Bimonthly, Established in 1959
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In this issue

special article

Unravelling psychosis: Psychosocial epidemiology,mechanism, and meaning


Summary: This paper reviews a revolution in our understanding of psychosis over the last 20 years. To a major extent, this has resulted from a process of cross-fertilization between psychosocial epidemiology and cognitive behavior therapy for psychosis (CBT-p). This encouraged complementary strategies for the acquisition and analysis of data. These include the use of a range of dependent variables related to psychosis,and the exploitation of data from cross-sectional and longitudinal epidemiological surveys, virtual reality experiments, experience sampling methodology, and treatment trials. The key element is to investigate social and psychological measures in relation to each other. This research has confirmed the role of the external social world in the development and persistence of psychotic disorder. In addition, several psychological drivers of psychotic experiences have been identified. There is now persuasive evidence that the influence of social factors in psychosis is significantly mediated by non-psychotic symptoms, particularly mood symptoms and other attributes of affect such as insomnia. Psychotic symptoms are also driven by reasoning biases such as jumping to conclusions and belief inflexibility, though little is known about social influences on such biases. It is now clear that there are many routes to psychosis and that it takes many forms. Treatment of all kinds should take account of this: the dependence of CBT-p on a detailed initial formulation in terms of psychological processes and social influences is an example of the required flexibility. Individual mediators are now being targeted in specific forms of CBT-p, with good effect. This in turn corroborates the hypothesized role of non-psychotic symptoms in mediation, and attests to the power of the approaches described.

Key words: epidemiology; social factors; psychosis; cognitive behavior therapy

Systematic review and meta-analysis

Prenatal choline and the development of schizophrenia
Robert FREEDMAN, Randal G. ROSS

Background: The primary prevention of illness at the population level, the ultimate aim of medicine, seems out of reach for schizophrenia. Schizophrenia has a strong genetic component, and its pathogenesis begins long before the emergence of psychosis, as early as fetal brain development. Cholinergic neurotransmission at nicotinic receptors is a pathophysiological mechanism related to one aspect of this genetic risk. Choline activates these nicotinic receptors during fetal brain development. Dietary supplementation of maternal choline thus emerges as a possible intervention in pregnancy to alter the earliest developmental course of the illness. 

Aims: Review available literature on the relationship of choline supplementation or choline levels during pregnancy and fetal brain development.
Methods: A Medline search was used to identify studies assessing effects of choline in human fetal development. Studies of other prenatal risk factors for schizophrenia and the role of cholinergic neurotransmission in its pathophysiology were also identified.
Results: Dietary requirements for choline are high during pregnancy because of its several uses, including membrane biosynthesis, one-carbon metabolism, and cholinergic neurotransmission. Its ability to act directly at high concentrations as a nicotinic agonist is critical for normal brain circuit development. Dietary supplementation in the second and third trimesters with phosphatidyl-choline supports these functions and is associated generally with better fetal outcome. Improvement in inhibitory neuronal functions whose deficit is associated with schizophrenia and attention deficit disorder has been observed.
Conclusions: Prenatal dietary supplementation with phosphatidyl-choline and promotion of diets rich in choline-containing foods (meats, soybeans, and eggs) are possible interventions to promote fetal brain development and thereby decrease the risk of subsequent mental illnesses. The low risk and short (six month)duration of the intervention makes it especially conducive to population-wide adoption. Similar findings with folate for the prevention of cleft palate led to recommendations for prenatal pharmacological supplementation and dietary improvement. However, definitive proof of the efficacy of prenatal choline supplementation will not be available for decades (because of the 20-year lag until the onset of schizophrenia), so public health officials need to decide whether or not promoting choline supplementation is justified based on the limited information available.
Keywords: schizophrenia; fetal development; pregnancy; prevention; choline; receptors, nicotinic

Original research article

Efficacy and safety of the Chinese herbal medicine shuganjieyu with and without adjunctive repetitive transcranial magnetic stimulation (rTMS) for geriatric depression: a randomized controlled trial
Minmin XIE, Wenhai JIANG, Haibo YANG

Background: Pharmacological treatment of geriatric depression is often ineffective because patients cannot tolerate adequate doses of antidepressant medications. 

Aims: Examine the efficacy and safety of shuganjieyu – the first Chinese herbal medicine approved for the treatment of depression by China’s drug regulatory agency — with and without adjunctive treatment with repetitive transcranial magnetic stimulation (rTMS) in the treatment of geriatric depression.
Methods: Sixty-five inpatients 60 or older who met ICD-10 criteria for depression were randomly assigned to an experimental group (shuganjieyu + rTMS) (n=36) or a control group (shuganjieyu + sham rTMS)(n=29). All participants received 4 capsules of shuganjieyu daily for 6 weeks. rTMS (or sham rTMS)was administered 20 minutes daily, five days a week for 4 weeks. Blinded raters used the Hamilton Rating Scale for Depression (HAMD-17) and the Treatment Emergent Symptom Scale to assess clinical efficacy and safety at baseline and 1, 2, 4, and 6 weeks after starting treatment. Over the six-week trial, there was only one dropout from the experimental group and two dropouts from the control group.
Results: None of the patients had serious side effects, but 40% in the experimental group and 50% in the control group experienced minor side effects that all resolved spontaneously. Both groups showed substantial stepwise improvement in depressive symptoms over the 6 weeks. Repeated measures ANOVA found no differences between the two groups. After 6 weeks, 97% of the experimental group had experienced a 25% or greater drop in the level of depression, but only 20% had experience a 50% or greater drop in the level of depression; the corresponding values in the control group were 96% and 19%.There were some minor, non-significant differences in the onset of the treatment effect between the different types of depressive symptoms, but by the second week of treatment all five HAMD-17 subscale scores had improved significantly in both groups.
Conclusions: The Chinese herbal medicine shuganjieyu is effective and safe in the treatment of geriatric depression, but only a minority of patients have greater than 50% improvement in their depressive symptoms after 6 weeks of treatment. Adjunctive use of rTMS with shuganjieyu does not improve the overall outcome and does not significantly speed up the onset of action of shuganjieyu.
Key words: shuganjieyu; Chinese herbal medicine; repetitive transcranial magnetic stimulation; geriatric depression; China
Gene-based and pathway-based genome-wide association study of alcohol dependence
Lingjun ZUO, Clarence K. ZHANG, Frederick G. SAYWARD, Kei-Hoi CHEUNG, Kesheng WANG, John H. KRYSTAL,

Background: The organization of risk genes within signaling pathways may provide clues about the converging neurobiological effects of risk genes for alcohol dependence. 

Aims: Identify risk genes and risk gene pathways for alcohol dependence.
Methods: We conducted a pathway-based genome-wide association study (GWAS) of alcohol dependence using a gene-set-rich analytic approach. Approximately one million genetic markers were tested in the discovery sample which included 1409 European-American (EA) alcohol dependent individuals and 1518 EA healthy comparison subjects. An additional 681 African-American (AA) cases and 508 AA healthy subjects served as the replication sample.
Results: We identified several genome-wide replicable risk genes and risk pathways that were significantly associated with alcohol dependence. After applying the Bonferroni correction for multiple testing, the ‘cellextracellular matrix interactions’ pathway (p
Conclusions: These findings provide new evidence highlighting several genes and biological signaling processes that may be related to the risk for alcohol dependence.
Key words: gene-based GWAS; pathway-based GWAS; cell-extracellular matrix interaction pathway; PXN;paxillin; alcohol dependence


Clinical and research value of the new diagnostic criteria for Alzheimer’s disease

Summary: The use of biomarkers in the diagnosis of Alzheimer’s disease (AD) has been increasingly emphasized, but the feasibility and value of using biomarkers in clinical practice remain limited. However,the use of biomarkers in clinical and pharmaceutical research about AD may prove quite useful in clarifying the pathology underlying AD and, thus, help in the early identification of effective preventive and therapeutic interventions. Moreover, wide adoption of the new diagnostic criteria will improve comparability of research results across studies, and, thus, allow for the combination and comparison of study results using meta-analytic techniques – the types of analyses needed to definitively answer fundamental questions about the etiology, course, prevention, and treatment of AD. 

Keywords: Alzheimer’s disease; diagnostic criteria; biomarkers
Are the revised diagnostic criteria for Alzheimer’s disease useful in low- and middle-income countries?
Cece YANG, Shifu XIAO

Summary: Alzheimer’s Disease (AD) is a leading cause of disease burden among elderly individuals that is increasingly important in middle-income countries like China where improvements in overall health (which increase longevity) and other factors are leading to a rapidly aging population. The diagnostic criteria for AD have recently been revised to reflect advances in the understanding of the condition over the past three decades. Different international organizations have proposed algorithms for diagnosing AD that subdivide the AD spectrum into overlapping stages and, in some cases, require the concurrent presence of memory impairment and specific biomarkers. There are, however, several substantial limitations to these revised criteria: highly trained clinicians are needed to make the fine discriminations between the stages; the role of the proposed biomarkers in the onset and course of AD remain uncertain; and assessment of these biomarkers requires the use of expensive, high-tech equipment by well-trained technicians. These problems limit the clinical utility of these diagnostic criteria, particularly in low-resource settings where the clinicians responsible for identifying and treating individuals with AD have limited training and where the equipment needed to identify the biomarkers are either non-existent or in short supply. 

Key words: Alzheimer’s disease; diagnostic criteria; low- and middle-income countries


Finding a solution to psychosis: The emergence of a new path
Xin YU

Summary: The transition from a dichotomous diagnostic classification system to the more holistic approach to understanding mental disorders engendered by the so-called biopsychosocial model has definite advantages, but it runs the risk of sacrificing methodological rigor to achieve all-inclusiveness. The Special Article by Bebbington on understanding psychosis in this issue attempts to show that high-quality psychosocial epidemiological research on the development of psychosis can, at least partially, overcome these limitations. Bebbington’s emphasis on the importance of non-psychotic symptoms such as disturbance in sleep and mood in the development of psychosis provides a new perspective on the conceptualization of psychosis, but I remain unconvinced about the usefulness of such symptoms in the differentiation of valid sub-categories of schizophrenia or other psychoses. 

Key words: dichotomous classification; biopsychosocial model; psychotic disorders; psychosis; psychiatric epidemiology
The transdiagnostic dimension of psychosis: Implications for psychiatric nosology and research

Summary: If psychosis is a transdiagnostic dimension, the expression of which is governed by a dynamic set of contextual and emotional factors that are amenable to treatment, current approaches in psychiatric nosology and therapeutic research may need to be revised. The dominant approach to date is to clinically and conceptually situate psychotic symptoms in the construct of schizophrenia. However, schizophrenia,which has a lifetime prevalence of 1%, only represents the poor outcome fraction of a much broader spectrum of psychotic disorders which have a lifetime prevalence of 3.5%. Therefore, research findings in schizophrenia may reflect mechanisms of prognosis rather than fundamental associations with psychosis and other symptom domains per se. Similarly, the discovery that up to 30% of individuals with non-psychotic common mental disorders have subthreshold psychotic symptoms that situate them on the transdiagnostic dimension of psychosis – and which impact clinical severity and treatment response – indicates that the rigid separation between ‘psychotic’ and ‘non-psychotic’ hampers both clinical practice and research.Diagnostic manuals in psychiatry would benefit from a system of transdiagnostic dimensions, including a transdiagnostic dimension of psychosis. Introduction of transdiagnostic dimensions allows for a system combining a nomothetic (i.e., group-specific) categorical diagnosis with an idiographic (i.e., person-specific)combination of dimensional scores. The advantage of such a system is that it encourages consideration of how symptoms dynamically interact with each other in a network of psychopathology, and of how this network is impacted by the social world. 

Key words: psychosis; diagnosis; nosology; epidemiology; schizophrenia; transdiagnostic

Case report

Case report of visual hallucinations in anxiety

Summary: Hallucinations rarely occur in individuals with anxiety disorders. This case report describes a 36-year-old male with Social Phobia and Agoraphobia with Panic Attacks who had prominent visual hallucinations that were both distressing and incapacitating. Treatment with sertraline 200 mg/d,clonazepam 1 mg/d, and propranolol 20 mg/day for one month completely resolved both his anxiety and the hallucinations, after which he was able to return to his social and occupational life. The report underscores the fact that visual hallucinations are not always indicators of a psychotic disorder, they may be present across a spectrum of mental disorders. In cases where hallucinations occur in nonpsychotic disorders, treatment of the underlying condition usually simultaneously resolves the associated hallucinations without the need to resort to the use of antipsychotic medication. Detailed analyses of such unusual cases can help improve our understanding of the pathogenesis of psychotic-like symptoms. 

Key words: visual hallucinations; anxiety disorders; case report; India

Biostatistics in psychiatry

Decision tree methods: applications for classification and prediction
Yan-yan SONG, Ying LU

Summary: Decision tree methodology is a commonly used data mining method for establishing classification systems based on multiple covariates or for developing prediction algorithms for a target variable. This method classifies a population into branch-like segments that construct an inverted tree with a root node, internal nodes, and leaf nodes. The algorithm is non-parametric and can efficiently deal with large,complicated datasets without imposing a complicated parametric structure. When the sample size is large enough, study data can be divided into training and validation datasets. Using the training dataset to build a decision tree model and a validation dataset to decide on the appropriate tree size needed to achieve the optimal final model. This paper introduces frequently used algorithms used to develop decision trees(including CART, C4.5, CHAID, and QUEST) and describes the SPSS and SAS programs that can be used to visualize tree structure. 

Key words: decision tree; data mining; classification; prediction