The epidemiology of schizophrenia: replacing dogma with knowledge

Major advances have been made in our understanding of the epidemiology of schizophrenia. We now know that the disorder is more common and severe in young men, and that the incidence varies geographically and temporally. Risk factors have been elucidated; biological risks include a family history of the disorder, advanced paternal age, obstetric complications, and abuse of drugs such as stimulants and cannabis. In addition, recent research has also identified social risk factors such as being born and brought up in a city, migration, and certain types of childhood adversity such as physical abuse and bullying, as well as social isolation and adverse events in adult life. Current research is focussing on the significance of minor psychotic symptoms in the general population, gene-environmental interaction, and how risk factors impact on pathogenesis; perhaps all risk factors ultimately impact on striatal dopamine as the final common pathway.     

The epidemiology of anxiety disorders: a review

Epidemiological studies show that anxiety disorders are highly prevalent and an important cause of functional impairment; they constitute the most frequent menial disorders in the community. Phobias are the most common with the highest rates for simple phobia and agoraphobia. Panic disorder (PD) and obsessive-compulsive disorder (OCD) are less frequent (2% lifetime prevalence), and there are discordant results for social phobia (SP) (2%-16%) and generalized anxiety disorder (GAD) (3%-30%). These studies underline the importance of an accurate definition of disorders using unambiguous diagnostic and assessment criteria. The boundaries between anxiety disorders are often ill defined and cases may vary widely according to the definition applied. Simple phobia, agoraphobia, and GAD are more common in vmrnen, while there is no gender différence for SP, PD, and OCD, Anxiety disorders are more common in separated, divorced, and widowed subjects; their prevalence is highest in subjects aged 25 to 44 years and lowest in subjects aged >65 years. The age of onset of the different types of anxiety disorders varies widely: phobic disorders begin early in life, whereas PD occurs in young adulthood. Clinical - rather than epidemiological - studies have examined risk factors such as life events, childhood experiences, and familial factors. Anxiety disorders have a chronic and persistent course, and are frequently comorbid with other anxiety disorders, depressive disorders, and substance abuse. Anxiety disorders most frequently precede depressive disorders or substance abuse, Comorbid diagnoses may influence risk factors like functional impairment and quality of life. It remains unclear whether certain anxiety disorders (eg, PD) are risk factors for suicide. The comorbidity of anxiety disorders has important implications for assessment and treatment and the risk factors should be explored. The etiology, natural history, and outcome of these disorders need to be further addressed in epidemiological studies.     

The genetic epidemiology of personality disorders

Genetic epidemiologic studies indicate that all ten personality disorders (PDs) classified on the DSM-IV axis II are modestly to moderately heritable. Shared environmental and nonadditive genetic factors are of minor or no importance. No sex differences have been identified. Multivariate studies suggest that the extensive comorbidity between the PDs can be explained by three common genetic and environmental risk factors. The genetic factors do not reflect the DSM-IV cluster structure, but rather: i) broad vulnerability to PD pathology or negative emotionality; ii) high impulsivity/low agreeableness; and iii) introversion. Common genetic and environmental liability factors contribute to comorbidity between pairs or clusters of axis I and axis II disorders. Molecular genetic studies of PDs, mostly candidate gene association studies, indicate that genes linked to neurotransmitter pathways, especially in the serotonergic and dopaminergic systems, are involved. Future studies, using newer methods like genome-wide association, might take advantage of the use of endophenotypes.     

Research on serotonin and suicidal behavior: neuroendocrine and molecular approaches

We carried out two studies to test the hypothesis that altered central serotonergic function, as assessed by lower prolactin (PRL) response to fenfluramine (D-FEN), is more closely associated with suicidal behavior than a particular psychiatric diagnosis. A D-FEN test was performed in 85 major depressed inpatients, 33 schizophrenic inpatients, and 18 healthy controls. We showed that PRL response to D-FEN is a marker of suicidality, regardless of psychiatric disorder. We then examined the association en the serotonin (5-hydroxytryptamine) receptor 5-HT(2A) gene polymorphism (T102C) and suicide in a sample of Brazilian psychiatric inpatients (95 with schizophrenia, 78 with major depression) and 52 healthy controls. No differences were found in genotypic frequencies across patients and controls. Overall, no differences were found between patients with (n=66) and without (n=107) a history of suicide attempt. We also compared patients with a history of severe suicide attempts (lethality>3; n=32) and patients without such a history (n=107), but they did not exhibit different genotypic frequencies either. These results show thai the 5-HT(2A) gene polymorphism (T102C) may not be involved in the genetic susceptibility to suicidal behavior.     

Core symptoms of major depressive disorder: relevance to diagnosis and treatment

The construct of major depressive disorder makes no etiological assumptions about populations with diverse symptom clusters. "Depressed mood" and "loss of interest or pleasure in nearly all activities" are core features of major depressive episode, though a strong case can be made to pay increasing attention to symptoms of fatigue, sleep disturbance, anxiety, and neurocognitive and sexual dysfunction in the diagnosis and evaluation of treatment outcome. Mood, guilt, work, and interest, as well as psychic anxiety, are consistently identified across validated subscales of the Hamilton Depression Rating Scale as prevalent and sensitive to change with existing treatments. A major limitation of these antidepressant therapies is their narrow spectrum of action. While the core "mood and interest" symptoms have been the main focus of attention, the associated symptoms listed above are often unaffected or exacerbated by current treatments. Careful clinical evaluation should address all of these dimensions, recognizing that improvement may occur sooner in some symptoms (eg, mood) compared with others (eg, sleep disturbance).     

Attention deficit-hyperactivity disorder and early-onset bipolar disorder: two facets of one entity?

Early-onset bipolar disorder (BD) and attention-deficithyperactivity disorder (ADHD) have recently been the subject of highly controversial debate, due to theories regarding underlying pathophysiological processes and a clinical overlap of symptoms. Epidemiological data, clinical aspect, neuroimaging, neurochemical, and genetic studies suggest that there may be a possible relationship between biological factors and clinical characteristic in the development of symptoms. However, longitudinal data supporting the hypothesis of a diagnostic shift from BD to ADHD symptoms and vice versa are currently not available. These would be essential to enable further investigations into whether these two disorders possibly represent two different aspects of an underlying common psychopathophysioiogical entity.     

Characteristics, experience, and treatment of schizophrenia in China

Assessment of differences in the characteristics, experience, and treatment of schizophrenia between China and the West highlights the importance of the interaction of biological and sociocultural factors in the onset and course of the disorder. China reports a much higher prevalence of schizophrenia in urban areas than in rural areas and, surprisingly a higher prevalence in women than in men. Despite differences in the diagnostic criteria for schizophrenia, the pattern of positive, negative, and cognitive symptoms is similar to that seen in the West. Almost ail medical treatment for schizophrenia is provided from specialized psychiatric hospitals, most of which are situated in urban centers. Antipsychotic medication (often the generic clozapine) is the mainstay of inpatient treatment. China developed a variety of innovative community-based treatment models in the 1980s, but the social and economic changes of the 1990s have made ii difficult to generalize these models. Overall, approximately 70% of the estimated 4.8 million persons with schizophrenia in China do not receive regular treatment.     

The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia

Specifying the complex genetic architecture of the "fuzzy" clinical phenotype of schizophrenia is an imposing problem. Utilizing metabolic, neurocognitive, and neurophysiological "intermediate" endophenotypic measures offers significant advantages from a statistical genetics standpoint. Endophenotypic measures are amenable to quantitative genetic analyses, conferring upon them a major methodological advantage compared with largely qualitative diagnoses using the Diagnostic and Statistical Manual of Mental Health, 4th Edition (DSM-IV). Endophenotypic deficits occur across the schizophrenia spectrum in schizophrenia patients, schizotypal patients, and clinically unaffected relatives of schizophrenia patients. Neurophysiological measures, such as P50 event-related suppression and the prepulse inhibition (PPI) of the startle response, are endophenotypes that can be conceptualized as being impaired because of a single genetic abnormality in the functional cascade of DNA to RNA to protein. The "endophenotype approach" is also being used to understand other medical disorders, such as colon cancer, hemochromatosis, and hypertension, where there is interplay between genetically conferred vulnerability and nongenetic stressors. The power and utility of utilizing endophenotypes to understand the genetics of schizophrenia is discussed in detail in this article.     

A dopaminergic deficit hypothesis of schizophrenia: the path to discovery

In contrast to the conventional view of dopamine involvement in schizophrenia, which posits hyperactive dopaminergic transmission, we propose that for unknown developmental and/or biochemical reasons, a primary defect occurs in efficient, tight dopaminergic synaptic transmission, triggering feedback activation and receptor upregulation, and resulting in the well-characterized increase in dopaminergic tone. This hypothesis is driven by suggestive evidence for subpopulations of dopamine D2 receptors delivering contrasting forms of dopaminergic transmission: synaptic receptors, responsible for basic dopaminergic function and subject to effective feedback control, and poorly controlled extrasynaptic receptors partly responsible for the positive symptoms of psychosis. Since the primary defect is dopamine deficiency, we term this theory the dopaminergic deficit hypothesis of schizophrenia. It is currently informing clinical studies with novel partial dopamine antagonists (dopamine stabilizers) such as ACR16, which preferentially target extrasynaptic receptors while leaving synaptic transmission and basic dopamine function intact.     

Functional neuroimaging and schizophrenia: a view towards effective connectivity modeling and polygenic risk

We review critical trends in imaging genetics as applied to schizophrenia research, and then discuss some future directions of the field. A plethora of imaging genetics studies have investigated the impact of genetic variation on brain function, since the paradigm of a neuroimaging intermediate phenotype for schizophrenia first emerged. It was initially posited that the effects of schizophrenia susceptibility genes would be more penetrant at the level of biologically based neuroimaging intermediate phenotypes than at the level of a complex and phenotypically heterogeneous psychiatric syndrome. The results of many studies support this assumption, most of which show single genetic variants to be associated with changes in activity of localized brain regions, as determined by select cognitive controlled tasks. From these basic studies, functional neuroimaging analysis of intermediate phenotypes has progressed to more complex and realistic models of brain dysfunction, incorporating models of functional and effective connectivity, including the modalities of psycho-physiological interaction, dynamic causal modeling, and graph theory metrics. The genetic association approaches applied to imaging genetics have also progressed to more sophisticated multivariate effects, including incorporation of two-way and three-way epistatic interactions, and most recently polygenic risk models. Imaging genetics is a unique and powerful strategy for understanding the neural mechanisms of genetic risk for complex CNS disorders at the human brain level.     

Medical and substance-related comorbidity in bipolar disorder: translational research and treatment opportunities

It is well established that individuals with bipolar disorder are differentially affected by substance-related as well as medical disorders (ie, cardiometabolic disorders, respiratory disorders, neurological disorders, and infectious diseases). Emerging evidence indicates that some comorbid conditions (eg, diabetes mellitus) in bipolar individuals may be subserved by overlapping neurobiological networks. Disturbances in glucocorticoid/insulin signaling and immunoinflammatory effector systems are points of pathophysiological commonality between bipolar disorder and "stress-sensitive" medical disorders. Subphenotyping bipolar disorder as a function of comorbidity and temporality of onset may provide an opportunity for refining disease pathophysiological models and developing innovative disease-modifying therapies.     

Interpersonal and social rhythm therapy: an intervention addressing rhythm dysregulation in bipolar disorder

Bipolar disorder is characterized by frequent recurrences, often related to noncompliance with drug treatment, stressful life events, and disruptions in social rhythms. Interpersonal and social rhythm therapy (IPSRT) was designed to directly address these problem areas. This article discusses the circadian basis of IPSRT and the importance of stable daily routines in the maintenance of the euthymic state, as well as the two large controlled trials which empirically support this intervention. The authors discuss the advantages of IPSRT as an acute intervention, as well as a prophylactic treatment for both bipolar I and II disorder. Using a case example, the authors describe how IPSRT is implemented in a clinical setting, detailing the therapeutic methods and processes involved.     

Cognitive neuroscience and brain imaging in bipolar disorder

Bipolar disorder is characterized by a combination of state-related changes in psychological function that are restricted to illness episodes, coupled with trait-related changes that persist through periods of remission, irrespective of symptom status. This article reviews studies that have investigated the brain systems involved in these state- and trait-related changes, using two techniques: (i) indirect measures of neurocognitive function, and (ii) direct neuroimaging measures of brain function during performance of a cognitive task. Studies of neurocognitive function in bipolar disorder indicate deficits in three core domains: attention, executive function, and emotional processing. Functional imaging studies implicate pathophysiology in distributed neural circuitry that includes the prefrontal and anterior cingulate cortices, as well as subcortical limbic structures including the amygdala and the ventral striatum. Whilst there have been clear advances in our understanding of brain changes in bipolar disorder, there are limited data in bipolar depression, and there is limited understanding of the influence of clinical variables including medication status, illness severity, and specific symptom dimensions.     

Challenges in the diagnosis and treatment of pediatric bipolar depression

There has been great public and academic interest in the diagnosis and treatment of bipolar disorders (BD) in children and adolescents over the past decade, originally in the US, but now extending internationally. Much of the interest in pediatric BD has focused on the unique manifestation of mania in younger populations. Depression is often overlooked, both as a topic, and as a clinical reality, in these children. While it is becoming clear that adults with BD spend the majority of their symptomatic time in depressive rather than manic episodes, less is known about the pediatric experience of bipolar depression. However, children and adolescents with BD clearly do experience significant depressive symptoms as well as depressive episodes, and therefore early recognition and treatment is necessary. This review addresses what is known about the prevalence, presentation, and treatment of depressive symptoms and episodes in youth with BD, and includes a discussion about the recognition and treatment of bipolar depressive episodes that occur before the first manic episode.     

Studies in schizophrenia: pathophysiology and treatment

Studies on the pathophysiology of schizophrenia have implicated the limbic cortex, using postmortem, structural, and functional data, especially in the hippocampus (HC) and the anterior cingulate cortex (ACC). We have made contributions to the literature consistent with this idea: first, we describe a positive significant correlation between psychotic symptoms in schizophrenia and neuronal activity in the ACC and HC, suggesting the involvement of limbic cortex in the mediation of symptoms in schizophrenia. Second, in the ACC and the anterior HC (but not in the posterior HC), regional cerebral blood flow (rCBF) is abnormal (ie, reduced in the ACC and elevated in the HC) in schizophrenia. Third, the relationship of rCBF to task difficulty in the ACC is altered in schizophrenia, suggesting a failure of participation of the ACC in effortful tasks. Lastly, connectivity between the ACC and HC during the performance of an auditory discrimination task is also lacking, suggesting that cognitive performance in schizophrenia lacks a functional limbic contribution. On the basis of these changes, we studied the effects of antipsychotic drugs in these abnormal areas in persons with schizophrenia. Both first- and second-generation antipsychotics produce functional alterations in these limbic cortical areas, in the direction of normals, putatively acting through the brain's own cortical-subcortical circuits.     

New findings in the genetics of major psychoses

Schizophrenia and bipolar disorder have a largely unknown pathophysiology and etiology, but they are highly heritable. Although linkage and association studies have identified a series of chromosomal regions likely to contain susceptibility genes, progress in identifying causative genes has been largely disappointing. However, rapid technological advances are beginning to lead to new insights. Systematic genome-wide association and follow-up studies have reported genome-wide significant association findings of common variants for schizophrenia and bipolar disorder. The risk conferred by individual variants is small, and some variants confer a risk for both disorders. In addition, recent studies have identified rare, large structural variants (copy number variants) that confer a greater risk for schizophrenia. This review summarizes recent developments in genetic research into schizophrenia and bipolar disorder, and discusses possible future directions in this field.     

Psychosis related to neurological conditions: pro and cons of the dis- / mis-connectivity models of schizophrenia

Schizophrenia is still a condition with obscure causes and psychopathology. This paper aims to discuss the "disconnectivity" hypothesis in relation to some neurological conditions which are known to alter brain connectivity, as well as mimicking some aspects of the disorder. After a short historical introduction to the concept, we will examine the evidence for connectivity problems in schizophrenia, separating the anatomical level from the functional level. Then, we will discuss three different issues concerning connectivity: i) local reduction in connectivity without neuronal loss (within the gray matter); ii) reduction in or alteration of long-range connectivity (within the white matter); and iii) abnormal targets for connections. For each of these aspects, we will look at the conditions able to reproduce anomalies capable of increasing susceptibility to schizophrenia. We conclude that psychosis is more likely to occur: i) when long-range connectivity is concerned; ii) when lesions result in lengthening and scattering of conduction times; and iii) when there are high dopamine levels, shedding light on or adding weight to the idea of an interaction between dopamine and connectivity.     

The treatment of schizophrenia: from premorbid manifestations to the first episode of psychosis

To achieve the best therapeutic results in schizophrenia--like most other disorders--primary prevention is preferable to early and prompt treatment, which, in turn, is preferable to treatment of chronically established illness. Unfortunately, there currently exist no accurate markers that can provide information regarding the future course of illness and guide treatment in asymptomatic or mildly symptomatic individuals. Therefore, most treatment efforts are currently focused on patients who have already experienced their first psychotic episode. This paper reviews the efforts to identify accurate markers heralding psychotic illness, as well as treatment considerations in the early phase of the disease.     

Challenges in the development of clinical trials for major depressive disorder: lessons learned from trials in minor depression

This paper reviews some of the challenges faced by individuals who design and implement clinical trials of potential antidepressant medications. Particular emphasis is placed on questioning the validity of some of the theoretical assumptions that form the underpinnings of most conventional trials. Work from our group developing clinical trial methodology for minor depression is used as an example of how alternate constructs may be helpful to differentiate drug-placebo differences.