Endophenotypes are an exciting and important area of research in genetically complex psychiatric diseases. They are biological markers between genotype and external phenotype that may indicate susceptibility to or manifest as early signs of a wide range of mental disorders. Identifying endophenotypes can enable researchers to tease apart the biological components of psychiatric diseases and thereby gain a better understanding of them. They may lead to more accurate prediction and to more effective prevention and treatment. Endophenotypes also have implications for (...) the philosophy of mind and the ethics of informed consent. (shrink)

How we ought to diagnose, categorise and respond to spectrum disabilities such as autism and Attention Deficit/Hyperactivity Disorder (ADHD) is a topic of lively debate. The heterogeneity associated with ADHD and autism is described as falling on various continua of behavioural, neural, and genetic difference. These continua are varyingly described either as extending into the general population, or as being continua within a given disorder demarcation. Moreover, the interrelationships of these continua are likewise often vague and subject to diverse interpretations. (...) -/- In this paper, I explore geneticists' and self-advocates’ perspectives concerning autism and ADHD as continua. These diagnoses are overwhelmingly analysed as falling on a continuum or continua of underlying traits, which supports the notion of “the neurodiversity spectrum”, i.e., a broader swath of human neural and behavioural diversity on which some concentrations of different functioning are diagnosed. I offer a taxonomy of conceptions of the genetic, phenotypic, and endophenotypic dimensionality within and beyond these diagnostic categories, and suggest that the spectrum of neurodiversity is characteristically endophenotypic. (shrink)

This paper provides a historical analysis of a shift in the way animal models of mental disorders were conceptualized: the shift from the mid-twentieth-century view, adopted by some, that animal models model syndromes classified in manuals such as the Diagnostic and Statistical Manual of Mental Disorders (DSM), to the later widespread view that animal models model component parts of psychiatric syndromes. I argue that in the middle of the twentieth century the attempt to maximize the face validity of animal models (...) sometimes led to the pursuit of the ideal of an animal model that represented a behaviorally defined psychiatric syndrome as described in manuals such as the DSM. I show how developments within psychiatric genetics and related criticism of the DSM in the 1990s and 2000s led to the rejection of this ideal and how researchers in the first decade of the twenty-first century came to believe that animal models of mental disorders should model component parts of mental disorders, adopting a so-called endophenotype approach. (shrink)

Studies associating interactions of 5-HTTLPR and life adversities with depression have yielded equivocal results. Studying endophenotypes may constitute a more powerful approach. In the current study, it was assessed whether interactions of 5-HTTLPR with childhood emotional abuse (CEA) and recent negative life events (RNLE) affect possible cognitive endophenotypes of depression, namely, attention-allocation bias and the ability to recognise others' mind states in 215 young adults of North-West European descent. The ability to classify others' negative mind states was found to be (...) increased with increasing RNLE in carriers of low-expressing Serotonin Transporter Linked Polymorphic Region (5-HTTLPR) alleles. Carriers of two low-expressing alleles also preferentially oriented attention towards negative information. Gene-environment interactions were not observed for attention allocation bias. No effects involving CEA were observed. These results suggest that low-expressing 5-HTTLPR alleles may confer increased risk for depression through enhanced recognition of negative facial expressions following RNLE. (shrink)

Depue & Morrone-Strupinsky's (D&M-S's) model of affiliation meets the criteria advanced for the definition of behavior systems and endophenotypes. We argue that its application in psychiatry could be useful for identifying a biological pathophysiology common to a variety of conditions that are currently classified in very different categories of psychiatric nosography, including autism, schizoid personality, primary psychopathy, and dismissing attachment.

The catch 22 situation in psychiatry is that for precise diagnostic categories/criteria, we need precise investigative tests, and for precise investigative tests, we need precise diagnostic criteria/categories; and precision in both diagnostics and investigative tests is nonexistent at present. The effort to establish clarity often results in a fresh maze of evidence. In finding the way forward, it is tempting to abandon the scientific method, but that is not possible, since we deal with real human psychopathology, not just concepts to (...) speculate over. Search for clear-cut definitions/diagnostic criteria in psychiatry must be relentless. There is a greater need to be ruthless and blunt in this, rather than being accommodative of diverse opinions. Investigative tests - psychological, serum, CSF, or neuroimaging - are only corroborative at present; they need to become definitive. Medicalisation appears most prominent in psychiatry; so, diagnostic proliferation and fuzziness appear inevitable. And yet, the established diagnostic entities need to forward greater and conclusive precision. Also, the need for clarity and precision must outweigh pandering to and mollifying diverse interests, moreso in the upcoming revision of diagnostic manuals. This is specially because the DSM-5, being an Association manual, may need to accommodate powerful member lobbies; and ICD-11 may similarly need to cater to diverse country lobbies. Finding precise biological correlates of psychiatric phenomena, whether through neuroimaging, molecular neurobiology and/or neurogenomics, is the right way forward. It is in the 1.5-kg structure in the cranium that all secrets of psychiatric conditions lie. Social forces, behavioural modification, psychosocial restructuring, study of intrapsychic processes, and philosophical insights are not to be discounted, but they are supplementary to the primary goal - studying and deciphering those brain processes that result in psychiatric malfunction. Experimental breakthroughs, both in psychiatric aetiology and therapeutics, will come mainly from biology and its adjunct, psychopharmacology; while supplementary and complementary breakthroughs will come from the psychosocial, cognitive and behavioural approaches; the support base will come from phenomenology, epidemiology, nosology and diagnostics; while insights and leads can hopefully come from many fields, especially the psychosocial, the behavioural, the cognitive and the philosophical. Major energies must now be marshalled towards finding biomarkers and deciphering the precise phenotype-genotype-endophenotype axis of psychiatric disorders. Energies also need to be focussed on unravelling those critical processes in the brain that tip the scale towards psychiatric disorders. At how those critical processes are set into motion by forces de novo, in utero, in the genes and their expression, by the environment's psychopathological social forces - stress, peer pressure, poverty, deprivation, alienation, malnutrition, discrimination of various types (caste, gender, race, etc.), mass conflicts (war, terror attacks, etc.), disasters (natural and man-made), religious/ideological fascism - or social institutions like marriage, family, work place, political governance, etc. Ultimately, we must decipher how the brain goes into malfunction when such varied forces impinge on it, which precise cortical areas and neuronal cellular and molecular processes are involved in such malfunction and its manifestation, as also which of these are involved when malfunction ceases and health is restored, and the psychosocial processes and institutions which aid such health restoration, as also those which promote well-being and help in primary prevention. Emphasis on the brain and its intimate neurological and molecular mechanisms will not impinge on, or nullify, importance of the 'mind,' wherein subtle and gross brain functions in the form of behaviour, thought and emotions in all their ramifications will continue to be the focus of psychological, cognitive, sociological, psychopharmacological, behavioural and philosophical research. Progress in brain research must move in tandem with progress in 'mind' research. (shrink)

Background: The broad autism phenotype includes subclinical autistic characteristics found to have a higher prevalence in unaffected family members of individuals with autism. These characteristics primarily affect the social aspects of language, communication, and human interaction. The current research focuses on possible neurobehavioral characteristics associated with the broad autism phenotype. Methods: We used a face-processing task associated with atypical patterns of gaze fixation and brain function in autism while collecting brain functional magnetic resonance imaging (fMRI) and eye tracking in unaffected (...) siblings of individuals with autism. Results: We found robust differences in gaze fixation and brain function in response to images of human faces in unaffected siblings compared with typically developing control individuals. The siblings’ gaze fixations and brain activation patterns during the face processing task were similar to that of the autism group and showed decreased gaze fixation along with diminished fusiform activation compared with the control group. Furthermore, amygdala volume in the siblings was similar to the autism group and was significantly reduced compared with the control group. Conclusions: Together, these findings provide compelling evidence for differences in social/emotional processing and underlying neural circuitry in siblings of individuals with autism, supporting the notion of unique endophenotypes associated with the broad autism phenotype. (shrink)

Research-based but highly accessible, this fresh, contemporary, and engaging volume helps students appreciate the science of psychology and understand how its principles apply to their own lives. Key features: Contemporary perspectives and references: giving careful consideration to the field's historical foundations, Psychology: Contemporary Perspectives provides a unique balance of traditional and contemporary perspectives. This approach invites students to develop a modern appraisal of psychology. Current research: the book covers the latest in evolutionary psychology and behavior genetics, ecological and evolutionary theories (...) of learning, cross-cultural work in cognition, the latest neuroscience data, and endophenotype research in the genetic causes of schizophrenia. Clear and compelling writing: exceptionally well written, Psychology: Contemporary Perspectives uses stories to help students connect with the principles of psychology. Rich pedagogy: all running features are integrated into the main body of the text, helping to maintain the flow of the narrative--and the attention of students! "Freeze Frame" snapshots underscoring the theme of each chapter tell the compelling stories of real-life individuals. "Living Psychology" applies psychology to students' everyday lives, helping them understand the benefits of what they are studying. "Critical Thinking about Psychology" sections give students the tools they need in order to effectively and objectively interpret research. "At the Forefront" highlights new and influential research in the field. Carefully selected study tools: placing an emphasis on "review, retrieve, and learn", Psychology: Contemporary Perspectives takes a "back-to-basics" approach to study tools. "In Summary" sections provide clear, concise chapter descriptions, offering students powerful tools for review. "Retrieve!" questions encourage students to test their knowledge of what they have just read. Each question includes the page numbers on which the relevant material was first presented, aiding in additional review and reinforcing learning. (shrink)

Notwithstanding the many strengths of the dynamic developmental theory, there remain challenges to be overcome before it can be incorporated into a true causal model of attention-deficit/hyperactivity disorder (ADHD). These include the development of reliable measures of reinforcement delay gradients, the validation of shortened reinforcement delay as an endophenotype, and the integration of this pathway with other potential pathways.

Sensory dysfunction has been shown to be a part of the pathophysiology of schizophrenia. Nowadays we have an objective, non-invasive tool with which to measure neural manifestations of sensory dysfunction. Defined as time-locked changes to external stimuli in the EEG, event-related potentials (ERPs) provide an objective index of information processing in the human brain. Importantly, ERPs may be analyzed through a variety of approaches such as conventional ERP analysis, analysis in the time-frequency domain, microstate segmentation and topographical analysis, as well (...) as source localisation analysis. Each of the methods gives distinct information; they also supplement each other. Here, an attempt is made to verify the validity of combining different approaches to study sensory dysfunction in neuropsychiatric disorders. For example, the data from a schizophrenic patient and an age- and sex-matched healthy subject generate a picture of the events which emerges after visual, proprioceptive and simultaneous presentation of stimuli in both modalities. This approach, though time-consuming, allows the visualisation of changes appearing in the malfunctioning brain as compared to the healthy brain. These methods could ultimately lead to a better establishment of one or more endophenotypes for the schizophrenic disorders. They might also serve as a way to track changes in response to various medications and therapies. (shrink)

The dynamic developmental theory (DDT) has benefited from the insights of the commentators, particularly in terms of the implications for the proposed steepened delay gradients in attention-deficit/hyperactivity disorder (ADHD). The introduction of modified memory processes as a basis for the delay gradients improved the links to aspects of ADHD. However, it remains unclear whether the hyperactive-impulsive and inattentive subtypes are separate subgroups or may be explained as different outcomes of the same genetic factors and thus explicable by the same principles. (...) The DDT suggests that altered reinforcement and extinction processes define an endophenotype in ADHD that can be related dimensionally to inattention, hyperactivity, and impulsivity. The relation between the suggested endophenotype, characterized by changes in basic learning mechanisms, and other endophenotypes characterized by delay aversion or response disinhibition, needs to be tested in future studies. (shrink)

It is suggested that general-purpose cognitive modules are the proper endophenotypes on which evolution has operated, not special purpose belief modules. These general-purpose modules operate to extract adaptive cultural patterns. Belief in souls may be adaptive and based in evolved systems without requiring that a specific cognitive system has evolved to support just such beliefs.

We discuss the latent variables construct, particularly in regard to the following: that latent variables are considered as the sole explanatory factor of a disorder; that pragmatic concerns are ignored; and that the relationship of these variables to biological markers is not addressed. Further, we comment on the relationship between bridge symptoms and causality, and discuss the proposal in relationship to other constructs (endophenotypes, connectionist-inspired networks).

The target article excludes ancestral neutrality as a cause for the inheritance of schizophrenia, with an argument relating to selection against a single allele in the Finnish population. However, drift would predominate over selection within subisolates of the Finnish population. Comparisons of subisolates with heterogeneous populations may provide clues to the endophenotypic structure of complex polygenetic heritable mental disorders. (Published Online November 9 2006).

A recent meta-analysis by Munafò, Durrant, Lewis, and Flint [Munafò, M. R., Durrant, C., Lewis, G., & Flint, J. . Gene × environment interactions at the serotonin transporter locus. Biological Psychiatry, 65, 211–219] questioned the meaning of studies searching for endophenotypes associated with the serotonin-transporter-linked promoter region polymorphism, including our study on visual perspective during autobiographical memory retrieval. However, the association of 3rd person perspective with vulnerability for depression does not rely only on genetics. External consistency is provided by the (...) influence of the 5-HTTLPR polymorphism on brain regions involved in emotion regulation and autobiographical memory retrieval . Internal consistency is provided by the increased prevalence of 3rd person perspective in both currently and previously depressed patients, as well as in depression-prone individuals. Further studies should examine therapeutic opportunities. (shrink)

At this point in time, it is hard to say which consequences for the concept of mental illness result from modern genetics. Current research projects are trying to find significant statistical correlations between the diagnosis of a disease and a gene locus or an endophenotype. Up until now, there has not been any identification of alleles or mutations causing mental illness. In the meantime, the relations between the genetic basis and the disease are given the term genetic vulnerability as (...) a placeholder; this concept simplifies the complex relations between the DNA and even the simplest cell functions observed in modern genetics. According to complex gene models like the systemic theory of DNA, it will not be possible to identify the genetic factors without a precise knowledge of the factors which modulate the gene expression. The significance of genetics as part of the concept of mental illness will not be able to be defined without further progress in developmental biology and psychology. Currently, psychological theory fails to acknowledge the complexity of the relationship between the DNA and the environment. Some starting points from which to develop such an understanding can be received from developmental studies and studies of the psychophylogenesis . An interdisciplinary concept of the biological basis of the psyche is needed. (shrink)

Developmental Coordination Disorder and Attention-Deficit/Hyperactivity Disorder are unique neurodevelopmental disorders with overlaps in executive functions and motor control. The conditions co-occur in up to 50% of cases, raising questions of the pathological mechanisms of DCD versus ADHD. Few studies have examined these overlaps in adults with DCD and/or ADHD. Therefore, to provide insights about executive functions and motor control between adults with DCD, ADHD, both conditions, or typically developed controls, this study used a stop-signal task and parallel EEG measurement. We (...) assessed executive performance via go accuracy and go reaction time, as well as motor response inhibition via stop-signal reaction time. This was complemented with analysis of event-related potentials. Based on existing investigations of adults with DCD or ADHD, we expected groups would not differ in behavioral performance on stop and go trials, but differences in ERPs, particularly in components N200 and P300 would be evident. The sample included N = 50 adults with DCD, ADHD, DCD + ADHD, and control participants. We replicated that there were no between-group differences for behavioral-level executive performance and motor response inhibition. However, on a physiological level, ERP components N200 and P300 differed between groups, particularly during successful response inhibition. These ERPs reflect potential endophenotypic differences not evident in overt behavior of participants with ADHD and/or DCD. This suggests a disorder specific employment of inhibition or general executive functions in groups of adults with DCD, DCD + ADHD, ADHD, or control participants. (shrink)

Current literature suggesting a shared endophenotype between individuals with anorexia nervosa and autism spectrum disorder related to executive functioning has several limitations: performance-based instead of ecologically valid measures of set-shifting are used, lack of comparisons between same-sex groups, and reliance on adult samples only. This was the first study directly comparing female youth with ASD to female youth with AN using an ecologically valid measure of EF. A secondary data analysis combined caregiver-reported EF on the Behavior Rating Inventory of (...) Executive Functioning for 22 female adolescent youth with AN and 29 female adolescent youth with ASD. EF in each group was compared to population norms, and EF was compared between groups. Compared to population norms, adolescents with AN had elevated scores on shift, initiate, and emotional control scales, and adolescents with ASD had elevated scores on all scales of the BRIEF and were more likely to have scores in the clinical range. There were significant differences between groups on all but three scales. The cognitive profiles and clinical scores of AN females were not comparable to those of ASD females. The findings reveal a clear clinical impairment in females with ASD but not in females with AN. The results do not support the hypothesis of similar real-world EF profiles between these groups. The results encourage further exploration into the similarities and distinctions between these two disorders. (shrink)

The DSM-III, DSM-IV, DSM-IV-TR and ICD-10 have judiciously minimized discussion of etiologies to distance clinical psychiatry from Freudian psychoanalysis. With this goal mostly achieved, discussion of etiological factors should be reintroduced into the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. A research agenda for the DSM-V advocated the "development of a pathophysiologically based classification system". The author critically reviews the neuroevolutionary literature on stress-induced and fear circuitry disorders and related amygdala-driven, species-atypical fear behaviors of clinical severity in adult (...) humans. Over 30 empirically testable/falsifiable predictions are presented. It is noted that in DSM-IV-TR and ICD-10, the classification of stress and fear circuitry disorders is neither mode-of-acquisition-based nor brain-evolution-based. For example, snake phobia and dog phobia are clustered together. Similarly, research on blood-injection-injury-type-specific phobia clusters two fears different in their innateness: 1) an arguably ontogenetic memory-trace-overconsolidation-based fear and 2) a hardwired fear of the sight of one's blood or a sharp object penetrating one's skin. Genetic architecture-charting of fear-circuitry-related traits has been challenging. Various, non-phenotype-based architectures can serve as targets for research. In this article, the author will propose one such alternative genetic architecture. This article was inspired by the following: A) Nesse's "Smoke-Detector Principle", B) the increasing suspicion that the "smooth" rather than "lumpy" distribution of complex psychiatric phenotypes may in some cases be accounted for by oligogenic transmission, and C) insights from the initial sequence of the chimpanzee genome and comparison with the human genome by the Chimpanzee Sequencing and Analysis Consortium published in late 2005. Neuroevolutionary insights relevant to fear circuitry symptoms that primarily emerge overconsolidationally are presented. Also introduced is a human-evolution-based principle for clustering innate fear traits. The "Neuroevolutionary Time-depth Principle" of innate fears proposed in this article may be useful in the development of a neuroevolution-based taxonomic re-clustering of stress-triggered and fear-circuitry disorders in DSM-V. Four broad clusters of evolved fear circuits are proposed based on their time-depths: 1) Mesozoic circuits hardwired by wild-type alleles driven to fixation by Mesozoic selective sweeps; 2) Cenozoic circuits relevant to many specific phobias; 3) mid Paleolithic and upper Paleolithic circuits ; 4) Neolithic circuits. More importantly, the author presents evolutionary perspectives on warzone-related PTSD, Combat-Stress Reaction, Combat-related Stress, Operational-Stress, and other deployment-stress-induced symptoms. The Neuroevolutionary Time-depth Principle presented in this article may help explain the dissimilar stress-resilience levels following different types of acute threat to survival of oneself or one's progency. PTSD rates following exposure to lethal inter-group violence are usually 5-10 times higher than rates following large-scale natural disasters such as forest fires, floods, hurricanes, volcanic eruptions, and earthquakes. The author predicts that both intentionally-caused large-scale bioevent-disasters, as well as natural bioevents such as SARS and avian flu pandemics will be an exception and are likely to be followed by PTSD rates approaching those that follow warzone exposure. During bioevents, Amygdala-driven and locus-coeruleus-driven epidemic pseudosomatic symptoms may be an order of magnitude more common than infection-caused cytokine-driven symptoms. Implications for the red cross and FEMA are discussed. It is also argued that hospital phobia as well as dog phobia, bird phobia and bat phobia require re-taxonomization in DSM-V in a new "overconsolidational disorders" category anchored around PTSD. The overconsolidational spectrum category may be conceptualized as straddling the fear circuitry spectrum disorders and the affective spectrum disorders categories, and may be a category for which Pitman's secondary prevention propranolol regimen may be specifically indicated as a "morning after pill" intervention. Predictions are presented regarding obsessive-compulsive disorder and "culture-bound" acute anxiety symptoms. Also discussed are insights relevant to pseudoneurological symptoms and to the forthcoming Dissociative-Conversive disorders category in DSM-V, including what the author terms fright-triggered acute pseudo-localized symptoms. Speculations based on studies of the human abnormal-spindle-like, microcephaly-associated gene, the microcephaly primary autosomal recessive gene, and the forkhead box p2 gene are made and incorporated into what is termed "The pre-FOXP2 Hypothesis of Blood-Injection-Injury Phobia." Finally, the author argues for a non-reductionistic fusion of "distal neurobiology" with clinical "proximal neurobiology," utilizing neurological heuristics. It is noted that the value of re-clustering fear traits based on behavioral ethology, human-phylogenomics-derived endophenotypes and on ontogenomics can be confirmed or disconfirmed using epidemiological or twin studies and psychiatric genomics. (shrink)

Temporal conceptualisation and investigation of brain-mind functioning, in health and in neuro-psychiatric disease, is a relatively new field in neuroscience. The cerebellum has long been suspected as the centre for the organization of timing in the brain. This article examines endophenotypes for temporal coding in schizophrenia, centring on aberrant, neuronal, input connectivity to the cerebellum.

Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as “missing heritability.” Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one (...) of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases. (shrink)