Neurobiology of Mental Illness

PAMELA SKLAR

Psychotic disorders disturb particularly human aspects of perception and cognition. The overall burden of suffering for patients, family, and society are huge, and these disorders have seemingly proven refractory to the best neurobiological and genetic experimental strategies. We remain without fundamental clarity regarding many key issues that could lead to improved diagnosis and treatment. There is now cause for optimism. In the last decade we have moved from knowing nothing about the types and number of genetic loci involved in these diseases to having a substantial understanding of rare and common variants that increase disease risk. The purpose of this section is to discuss the current state of research and understanding in nosology, genetics, genomics, biology, imaging, cognition, and pharmacology of psychotic disorders. Organizationally, the first five chapters cover the basic science and phenomenology of psychosis, the subsequent three chapters delve into animal and cellular models, and the final chapters address theoretical models and clinical aspects of psychosis and the neurobiology of bipolar disorder.

In Chapter 17, Morris Smith, Meissinger, and Malaspina discuss the historical evolution of the term “psychosis” and its prototypical disorder, schizophrenia, as well as its relationship to other mental illnesses with prominent psychotic symptoms such as bipolar disorder and schizoaffective disorder. They explain the development of current diagnostic schema, criteria, and reliability, as found in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Statistical Classification of Diseases and Related Health Problems (ICD). Importantly, since the current nosology is phenomenological and symptom-based, they discuss directions for the future and ways in which genetics and neurobiology are likely to drive a more refined understanding of the disease categories.

In Chapter 18, Sklar covers the current status of the genetics of psychotic disorders, in particular schizophrenia and bipolar disorder. While both disorders have been repeatedly demonstrated to be familial, until recently they have proven unyielding to standard genetic tools. This has dramatically changed over the last half decade, and several aspects of the underlying architecture—the type and number of genetic changes that lead to liability—are now well established. This chapter explores the role of structural variation and common and rare single nucleotide variation. The overall focus is on understanding that the genetics of these disorders is highly complex, being both polygenic and multifactorial, with the strong prediction that psychotic disorder genetics will be ultimately defined through future research.

In Chapter 19, genomic syndromes in psychotic disorder are discussed by Kirov, O’Donovan, and Owen. One of the most fertile areas of genetic discovery over the last five years has been identifying structural lesions, copy number variants (CNVs), in the genome that predispose individuals to schizophrenia, bipolar disorder, and autism. These lesions generally have strong effects, harbor many genes, and result in multiple phenotypes; the current understanding of the most robustly associated CNVs are reviewed. However, understanding the role of these lesions is a rapidly changing area that will be influenced by neurobiology, clinical studies, and integration with other types of genomic data.

In Chapter 20, the applications of neuroimaging techniques to study the brain in schizophrenia are explored. Heckers, Woodward, and Ongur synthesize a vast literature that includes computed tomography (CT), single photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI) of a variety of types, magnetic resonance imaging spectroscopy (MRS), and diffusion tensor imaging (DTI). Consistent observations regarding brain volume, connectivity, chemistry, and activation during psychosis have been observed and replicated, but the future lies in the exciting possibilities for deriving diagnostic markers by connecting neuroimaging with neurobiology, genetics, and clinical treatment.

In Chapter 21, Anticevic, Dowd, and Barch focus not on the psychotic symptoms such as delusions and hallucinations, but on abnormalities in cognitive functions that are responsible for some of the most debilitating aspects of schizophrenia and bipolar disorder. Over the years many direct tests of cognitive processing abnormalities in patients and controls have been made. Critical observations regarding working memory deficits in both its encoding and maintenance phase are leading to a deeper understanding of this aspect of schizophrenia. The direct connections that can be made through the use of functional neuroimaging are described and point to the involvement of the dorsolateral prefrontal cortex. In addition, dysfunction within reward and motivation systems are reviewed. Finally, exciting potential links with underlying biology and circuitry, particularly as they relate to the balance of excitatory and inhibitory signaling are drawn that should ultimately unravel the circuit changes responsible for symptom production and disease.

In Chapter 22, Pletnikov and Ross discuss the progress and limitations of using mouse models in studying psychotic disorders. The current generation of models is based largely on environmental exposures, drug-induced behaviors that correlated with pharmacological developments, or lesion studies, and mimic aspects of the phenotype, but not the underlying pathophysiology convincingly. However, there is great hope for the future in applying the mature and advanced transgenic tools and animal models to newly emerging, validated loci from genetic and genomic studies.

In Chapter 23, Curley and Lewis explore the cellular details of inhibitory neurotransmission, its role in the synchronized firing of cells and networks, and the strong connections with schizophrenia. They discuss the elegant studies that have led to understanding the basic structure of inhibitory neurons, their subtypes, transmitters, contacts, and organization, as well as the mechanisms used for controlling and timing the activity of large numbers of cortical pyramidal cells. Numerous intriguing observations regarding GABA signaling as well as interneuron abnormalities and upstream NMDA-receptor signaling that have been observed in patients with schizophrenia emphasize the importance of inhibitory signaling in the pathology of schizophrenia.

In Chapter 24, exploration of cellular aspects of brain function continues with a focus on synaptic physiology. In this chapter, Grant focuses attention on the billions of contacts through which nerve cells communicate. Understanding the neurotransmitter receptors, ion channels, and membrane proteins that are in play at the synapse, as well as disruptions in rare neurological and developmental disorders, is likely to point to common pathways that will also be relevant to schizophrenia and other psychotic disorders.

In Chapter 25, Kwon, Soda, and Tsai discuss the developmental theory of schizophrenia. They particularly focus on a series of developmental factors that have not been discussed elsewhere in this section including the environment, the role of myelin development, and pathways that are critical to neuronal development and neuronal migration.

In Chapter 26, Gur follows up the neurodevelopmental focus of the previous chapter with a clinical discussion of the proneness to psychosis. Identifying individuals with early symptoms that represent a “psychosis risk syndrome” is being helped forward through following neurobehavioral outcomes such as cognition in high-risk patients. This approach is complemented by detailed imaging measures investigating aspects of brain physiology, and increasingly, brain circuitry. These studies are frequently longitudinal, and the early work has largely been focused on, and will be discussed in relationship to, prodromal schizophrenia.

In Chapter 27, Tamminga and Ivleva review the neurochemical models of these illnesses. The evidence for and against the long-standing theories, including dopamine hyperfunction, glutamatergic hypofunctions, and altered inhibitory neurotransmission, are elucidated. The relation of these theories to treatment modalities is made clear, as well as a review of the current status of molecular targets for both the positive psychotic symptoms and cognitive dysfunction.

In Chapter 28, Burdick, Haggarty, and Perlis review the neurobiology of bipolar disorder. While there are genetic loci that overlap between schizophrenia and bipolar disorder, there are substantial differences between the two syndromes as well. In this chapter, the particular aspects of the clinical syndrome and neurobiology that appear more distinct from schizophrenia are covered, including evidence for involvement of circadian systems, mitochondrial function, and epigenetics.