精神病的跨诊断维度:对精神疾病的分类学与研究的意义（英文）

如果精神病是一种跨诊断的维度,精神病性症状的出现受动态变化的情境和情感因素左右,而后者又是可治疗的,那么目前精神科疾病的分类学和治疗研究的方法可能需要修改。迄今为此,无论在临床工作上还是在疾病概念上,占主导地位的方法是将精神病性症状置于精神分裂症的框架中。然而,终生患病率为1%的精神分裂症只代表了部分预后不佳的精神病谱系障碍,而后者发生更多,终生患病率为3.5%。因此,精神分裂症的研究结果可能反映了预后相关的机制,而非精神病和其他症状维度之间本质上的相关性。同样,常见的非精神病性精神障碍中高达30%的个体有阈下精神病性症状,他们会被归于精神病的跨诊断维度之下,这些精神症状还会影响临床严重程度和治疗有效性。上述发现也同样提示武断区分"精神病性"与"非精神病性"的做法妨碍了临床实践和研究。精神病学诊断手册可以借鉴跨诊断维度(包括精神病的跨诊断维度)的体系。引入跨诊断维度,则既能根据原则进行分类诊断(即疾病分组的特异性),又可结合个体特有的多维度综合评分(即个体特异性)。这样的益处在于促使人们思考在精神病理学中症状之间是如何动态地交互作用的,并思考社会环境是如何影响精神病理症状的。     

Antibodies to infectious agents in individuals at ultra-high risk for psychosis.

BACKGROUND: While there is evidence that some cases of schizophrenia may be associated with microbial infections, the role of microbial agents has not been investigated in people with emerging psychosis. METHODS: Participants were 105 help seeking ultra-high risk individuals. Psychiatric measures included the Brief Psychiatric Rating Scale and the Scale for the Assessment of Negative Symptoms. Serum IgG antibodies against human herpesviruses and Toxoplasma gondii were determined using immunoassay methods. Multiple linear regression with adjustment for age and sex was applied to test associations between serum antibodies and psychiatric measures. RESULTS: Higher levels of serum IgG antibodies against Toxoplasma gondii in Toxoplasma-positive individuals were significantly associated with more severe positive psychotic symptoms. No significant association was observed between antibody levels and psychiatric measures in individuals positive for human herpesviruses. CONCLUSIONS: In some individuals infection with Toxoplasma gondii may be an environmental factor contributing to the manifestation of positive psychotic symptoms.     

Clinical and serotonergic predictors of non-affective acute remitting psychosis in patients with a first-episode psychosis

Objective: The study aimed to establish clinical predictors of non‐affective acute remitting psychosis (NARP) and assess whether these patients showed a distinct serotonergic profile. Method: First‐episode never treated psychotic patients diagnosed of paranoid schizophrenia (n = 35; 21 men and 14 women) or NARP (n = 28; 15 men and 13 women) were included. Results: NARP patients showed significantly lower negative symptomatology, better premorbid adjustment, shorter duration of untreated psychosis, more depressive symptomatology and a lower number of 5‐HT2A receptors than the paranoid schizophrenia patients. In the logistic regression, the four variables associated with the presence of NARP were: low number of 5‐HT2A receptors; good premorbid adjustment; low score in the item ‘hallucinatory behaviour’ and reduced duration of untreated psychosis. Conclusion: Our findings support the view that NARP is a highly distinctive condition different from either affective psychosis or other non‐affective psychosis such as schizophrenia, and highlight the need for its validation.     

Animal models for screening anxiolytic-like drugs: a perspective

Contemporary biological psychiatry uses experimental animal models to increase our understanding of affective disorder pathogenesis. Modern anxiolytic drug discovery mainly targets specific pathways and molecular determinants within a single phenotypic domain. However, greater understanding of the mechanisms of action is possible through animal models. Primarily developed with rats, animal models in anxiety have been adapted with mixed success for mice, easy-to-use mammals with better genetic possibilities than rats. In this review, we focus on the three most common animal models of anxiety in mice used in the screening of anxiolytics. Both conditioned and unconditioned models are described, in order to represent all types of animal models of anxiety. Behavioral studies require careful attention to variable parameters linked to environment, handling, or paradigms; this is also discussed. Finally, we focus on the consequences of re-exposure to the apparatus. Test-retest procedures can provide new answers, but should be intensively studied in order to revalidate the entire paradigm as an animal model of anxiety.     

Duration of untreated psychosis and outcome in first-episode psychosis. Perspective from a developing country

OBJECTIVE: To investigate the association between duration of untreated psychosis (DUP) and treatment outcome in a sample of subjects from a developing country. METHOD: Forty-eight subjects with a first episode of psychosis were evaluated prior to treatment and at 3-month intervals over a period of 24 months. We first examined correlations between DUP and symptom improvement as measured on the Positive and Negative Symptom Scale (PANSS), and then performed multivariate analysis to determine the validity of DUP as a predictor of outcome. RESULTS: DUP was significantly correlated with improvement in PANSS total and negative subscale scores as well as the PANSS depression factor at 21 and 24 months. Multivariate analysis found DUP to be the only significant predictor of improvement in negative symptoms at 24 months. CONCLUSION: DUP was a significant predictor of outcome in a cohort form a developing country. This study provides support for early detection and intervention strategies.     

Comparison of the density of gamma-aminobutyric acid in the ventromedial prefrontal cortex of patients with first-episode psychosis and healthy controls

Background

Abnormality in the concentration and functioning of gamma-aminobutyric acid (γ-aminobutyric acid, GABA) in the brain is not only an important hypothetical link to the cause of schizophrenia but it may also be correlated with the cognitive decline and negative symptoms of schizophrenia. Studies utilizing high field magnetic resonance spectroscopy (MRS) report abnormal density of GABA in the ventromedial prefrontal cortex (vmPFC) of patients with chronic schizophrenia, but these results may be confounded by study participants’ prior use of antipsychotic medications.

Aim

Compare the density of GABA in the vmPFC of patients with first-episode psychosis to that in healthy controls and assess the relationship of GABA density in the vmPFC to the severity of psychotic symptoms.

Methods

Single-voxel ¹H-MRS was used to assess the concentration of GABA and other metabolites in the vmPFC of 22 patients with first-episode psychosis (10 with schizophrenia and 12 with schizophreniform disorder) and 23 healthy controls. Thirteen of the 22 patients were drug-naïve and 9 had used antipsychotic medication for less than 3 days. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the severity of psychotic symptoms in the patient group.

Results

The mean (sd) GABA density in the vmPFC was significantly higher in patients than in controls (2.28 [0.54] v. 1.93 [0.32] mM, t=2.62, p=0.012). The densities of other metabolites – including N-acetylaspartic acid (NAA), glutamic acid (GLU), and glutamine (GLN) – were not significantly different between patients and controls. Among the patients, GABA density in the vmPFC was not significantly correlated with PANSS total score or with any of the three PANSS subscale scores for positive symptoms, negative symptoms, and general psychopathology. GABA concentration was not associated with the duration of illness, but it was significantly correlated with patient age (r=0.47, p=0.026).

Conclusion

Elevation of GABA density in the vmPFC of patients with first-episode psychosis confirms that this abnormality is independent of medication use. The failure to find a correlation of GABA density in the vmPFC with the severity of psychotic symptoms needs to be confirmed in larger studies, but it suggests that there are several intervening steps between brain pathology and clinical symptoms.     

Searching for bridges between psychopathology and real-world functioning in first-episode psychosis: A network analysis from the OPTiMiSE trial

BackgroundNetwork analysis has been used to explore the interplay between psychopathology and functioning in psychosis, but no study has used dedicated statistical techniques to focus on the bridge symptoms connecting these domains. The current study aims to estimate the network of depressive, negative, and positive symptoms, general psychopathology, and real-world functioning in people with first-episode schizophrenia or schizophreniform disorder, focusing on bridge nodes.MethodsBaseline data from the OPTiMiSE trial were analyzed. The sample included 446 participants (age 40.0 ± 10.9 years, 70% males). The network was estimated with a Gaussian graphical model, using scores on individual items of the positive and negative syndrome scale (PANSS), the Calgary depression scale for schizophrenia, and the personal and social performance scale. Stability, strength centrality, expected influence (EI), predictability, and bridge centrality statistics were computed. The top 20% scoring nodes on bridge strength were selected as bridge nodes.ResultsNodes from different rating scales assessing similar psychopathological and functioning constructs tended to cluster together in the estimated network. The most central nodes (EI) were Delusions, Emotional Withdrawal, Depression, and Depressed Mood. Bridge nodes included Depression, Conceptual Disorganization, Active Social Avoidance, Delusions, Stereotyped Thinking, Poor Impulse Control, Guilty Feelings, Unusual Thought Content, and Hostility. Most of the bridge nodes belonged to the general psychopathology subscale of the PANSS. Depression (G6) was the bridge node with the highest value.ConclusionsThe current study provides novel insights for understanding the complex phenotype of psychotic disorders and the mechanisms underlying the development and maintenance of comorbidity and functional impairment after psychosis onset.     

The psychobiology of resilience and vulnerability to anxiety disorders: implications for prevention and treatment

Much of the research on the neurobiology of human anxiety disorders has focused on psychopaihological abnormalities in patients with anxiety disorders. While this line of research is obviously important, more investigation is needed to elucidate the psychobiology of resilience to extreme stress. Study of the psychobiology of resilience has the potential to identify neurochemical, neuropeptide, and hormonal mediators of vulnerability and resilience to severe stress. In addition, the relevance of neural mechanisms of reward and motivation, fear responsiveness, and social behavior to character traits associated with risk and resistance to anxiety disorders may be clarified. These areas of investigation should lead to improved methods of diagnosis, novel approaches to prevention, and new targets for antianxiety drug discovery.     

Comparison of participants and nonparticipants in a neuroendocrine investigation of psychosis.

Of all neuroleptic-naive, acutely psychotic subjects admitted to hospital over a 2-year period (n = 62), 27 participated in a neuroendocrine study and 35 did not participate (51% refused consent, 19% were incapable of consent and 31% started neuroleptics immediately). However, all nonparticipants agreed to psychopathological evaluation, thus allowing comparison between participants and nonparticipants. The 2 groups were similar in most respects, except that more nonparticipants were hostile. Among subjects with schizophrenia, 47% of nonparticipants had the paranoid subtype vs 8% of participants. There was also a trend towards longer illness duration in nonparticipants. These results underline the need for neurobiological studies of psychosis to consider sample bias as a confounding variable.     

Relationship of the serotonin transporter with prolactin response to meta-chlorophenylpiperazine in cocaine dependence

Background: Preclinical evidence indicates that exposure to cocaine influences the activity of the serotonin transporter (5-HTT) as well as several 5-HT receptor subtypes. However, little is known about the relationship between the 5-HTT and 5-HT receptors following cocaine exposure in humans. Objective: We examined the relationship between platelet 5-HTT, a presynaptic 5-HT measure, and prolactin (PRL) response to meta-chlorophenylpiperazine (m-CPP), a postsynaptic 5-HT receptor agonist in cocaine dependent individuals. Methods: Platelet [3H] paroxetine binding sites were assayed and the m-CPP challenge test was performed in 35 African American cocaine dependent individuals and 33 controls. Clinical measures included assessments of drug use severity and depression. Results: Cocaine subjects showed reduced Bmax of [3H] paroxetine (t = 4.67, p < 0.01) and blunted PRL response to m-CPP (F = 21.86, p < 0.01) compared to controls. There was a positive correlation between Bmax and delta PRL [peak − baseline PRL] in cocaine subjects (r = 0.50, p < 0.01) but not in controls (r = 0.19). ANCOVA analyses showed that the cocaine subgroup with moderate and severe reduction in Bmax showed a greater blunting in PRL response compared to the subgroup with mild Bmax reductions (F = 9.44, p < .005). Multivariate regression models showed that the main effects as well as the interaction of Bmax and severity of cocaine use significantly contributed to impaired PRL response (F = 17.90, p < .001). Conclusions: Disturbances in serotonin transporter binding and post-synaptic 5-HT receptor function seem to be associated in cocaine-dependent subjects. Severity of cocaine use appears to mediate this relationship. Whether there is a causal association between the two measures, or cocaine has separate and independent pre- and post-synaptic effects needs to be clarified.     

Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth.

BACKGROUND: Infections during fetal life or neonatal period, including infections with Toxoplasma gondii, may be associated with a risk for schizophrenia and other mental disorders. The objectives of this study were to study the association between serological markers for maternal and neonatal infection and the risk for schizophrenia, related psychoses, and affective disorders in a national cohort of newborns. METHODS: This study was a cohort-based, case-control study combining data from national population registers and patient registers and a national neonatal screening biobank in Denmark. Patients included persons born in Denmark in 1981 or later followed up through 1999 with respect to inpatient or outpatient treatment for schizophrenia or related disorders (ICD-10 F2) or affective disorders (ICD-10 F3). RESULTS: Toxoplasma gondii immunoglobulin G (IgG) levels corresponding to the upper quartile among control subjects were significantly associated with schizophrenia risk (odds ratio [OR] = 1.79, p = .045) after adjustment for urbanicity of place of birth, year of birth, gender, and psychiatric diagnoses among first-degree relatives. There was no significant association between any marker of infection and other schizophrenia-like disorders or affective disorders. CONCLUSIONS: Our study supports an association between Toxoplasma gondii and early-onset schizophrenia. Further studies are needed to establish if the association is causal and if it generalizes to cases with onset after age 18.     

Prevalence and predictors of parasuicide in chronic psychosis. UK700 group

OBJECTIVE: This study estimates the prevalence of and risk factors for parasuicide in a large community-based sample of patients with chronic psychosis. METHOD: A total of 704 subjects with chronic psychosis were interviewed using a battery of instruments. The 2-year prevalence of parasuicide was estimated and a comparison was made between attempters and nonattempters on a wide range of sociodemographic and clinical variables. RESULTS: The 2-year prevalence of parasuicide was 18.8%. Attempters were significantly more likely to be younger, of white ethnic origin, to have a diagnosis of affective disorder, to be currently depressed, to have experienced more auditory hallucinations and to have received treatment with antipsychotic drugs for a longer period. CONCLUSION: Parasuicide was found to present a considerable clinical problem in this group. Continual risk assessment is essential to reduce this unacceptably high rate.     

Young people at risk for psychosis: case finding and sample characteristics of the Oulu Brain and Mind Study

Aim: Set within the general population‐based Northern Finland Birth Cohort 1986, the Oulu Brain and Mind Study aims to explore the causes and pathogenesis of psychotic illness by following young people at risk for psychosis due to having a first‐degree relative with psychotic illness or due to having experienced psychotic‐like symptoms themselves. We report the study methods and explore the relationship between these definitions of high risk for psychosis and operational criteria for a prodromal psychosis syndrome based on interview. Methods: Prospectively collected data from earlier follow‐ups of this cohort were combined with health register data to categorize subjects as those with familial risk (n = 272), symptomatic risk (n = 117), psychosis (n = 78), attention deficit hyperactivity disorder (ADHD) (n = 103) and a sample of controls (n = 193) drawn randomly from the remaining cohort. The Structured Interview for Prodromal Syndromes (SIPS) was applied to all, 295 participants together with questionnaires measuring psychosis vulnerability and schizotypal traits. Results: There were 29 (10%) current prodromal cases. Criteria for the current prodromal syndrome were fulfilled by 12% of the familial risk group and 19% of the symptomatic risk group, compared with 5% of the ADHD group and 4% of controls. Conclusion: We successfully detected young people with a prodromal psychosis syndrome although relatively few subjects deemed to be at high risk met the full operational criteria according to the SIPS interview. Combining methods from familial, clinical and psychometric high‐risk approaches provides a tractable method for studying risk of psychosis in the general population.     

Conceptualization of the liability for schizophrenia: clinical implications

Historically, the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria for schizophrenia have emphasized several features, including symptoms of psychosis, a dissociation of symptoms from their etiology, a reliance on clinical symptoms, and a categorical approach to classifying the disorder. Although these emphases are quite useful, they have limitations. We review these here, and stress the importance of incorporating recent data on the genetic /biological and neurodevelopmental origins of schizophrenia into current conceptions of the disorder. We also review "schizotaxia, " which is a concept thai embodies this point of view, occurs before the onset of psychosis, and is hypothesized to represent the liability for schizophrenia. If our hypothesis on this point is correct, the identification of schizotaxic individuals will eventually facilitate the development of prevention strategies by identifying a premorbid (but clinically significant) condition for schizophrenia. Moreover, the identification of biological or neuropsychological components of schizotaxia will provide more specific bases for developing novel treatment interventions. Our initial attempts to develop protocols for the assessment and treatment of schizotaxia are encouraging, and will be reviewed.     

Patterns, predictors and impact of substance use in early psychosis: a longitudinal study

OBJECTIVE: The purpose was to determine the prevalence of substance use and its impact on outcome 3 years after presentation for a first-episode of psychosis. METHOD: Subjects were 203 consecutive admissions to an early psychosis program. Assessments included substance use, positive, negative and depressive symptoms and social functioning. Assessments occurred at baseline, and 1-, 2- and 3-year follow-ups. RESULTS: The prevalence of substance misuse was high with 51% having a substance use disorder (SUD), 33% with cannabis SUD and 35% with an alcohol SUD. Numbers with an alcohol SUD declined considerably by 1 year and for cannabis SUD by 2 years. Substance misuse was significantly associated with male gender, young age and age of onset and cannabis misuse with increased positive symptoms. CONCLUSION: This study confirms the high rates of substance misuse, in particular cannabis, in first-episode psychosis. It further demonstrates that these rates can be reduced.