticotropic hormone [ACTH] and cortisol), and the immune system (number and activity of natural killer [NK] cells) were measured. Peak responses were calculated to examine the relationship between stress-induced activation of the different systems. Subjective stress and anxiety before and during the task were assessed. Patients and controls displayed similar autonomic responses to acute stress. However, there was an impaired HPA axis response, slow onset and return of ACTH, and flattened cortisol response and a reduced increase in number NK cells and NK cell activity in patients with a first episode of psychosis. Furthermore, in patients, the relationship between the different stress response systems was weaker or absent compared with controls. These findings indicate that impairments in stress processing are associated with the endophenotype of psychosis and are not a result of illness progression or antipsychotic medication.
schizophrenia; stress; autonomic nervous system; neuroendocrine; immune; first-episode psychosis
The debate endures as to whether schizophrenia and bipolar disorder are separate entities or different manifestations of a single underlying pathological process. Here, we argue that this sterile argument obscures the fact that the truth lies somewhere in between. Thus, recent studies support a model whereby, on a background of some shared genetic liability for both disorders, patients with schizophrenia have been subject to additional genetic and/or environmental factors that impair neurodevelopment; for example, copy number variants and obstetric complications are associated with schizophrenia but not with bipolar disorder. As a result, children destined to develop schizophrenia show an excess of neuromotor delays and cognitive difficulties while those who later develop bipolar disorder perform at least as well as the general population. In keeping with this model, cognitive impairments and brain structural abnormalities are present at first onset of schizophrenia but not in the early stages of bipolar disorder. However, with repeated episodes of illness, cognitive and brain structural abnormalities accumulate in both schizophrenia and bipolar disorder, thus clouding the picture.
schizophrenia; bipolar disorder; environmental factors; neurodevelopment
Some but not all previous studies have found abnormal glucose tolerance or fasting glucose concentrations in antipsychotic-naïve patients with nonaffective psychosis. Our finding of abnormal glucose tolerance in patients with nonaffective psychosis could not be attributed to confounding by age, ethnicity, gender, smoking, socioeconomic status (SES), hypercortisolemia, or body mass index (BMI). However, other factors merit consideration as potential confounders of this association.
An extended sample of newly diagnosed, antipsychotic-naive patients with schizophrenia and related disorders and matched controls were administered an oral glucose tolerance test. Confounding factors related to diet, self-care/access to care, and drug abuse were evaluated.
After accounting for the variance due to age, ethnicity, gender, smoking, SES, morning cortisol concentrations, BMI (or waist–hip ratio), our previous finding of abnormal glucose tolerance in these patients was confirmed. This difference could not be attributed to confounding by substance abuse; blood concentrations of vitamin B12, folate, or homocysteine; aerobic conditioning as measured by resting heart rate; or duration of untreated psychosis.
These results provide further evidence that people with schizophrenia and related disorders have abnormal glucose tolerance and an increased risk of diabetes prior to antipsychotic treatment and independent of health habits and access to care. Other measures should also be examined.
diabetes; inflammation; schizophrenia; diet; stress
Longitudinal data suggest heterogeneity in the long-term course of schizophrenia. It is unclear how older adults with schizophrenia perceive changes in their experience of schizophrenia over the lifespan. We interviewed 32 adults aged 50 years and older diagnosed with schizophrenia (mean duration 35 years) about their perceived changes in the symptoms of schizophrenia and functioning over the lifespan. Interview transcripts were analyzed using grounded theory techniques of coding, consensus, co-occurrence, and comparison. The study was conducted by a research partnership involving a multidisciplinary team of academic researchers, community members, and mental health clients engaged in all aspects of study design, interviewing, and analysis and interpretation of data. Results revealed that, in regard to early course of illness, participants experienced confusion about diagnosis, active psychotic symptoms, and withdrawal/losses in social networks. Thereafter, nearly all participants believed that their symptoms had improved, which they attributed to increased skills in self-management of positive symptoms. In contrast to consistency among participants in describing illness course, there was marked heterogeneity in perceptions about functioning. Some participants were in despair about the discrepancy between their current situations and life goals, others were resigned to remain in supported environments, and others working toward functional attainments and optimistic about the future. In conclusion, middle-aged and older adults with schizophrenia believed that their symptoms had improved over their lifespan, yet there was substantial variability among participants in how they perceived their functioning. Functional rehabilitation may need to be tailored to differences in perceptions of capacity for functional improvement.
aging; psychosis; disability; qualitative research; quality of life
It is commonly assumed that there are clear lines of demarcation between anxiety and depressive disorders on the one hand and psychosis on the other. Recent evidence, however, suggests that this principle may be in need of updating.
Depressive and/or anxiety disorders, with no previous history of psychotic disorder, were examined for the presence of psychotic symptoms in a representative community sample of adolescents and young adults (Early Developmental Stages of Psychopathology study; n = 3021). Associations and consequences of psychotic symptomatology in the course of these disorders were examined in terms of demographic distribution, illness severity, onset of service use, and risk factors.
Around 27% of those with disorders of anxiety and depression displayed one or more psychotic symptoms, vs 14% in those without these disorders (OR 2.23, 95% CI 1.89–2.66, P < .001). Presence as compared with nonpresence of psychotic symptomatology was associated with younger age (P < .0001), male sex (P < .0058), and poorer illness course (P < .0002). In addition, there was greater persistence of schizotypal (P < .0001) and negative symptoms (P < .0170), more observable illness behavior (P < .0001), greater likelihood of service use (P < .0069), as well as more evidence of familial liability for mental illness (P < .0100), exposure to trauma (P < .0150), recent and more distant life events (P < .0006–.0244), cannabis use (P < .0009), and any drug use (P < .0008).
Copresence of psychotic symptomatology in disorders of anxiety and depression is common and a functionally and etiologically highly relevant feature, reinforcing the view that psychopathology is represented by a network or overlapping and reciprocally impacting dimensional liabilities.
psychosis; anxiety disorder; depression; comorbidity; epidemiology
Clinically defined psychosis is recognizable and distinguishable from nonclinical or subclinical psychosis by virtue of its clinical relevance (ie, its associated distress and its need for care and/or treatment). According to the continuum hypothesis, subclinical psychosis is merely quantitatively different from more extreme phenotypic expressions and as such should also be indicative of distress and help-seeking behavior but to a lesser extent. Using data from the Adult Psychiatric Morbidity Survey, the current study focused on self-reported psychosis and help-seeking experiences in a general population sample free from clinically defined psychosis (N = 7266). After statistically controlling for the effects of a series of potential help-seeking correlates the findings showed that subclinical psychosis symptom experience was significantly associated with various forms of help-seeking behavior. Individuals who reported subclinical experiences of thought control, paranoia, and strange experiences were on average 2 times more likely to attend their general practitioner for emotional problems compared with those individuals who reported no psychosis. Individuals who reported subclinical experiences of paranoia were 3 times more likely to be in receipt of counseling/therapy compared with those with no experience of paranoia. Multiple subclinical psychotic experiences also predicted elevated help-seeking behavior. These findings may have a positive impact on the detection of individuals who are at increased risk of psychological distress and aid in the design and implementation of more effective treatments at both clinical and subclinical levels.
psychosis continuum; phenotype; prodrome; treatment; epidemiology
Rates of self-reported psychotic experiences (SRPEs) in general population samples are high; however the reliability against interview-based assessments and the clinical significance of false-positive (FP) ratings remain unclear. Design: The second Netherlands Mental Health Survey and Incidence Study-2, a general population study.
Trained lay interviewers administered a structured interview assessing psychopathology and psychosocial characteristics in 6646 participants. Participants with at least one SRPE (N = 1084) were reassessed by clinical telephone interview.
Thirty-six percent of participants with SRPEs were confirmed by clinical interview as true positive (TP). SPREs not confirmed by clinical interview (FP group) generated less help-seeking behavior and occurred less frequently compared with TP experiences (TP group). However, compared with controls without psychotic experiences, the FP group more often displayed mood disorder (relative risk [RR] 1.7, 1.4–2.2), substance use disorder (RR 2.0, 1.6–2.6), cannabis use (RR 1.5, 1.2–1.9), higher levels of neuroticism (RR 1.8, 1.5–2.2), affective dysregulation, and social dysfunction. The FP group also experienced more sexual (RR 2.0, 1.5–2.8) and psychological childhood trauma (RR 2.1, 1.7–2.6) as well as peer victimization (RR 1.5, 1.2–2.0) and recent life events (RR 2.0, 1.6–2.4) than controls without psychotic experiences. Differences between the FP group and the TP group across these domains were much smaller and less conclusive.
SRPEs not confirmed by clinical interview may epresent the softest expression of an extended psychosis phenotype that is phenotypically continuous with clinical psychosis but discontinuous in need for care.
diagnosis; schizophrenia; trauma; cannabis; epidemiology; false positive
Abnormal connectivity of the anticorrelated intrinsic networks, the task-negative network (TNN), and the task-positive network (TPN) is implicated in schizophrenia. Comparisons between schizophrenic patients and their unaffected siblings enable further understanding of illness susceptibility and pathophysiology. We examined the resting-state connectivity differences in the intrinsic networks between schizophrenic patients, their unaffected siblings, and healthy controls.
Resting-state functional magnetic resonance images were obtained from 25 individuals in each subject group. The posterior cingulate cortex/precuneus and right dorsolateral prefrontal cortex were used as seed regions to identify the TNN and TPN through functional connectivity analysis. Interregional connectivity strengths were analyzed using overlapped intrinsic networks composed of regions common to all subject groups.
Schizophrenic patients and their unaffected siblings showed increased connectivity in the TNN between the bilateral inferior temporal gyri. By contrast, schizophrenic patients alone demonstrated increased connectivity between the posterior cingulate cortex/precuneus and left inferior temporal gyrus and between the ventral medial prefrontal cortex and right lateral parietal cortex in the TNN. Schizophrenic patients exhibited increased connectivity between the left dorsolateral prefrontal cortex and right inferior frontal gyrus in the TPN relative to their unaffected siblings, though this trend only approached statistical significance in comparison to healthy controls.
Resting-state hyperconnectivity of the intrinsic networks may disrupt network coordination and thereby contribute to the pathophysiology of schizophrenia. Similar, though milder, hyperconnectivity of the TNN in unaffected siblings of schizophrenic patients may contribute to the identification of schizophrenia endophenotypes and ultimately to the determination of schizophrenia risk genes.
schizophrenia; unaffected sibling; default mode network; functional connectivity; resting-state
systematic review; meta-analysis; randomized clinical trials
The at-risk mental state (ARMS) is associated with a very high risk of psychosis, but it is difficult to predict which individuals will later develop psychosis on the basis of their presenting symptoms. We investigated psychopathological dimensions in subjects with an ARMS and examined whether particular symptom dimensions predicted subsequent transition to psychosis.
The sample comprised 122 subjects (aged 16–35 years) meeting Personal Assessment and Crisis Evaluation clinic criteria for the ARMS recruited through Outreach and Support in South London, a clinical service for people with an ARMS. A principal axis factor analysis was performed on symptom scores, obtained at presentation from the Comprehensive Assessment of the At-Risk Mental State, using Varimax rotation. The relationship between dimension scores and transition to psychosis during the following 24 months was then examined employing Cox regression analysis.
Factor analysis gave rise to a 5-factor solution of negative, anxiety, disorganization/cognitive, self-harm, and manic symptom dimensions, accounting for 37% of the total variance. Scores on the negative and on the disorganization/cognitive dimensions were associated with transition to psychosis during the follow-up period (P = 0.044 and P = 0.005, respectively).
The symptoms of the ARMS have a dimensional structure similar to that evident in patients with schizophrenia except for the positive symptom dimension. The association between scores on the disorganization/cognitive and negative dimensions and later transition is consistent with independent evidence that formal thought disorder, subjective cognitive impairments, and negative symptoms are linked to the subsequent onset of psychosis.
prodrome; psychopathology; schizophrenia
The goal of the present analyses was to examine the hypothesis that mild forms of thought disorder (TD) may serve as an indicator of genetic liability for schizophrenia. A subset of 232 subjects drawn from the New York High-Risk Project was used to compare individuals at high risk for schizophrenia (ie, offspring of parents with schizophrenia; n = 63) with 2 groups of individuals at low risk for schizophrenia (ie, offspring of parents with affective disorder [n = 52] and offspring of psychiatrically normal parents [n = 117]). Subjects were administered the Rorschach Inkblot Test, and their responses were assessed according to the Thought Disorder Index (TDI). The high-risk offspring displayed significantly more TD than the other 2 groups, as shown by significantly higher TDI scores. Moreover, they had more deviant verbalizations, according to their significantly higher scores on a composite Idiosyncratic Verbalizations score. As expected, the offspring who developed psychosis produced more TD in adolescence than those who did not develop psychosis. In the sample as a whole, TD scores during late adolescence/early adulthood were positively associated with schizotypal features during mid-adulthood. These findings support the assertion that the presence of TD serves as an endophenotypic marker of a schizophrenia diathesis.
schizophrenia; endophenotype; genetic liability; psychosis; schizotypal features
In the 20th century, catatonia was usually deemed a subtype of schizophrenia. Recently, the nature and classification of catatonia are being reconsidered. This study is the first to describe catatonia using prospectively collected data and to examine how catatonic schizophrenia differs from, or resembles, other types of schizophrenia.
Data were analyzed in a cohort of 90 079 offspring followed from birth till ages 29–41 years. Proportional hazards models were used, calculating time to first psychiatric hospital admission, to compare risk factors for catatonic schizophrenia vs “other schizophrenia.”
Of 568 cases of schizophrenia, 43 (7.6%) had catatonic schizophrenia. The sexes were equally at risk for catatonic schizophrenia in contrast to other schizophrenia, for which the incidence was higher in males (1.70, 1.42–2.03, P < .0001). Advancing paternal age had no influence on the risk of catatonic schizophrenia in contrast to other schizophrenia, in which the risk to offspring of fathers age 35+ was 1.27 (1.03–1.57, P = .03) compared with those of younger fathers. Those with catatonic schizophrenia were somewhat more likely to have older mothers (aged 35+) (relative risk = 2.14, 0.85–5.54) while maternal age was not related to other schizophrenia. Both were equally affected by parental history of schizophrenia. Patients with catatonia were significantly more likely to attempt suicide (P = .006).
Patients with catatonic schizophrenia show a somewhat different profile of risk factors from those with other types of schizophrenia in this cohort and are more likely to attempt suicide. This lends some support to the hypothesis that catatonic schizophrenia may have a distinct etiology.
sex differences; suicide; paternal age; cohort
meta-analysis; policy; Cochrane
Some commentaries express concern that the At-Risk Mental State (ARMS) designation can be stigmatizing and induce a lasting sense of personal fragility. However, no studies have actually explored the personal perspectives of those so categorized. The purpose of this study was to explore how adolescents with an ARMS label understand and experience their condition medically and personally. Six participants receiving an ARMS diagnosis were interviewed and the data analyzed using interpretative phenomenological analysis. Three superordinate themes emerged: “It is better to say it,” “How others would take me,” and “Just to have somebody to talk to.” The participants’ experiences of being labeled were generally positive with limited instances of stigmatization by family and friends. Like most psychiatric diagnoses, the ARMS label has the potential to generate stigma. In practice, however, this sample of young people appeared to respect being told about the condition and to value the opportunity of talking about their experiences with mental health professionals and significant others.
psychosis; risk; prodrome; youth
While a great deal of research has been conducted on prodromal risk syndromes in relation to help-seeking individuals who present to the clinic, there is a lack of research on prodromal risk syndromes in the general population. The current study aimed first to establish whether prodromal risk syndromes could be detected in non-help-seeking community-based adolescents and secondly to characterize this group in terms of Axis-1 psychopathology and general functioning. We conducted in-depth clinical interviews with a population sample of 212 school-going adolescents in order to assess for prodromal risk syndromes, Axis-1 psychopathology, and global (social/occupational) functioning. Between 0.9% and 8% of the community sample met criteria for a risk syndrome, depending on varying disability criteria. The risk syndrome group had a higher prevalence of co-occurring nonpsychotic Axis-1 psychiatric disorders (OR = 4.77, 95% CI = 1.81–12.52; P < .01) and poorer global functioning (F = 24.5, df = 1, P < .0001) compared with controls. Individuals in the community who fulfill criteria for prodromal risk syndromes demonstrate strong similarities with clinically presenting risk syndrome patients not just in terms of psychotic symptom criteria but also in terms of co-occurring psychopathology and global functioning.
at risk mental states; epidemiology; ultra-high risk; clinical high risk
The concept of cognitive insight was introduced in 2004 to describe the capacity of patients with psychosis to distance themselves from their psychotic experiences, reflect on them, and respond to corrective feedback. The Beck Cognitive Insight Scale (BCIS) was developed to evaluate these aspects of cognitive flexibility and to complement scales that describe the lack of awareness of mental illness and its characteristics. The BCIS has generated a moderate research literature, which is the subject of the current review. Several independent groups have demonstrated that the BCIS is reliable, demonstrates convergent and construct validity, and distinguishes patients with psychosis from healthy controls and patients without psychosis. While the majority of the studies have focused on the relationship of the BCIS to delusions, several have examined its relationship to negative symptoms, depression, anxiety, and functional outcome. Cognitive insight has predicted positive gains in psychotherapy of psychosis, and improvement in cognitive insight has been correlated with improvement in delusional beliefs. Finally, preliminary findings relate neurocognition, metacognition, and social cognition, as well as reduced hippocampal volume to cognitive insight. A heuristic framework is presented to guide future research.
insight; psychosis; delusions; psychosocial treatment
Cannabis use is highly prevalent among people with schizophrenia, and coupled with impaired cognition, is thought to heighten the risk of illness onset. However, while heavy cannabis use has been associated with cognitive deficits in long-term users, studies among patients with schizophrenia have been contradictory. This article consists of 2 studies. In Study I, a meta-analysis of 10 studies comprising 572 patients with established schizophrenia (with and without comorbid cannabis use) was conducted. Patients with a history of cannabis use were found to have superior neuropsychological functioning. This finding was largely driven by studies that included patients with a lifetime history of cannabis use rather than current or recent use. In Study II, we examined the neuropsychological performance of 85 patients with first-episode psychosis (FEP) and 43 healthy nonusing controls. Relative to controls, FEP patients with a history of cannabis use (FEP + CANN; n = 59) displayed only selective neuropsychological impairments while those without a history (FEP − CANN; n = 26) displayed generalized deficits. When directly compared, FEP + CANN patients performed better on tests of visual memory, working memory, and executive functioning. Patients with early onset cannabis use had less neuropsychological impairment than patients with later onset use. Together, these findings suggest that patients with schizophrenia or FEP with a history of cannabis use have superior neuropsychological functioning compared with nonusing patients. This association between better cognitive performance and cannabis use in schizophrenia may be driven by a subgroup of “neurocognitively less impaired” patients, who only developed psychosis after a relatively early initiation into cannabis use.
schizophrenia; psychosis; marijuana; drug; neuropsychology; comorbidity
psychosis; diagnosis; risk; phenotype
Quality of life (QOL) has been recognized as a crucial domain of outcome in schizophrenia treatment, and yet its determinants are not well understood. Recent meta-analyses suggest that symptoms have only a modest relationship to QOL (Eack SM, Newhill CE. Psychiatric symptoms and quality of life in schizophrenia: a meta-analysis. Schizophr Bull. 2007;33:1225–1237). Individuals with schizophrenia show 1–2 SD deficits on measures of elementary neurocognition, and links between these deficits and objective measures of community functioning (eg, employment and independent living) are well established. While objective measures of community functioning and measures of QOL would appear to be closely related, studies investigating the ability of neurocognitive variables to predict QOL in individuals with schizophrenia have yielded conflicting results. One potential explanation for opposing findings in the schizophrenia literature is the interchangeable use of objective and subjective indices of QOL. This study used quantitative methods of meta-analysis to clarify the relationship between neurocognitive determinants of objective QOL (ie, observable, clinician-rated) and subjective QOL (ie, patient satisfaction) separately in individuals with schizophrenia. A total of 20 studies (10 objective and 10 subjective) consisting of 1615 clients were aggregated from relevant databases. Weighted effect size analysis revealed that there were small–moderate relationships (d ≤ 0.55) between crystallized verbal ability, working memory verbal list learning, processing speed, and executive function and objective indices of QOL. In contrast, results revealed either nonsignificant or inverse relationships for the vast majority of neurocognitive measures and measures of subjective QOL. Moderating variables and implications for future research and treatment development are discussed.
outcome; cognition; psychotic illness
This article presents a report on the first meeting of the International Consortium on Hallucination Research, which took place on September 13–14, 2011 at the Institute of Psychiatry, London. The first day of the meeting served to reflect on the current state of knowledge regarding auditory hallucinations in different diagnostic groups, based on the presentations from the phenomenology, cognition, emotion, electrophysiology, neurochemical, neuroimaging, genetics, treatment, and computational modeling working groups. The second day comprised a discussion forum where the most important and urgent questions for future research were identified. The meeting recognized that a lot has been achieved in auditory hallucination research but that much still remains to be done. Here, we outline the top 16 goals for research on auditory hallucinations, which cover topics of conceptual importance, academic and treatment issues, scientific rigor, and cross-disciplinary collaboration. Concerted and coordinated actions will be required to make substantial research progress.
auditory hallucinations; meeting; phenomenology; cognition; electrophysiology; neuroimaging; treatment