Neurobiology of Schizophrenia, Mood Disorders, and Anxiety Disorders

Chapter 19

Neurobiology of Schizophrenia, Mood Disorders, and Anxiety Disorders∗

Lorey K. Takahashi

Mental illnesses are common and found in different cultures and across the socioeconomic spectrum. When left untreated, the consequences can be devastating. This chapter provides an introduction to the neurobiology of schizophrenia, mood disorders, and some anxiety disorders. The etiology and pathophysiology of mental illnesses are diverse and complex. Diagnostic criteria are constantly being updated to more precisely diagnose and effectively treat the disorders. Every mental disorder manifests a range of symptoms that vary in intensity. Symptom variations likely reflect individual differences in neural pathologic brain structures or functions, or both, which affect treatment. Risk factors, such as exposure to uncontrollable psychosocial stress, may precipitate the onset of mental disorders and point to the challenge in understanding how diseased genes and environmental factors interact.

The development of visual and quantitative structural and functional neuroimaging techniques provides insight into the pathophysiologic basis of mental disorders. In schizophrenia, neuroanatomic, functional, and neurochemical alterations associated with this debilitating illness have uncovered abnormal brain regions along with a host of candidate genes that confer risk. Similarly, in mood and anxiety disorders, brain scans are revealing structural and functional abnormalities. Notably, many brain regions implicated in normal cognitive and emotional processing are found in schizophrenia, mood, and anxiety disorders. The future lies in unraveling how the highly interconnected brain structures modulated by neurotransmitters, neuropeptides, and hormones operate in normal to abnormal mental states.

Knowledge of the pathophysiology associated with a specific mental illness has guided the development of pharmacologic medications. Although second- and third-generation drugs with fewer side effects are now available, many individuals continue to suffer; and to complicate diagnosis and treatment, psychiatric disorders, such as depression and anxiety, often coexist. Identifying and characterizing diseased genes and environmental triggers in mental illness will offer hope in developing effective therapies that alleviate symptoms and lessen or reverse the pathophysiologic alterations.

Schizophrenia

Schizophrenia is a serious psychiatric illness that strikes 1% of the world’s population. The illness is equally prevalent in males and females and emerges in young adults during the late teens and early twenties, with a slightly earlier onset in males than in females. Schizophrenia is the term coined originally by Eugen Bleuler in 1911 to describe a collection of illnesses characterized by thought disorders, which reflect a break in reality or splitting of the cognitive from the emotional side of one’s personality. A schizophrenic individual may exhibit a feeling of happiness when recollecting a terrible event or emotional indifference when describing a joyful occasion. Today, disorganized thought in schizophrenia is characterized by positive and negative symptoms including auditory hallucinations, paranoid delusions, and cognitive deficits that have devastating effects on the individual and the individual’s family.

Etiology and Pathophysiology

Genetic Predisposition

Schizophrenia is a heritable disorder. In monozygotic twins, the concordance rate varies from 30% to 50%. This variability may stem from different diagnostic criteria and methodologic or sampling differences across studies. In dizygotic twins and siblings the concordance rate decreases to 12%, which is still considerably higher than the 1% figure found in the general population.

Nonetheless, schizophrenia is not a simple genetic disorder in which inherited disease alleles will always lead to illness. Schizophrenia likely involves several genes located on different chromosomes and differs from mendelian disorders, in which genes are fully penetrant and recognized as the primary cause of disease (e.g., genes for Huntington disease). As indicated by the 50% concordance rate in monozygotic twins, the genes for schizophrenia show reduced penetrance, resulting in individuals who carry the disease genes without manifesting the illness. Further complicating the search for the specific genes that confer risk of schizophrenia is the variability in biologic and phenotypic traits among individuals who manifest the illness (see What’s New? Copy Number Variations Increase in Schizophrenia and in Offspring of Older Fathers).

WHAT’S NEW?

Copy Number Variations Increase in Schizophrenia and in Offspring of Older Fathers

Copy number variations (CNVs) involving deletions or duplications of several million base pairs of DNA sequence of the genome are increasingly recognized to elevate the risk of serious neurodevelopmental disorders including schizophrenia, autism, epilepsy, and mental retardation. Concerning schizophrenia, large CNV deletions involving multiple genes show increased penetrance accompanied with severe phenotypic symptoms of the disease. For example, CNV deletion at 22q11.2, which consists of 1.5 to 3.0 megabases of DNA, is reported to increase the risk of schizophrenia by 20- to 30-fold in comparison to the general population. Research linking 22q11.2 deletion to schizophrenia as well as other recently identified CNV deletions occurring at distinct loci will accelerate our genetic understanding of the pathogenesis of the disease and have implications for genetic counseling and clinical management.

Of further potential clinical relevance of the role of CNVs in schizophrenia, offspring of fathers who are age 50 or more have a twofold to threefold increased risk of the disease when compared to fathers who are in their twenties. Although the causal mechanisms remain unclear, a recent study using a mouse model reported that offspring sired by older male mice exhibited an increase in spontaneously occurring (de novo) CNVs. Six de novo CNVs were found in the offspring of aged male mice and none from the younger control group. When the CNVs in the mouse brain were then mapped to the human genome, three de novo CNVs were found to have genes on human chromosomes linked to brain development and schizophrenia. These results suggest that paternal-age–related mutations in the germline contribute to offspring de novo CNVs that may underlie schizophrenia.

Data from Bassett AS et al: Am J Psychiatry 167:899–914, 2010; Flatscher-Bader T et al: Transl Psychiatry 1:e34, 2011; Moreno-DeLuca D, Cubells JF: Curr Psychiatry Rep 13:129–137, 2011.

Prenatal and Perinatal Vulnerability Factors

Because the concordance rate of schizophrenia in monozygotic twins is never 100% as in mendelian disorders, environmental factors likely play an important role in increasing the risk of developing the disorder. A leading hypothesis suggests that early environmental factors interfere with genetically programmed neural developmental alterations that eventually compromise normal brain structures and functions.1 An early brain defect may remain silent and not dramatically affect the individual until subsequent development requires adaptive use of brain structures.2 Several hypothesized early environmental factors that may alter brain development and increase the risk of developing schizophrenia include exposure to prenatal infection, prenatal nutritional deficiencies, perinatal complications (such as birth defects and neonatal hypoxia), and upbringing in an urban environment.3

Neuroanatomic and Functional Abnormalities

Neuroanatomic Alterations

Advanced neuroimaging techniques have revealed evidence of structural brain abnormalities in schizophrenia.4,5 A consistent finding is the enlargement of the lateral and third ventricles and the widening of frontocortical fissures and sulci (Figure 19-1). Schizophrenics with cerebral ventricular enlargement often exhibit cognitive impairments and negative symptoms, and respond poorly to treatment. Other studies reported a reduction in the thalamus and temporal lobe areas (e.g., amygdala, hippocampus, and parahippocampal gyrus).6 A reduction in thalamus size may disrupt neurotransmission between the cortex and primary sensory and motor areas. Temporal lobe alterations may contribute to the production of positive schizophrenic symptoms, such as hallucinations, delusions, and thought disorder.

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FIGURE 19-1 Magnetic Resonance Imaging (MRI) Comparison of Normal Brain and Brain with Schizophrenia.Three-dimensional MRI reconstructions showing A, the cerebroventricles (gray regions) and hippocampus (yellow regions) of a schizophrenic patient, and B, those of a healthy individual. Note the enlarged cerebroventricles and reduced hippocampal volume of the brain of the schizophrenic individual. (From Gershon ES, Rieder RO: Sci Am 267:128, 1992. Original illustrations by Nancy C. Andreason, University of Iowa.)

Brain imaging studies in adolescents with early onset schizophrenia reveal progressive loss of cortical gray matter in temporal lobes, somatosensory and motor cortices, and the dorsolateral cortex (Figure 19-2). Of clinical concern is the loss of cortical tissue, which is evident by the time the individual seeks treatment and continues throughout the course of the illness despite the use of antipsychotic medication.7 The progressive loss in frontal lobe volume is accompanied by increased severity of negative symptoms and further reductions in cognitive functioning. These results highlight the ineffectiveness of current medications for schizophrenia to attenuate or reverse the loss of frontal brain tissue.

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FIGURE 19-2 Accelerated Gray Matter Loss in Brains of Early Onset Schizophrenic Adolescents.Annual gray matter loss ranging from 2% to 5% was found in 13- to 18-year-old schizophrenics—compared with age-matched healthy adolescents. (From Thompson PM et al: Proc Natl Acad Sci U S A 98:11650, 2001.)

Brain abnormalities in schizophrenia are believed to originate in the prenatal period of cell proliferation and migration. Reelin, an extracellular matrix protein involved in neuronal migration during development and in synaptic function during adulthood, is reduced in the prefrontal cortex and hippocampus of schizophrenic individuals.8,9 Reelin is concentrated in interneurons that contain gamma-aminobutyric acid (GABA), the most widespread inhibitory neurotransmitter. Furthermore, in the dorsal prefrontal cortex of schizophrenic brains, the level of glutamic acid decarboxylase, the major enzyme in GABA biosynthesis, is reduced, which likely impairs normal cognitive/emotional functions.

Pathophysiologic changes in the dorsal prefrontal cortex are believed to contribute to the production of negative symptoms in schizophrenia (Figure 19-3). In particular, the dorsolateral prefrontal cortex (DLPFC) (Brodmann areas 9, 10, 46, 47) is intricately involved in the initiation and maintenance of goal-directed activities and in solving cognitive problems related to working memory. Working memory involves the brief storage and use of information to complete cognitive tasks such as language comprehension, learning, and reasoning. Blood flow and metabolism normally increase in the DLPFC during working memory processing but not in schizophrenics, who also perform poorly in tests of working memory. Thus the dorsolateral prefrontal cortex appears to be hypoactive in schizophrenia.

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FIGURE 19-3 The Prefrontal Cortex.The prefrontal cortex consists of a dorsolateral (blue) and an orbitofrontal (green) region.
Neurotransmitter Alterations

The onset of schizophrenia was initially hypothesized to stem from abnormally high concentrations of the brain neurotransmitter dopamine. This dopamine hypothesis of schizophrenia was proposed on the basis of pharmacologic studies showing that antipsychotic drugs were potent blockers of brain dopamine receptors. A strong positive correlation was found between the clinical potencies of first-generation antipsychotic drugs (e.g., chlorpromazine, fluphenazine, and haloperidol) and their affinity for the dopamine D2 receptor. In addition, drugs at high doses that dramatically increased dopaminergic transmission—such as levodopa (l-dopa), cocaine, and amphetamine—produced schizophrenic-like psychosis, which was reversed by dopamine blockers.

A current view of the dopamine hypothesis of schizophrenia is that brain dopamine pathways are altered in different ways (Figure 19-4). For example, the negative symptoms and cognitive alterations in schizophrenia are proposed to result from reduced dopaminergic neurotransmission in the mesocortical dopamine pathway.10 This hypodopaminergic transmission in the prefrontal cortex contrasts with the hypothesized hyperdopaminergic secretion, in mesolimbic brain regions, which may contribute to the production of positive schizophrenic symptoms. The mesolimbic dopamine pathway innervates temporal lobe structures including the hippocampal formation and amygdala, as well as the nucleus accumbens and anterior cingulate cortex.

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FIGURE 19-4 The Dopamine System.Dopamine cell bodies are located in the substantia nigra, where they project to the stratum (nigrostriatal pathway); and in the ventral tegmental area, where they project to the frontal and cingulate cortex (mesocortical pathway), the striatum, the hippocampus, and other limbic structures (mesolimbic pathway). Dopamine nuclei are also located in the hypothalamus and project to the pituitary.

Another neurotransmitter system that may underlie the pathogenesis of schizophrenia is the excitatory neurotransmitter glutamate and its actions on the N-methyl-d-aspartate (NMDA) receptor subtype. The glutamate hypothesis of schizophrenia proposes that underactivation of glutamate receptors contributes to schizophrenia.11 In schizophrenia, glutamate concentrations in the cerebrospinal fluid (CSF) are reduced along with a decrease in cortical glutamate synthesis. Furthermore, in unaffected individuals, blocking the glutamate NMDA receptor with antagonists, such as phencyclidine (PCP) and ketamine, facilitates the positive and negative symptoms of schizophrenia. PCP users report auditory hallucinations and disorientation, and may become violent from their delusions. In monkeys, chronic PCP treatment impairs cognitive performance in a test associated with prefrontal cortical damage.12

Clinical Manifestations

The symptoms of schizophrenia are currently divided into three broad categories of positive, negative, and cognitive symptoms (Box 19-1). Positive symptoms frequently occur during a psychotic episode, when an individual loses touch with reality and experiences something that should be absent (e.g., hallucinations). Negative symptoms are characterized by disruptions in normal emotional states and expressions. Cognitive symptoms are fairly common and involve problems with thought processes that severely impair the ability to perform routine daily tasks that involve attention, planning, and social skills. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR),13 schizophrenia is diagnosed when an individual exhibits delusions, hallucinations, negative symptoms, or social/occupational dysfunctions for at least 6 months and at least two of the common symptoms of the disorder—delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, or presence of negative symptoms—must occur for 1 month (or less if successfully treated).

BOX 19-1   MAJOR SYMPTOMS OF SCHIZOPHRENIA

Positive Symptoms

Psychotic Dimension

Psychotic dimension refers to hallucinations and delusions and reflects a person’s confusion or loss of touch with the external world. Hallucinations and delusions are classified as positive symptoms and are the most common in schizophrenia.

Hallucinations

A hallucination is a perception experienced without external stimulation of the sense organs. Sensory hallucinations can be auditory, tactile, visual, gustatory, and olfactory. For example, the schizophrenic individual may hear

WHAT’S NEW?

Controversies in Mental Health Research

The Diagnostic and Statistical Manual of Mental Disorders—or “DSM” —is published by the American Psychiatric Association, and has been considered the authoritative guide to diagnosing mental disorders. First published in 1952, the DSM has undergone several revisions, and not until the 1980 publication of the DSM-III did the manual dramatically impact mental health professionals, including psychiatrists, clinical psychologists, social workers, and nurses. The DSM-III became known as the “bible of psychiatry” because it introduced a new set of criteria to standardize the diagnoses of mental disorders by categorizing symptoms presumably unique to each mental illness, such as schizophrenia and bipolar disorder. This categorical symptom approach stimulated research on the etiology and pathophysiology of diverse mental disorders and began to impact public health policy, education, and reimbursement decisions made by insurance companies. Modest categorical changes were subsequently made in the 1994 edition of DSM-IV and a text revision of DSM-IV, called DSM-IV-TR, was published in 2000.

The highly anticipated DSM-5 published in 2013 and represents the culmination of more than 10 years of revision work involving more than 1500 experts in the psychiatric, psychologic, psychiatric nursing, pediatric, neurologic, social work, and related disciplines from 39 countries. Users familiar with earlier DSM versions will encounter two major changes in DMS-5. One major change includes reordering the chapters based on the relatedness of disorders in terms of similar underlying vulnerabilities and symptoms. This change in each chapter is intended to align the DMS-5 with the World Health Organization’s International Classification of Diseases, ed 11, in order to further facilitate communication and diagnosis of disorders.

The second major change is to replace the multiaxial system of diagnosis with a nonaxial documentation by combining the former Axes I, II, and III with separate notations for psychosocial and contextual factors (formerly Axis IV) and disability (formerly Axis V). Notably, the DSM-5 will not increase the number of mental disorders; instead, fewer disorders will be found in DSM-5 than in DSM-IV. However, any change by DSM in the diagnosis of mental health that defines “normal” behavior will be of concern, especially by advocacy groups and insurance companies. For example, one controversial change in the DSM-5 will be to potentially diagnose any child over the age of 6 who displays irritability or frequent angry outbursts with “disruptive mood dysregulation disorder.” This new diagnosis was included to provide parents or caregivers the opportunity to plan interventions for children who exhibit problems controlling their emotions. However, advocacy groups questioned whether such a diagnosis would stigmatize children and may lead to unnecessary drug prescriptions. Another change is a grief and depression diagnosis. Whereas previous DSM versions prevented a diagnosis of depression in a person grieving the death of a loved one, the DMS-5 will allow depression diagnoses in the bereaved. The rationale was to provide those with chronic grief to be diagnosed with, and obtain treatment for, depression. However, some healthcare professionals questioned whether diagnosing normal grieving as depression is necessary at all, as in the previous DSM.

Although the new DSM-5 is expected to be used by many clinicians for diagnosing and treating mental disorders, some prominent researchers and clinicians have begun to question the way mental illnesses are currently viewed by categorizing and diagnosing symptoms. In particular, the current categorical symptom diagnoses guide to mental disorders does not guarantee effective treatment. A patient may exhibit multiple symptoms that overlap with a diagnosis for different disorders and that may explain why specific clinical treatment will not always relieve or temper mental illness. What appears to be missing in our present understanding of mental disorders are the causes and underlying brain mechanisms that trigger the onset of the illness.

To address this issue, Dr. Thomas Insel, Director of the National Institute of Mental Health, and other prominent scientists are hoping to steer psychiatric research away from classifying symptoms to a fundamental approach of identifying the genes, molecules, and pathophysiologic brain circuits that cause mental disorders. To do so, Dr. Insel started a federal project called Research Domain Criteria to fund research that investigates the biologic basis, and not the symptom categories, of mental disorders. Research projects are beginning to unravel brain functions that broadly implicate neural systems linked to memory, fear, anhedonia, and stress, which affect many people with mental illness. Future treatments that target pathophysiologic neural systems with new drugs or with cognitive-behavioral methods may be more beneficial to psychiatric patients than currently available treatments for psychiatric symptoms.

Data from Adam D: Nature 496:416–418, 2013; American Psychiatric Association: www.dsm5.org; Halter MJ et al: J Psychosoc Nurs 51:30–39, 2013; Insel TR et al: Neurosci Biobehav Rev (in press); Stringaris A: J Child Psychol Psychiatr 54:501, 2013.

voices, experience touch or electrical sensations, report images of animate and inanimate objects, or complain of unpleasant tastes and odors. These hallucinations may occur alone or together.

Disorganized Behavior

Disorganized behavior includes disorganized speech and disorganized or bizarre behavior. Incongruity of affect is another dimension of disorganized behavior.

Treatment

The use of chlorpromazine in the mid-1950s dramatically altered the treatment of schizophrenia, which previously required extensive institutional hospitalization. The drug was especially effective in reducing positive symptoms such as hallucinations and delusions as well as thought disorders and hyperactivity. The beneficial effects of chlorpromazine and similar first-generation antipsychotic drugs like haloperidol on positive symptoms were believed to stem from their ability to block the dopamine D2-receptor subtype, especially in the overly active mesolimbic dopamine pathways.

However, D2-receptor blockade, such as in the striatum, produces a notable neurologic side effect resembling Parkinson disease—a disorder associated with degeneration of dopamine cell bodies in the substantia nigra that project to the striatum. A related side effect of conventional antipsychotics that develops in 15% to 20% of schizophrenics after several years of treatment is a condition called tardive dyskinesia. This condition is characterized by tic-like jerky movements, such as smacking the lips or flicking the tongue, unsteady gait, or rocking back and forth when seated. Other side effects may include sedation, hypotension, akathisia (motor restlessness), constipation, weight gain, amenorrhea, and, less frequently, hepatotoxicity and electrocardiographic changes.

Although the majority of schizophrenic individuals obtained some positive symptom relief from the first-generation or conventional antipsychotics, approximately 20% failed to respond to D2-blocking drugs (Box 19-2), especially those with pronounced symptoms of apathy, disorientation, and social withdrawal. However, some of these treatment-resistant individuals responded to a second generation of drugs that became known as atypical antipsychotic drugs.14 Atypical antipsychotics also were shown to have superior efficacy in reducing not only the positive but also the negative symptoms in comparison with conventional antipsychotics. For example, clozapine improve some cognitive functions (such as verbal fluency, verbal learning, and memory) and some physical functions (such as psychomotor speed). In addition, the notable neurologic side effects that accompany the use of the conventional antipsychotics were diminished.

BOX 19-2   MEDICATIONS USED IN THE TREATMENT OF SCHIZOPHRENIA

Generic Name Brand Name
Conventional Antipsychotics
Chlorpromazine Thorazine
Fluphenazine Prolixin
Haloperidol Haldol
Perphenazine Trilafon
Pimozide Orap
Prochlorperazine Compazine
Thioridazine Mellaril
Thiothixene Navane
Trifluoperazine Stelazine

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Second-Generation Atypical Antipsychotics

Aripiprazole Abilify
Clozapine Clozaril
Loxapine Loxitane
Molindone Moban
Olanzapine Zyprexa
Paliperidone Invega
Quetiapine Seroquel
Risperidone Risperdal
Ziprasidone Geodon

Unlike conventional antipsychotics, atypical drugs appear to work by blocking a range of neurotransmitter receptors. For example, clozapine blocks not only D2 receptors but also D1, D3, D4, and D5 receptors and serotonin (5-hydroxytryptamine, i.e., HT2, 5-HT6, 5-HT7); norepinephrine; and cholinergic and histamine receptors. Risperidone and ziprasidone have higher affinity for blocking 5-HT2 than D2 receptors. The higher 5-HT2/D2-receptor–binding ratio of atypical antipsychotics in comparison with conventional drugs may reflect a normalization of serotonin-dopamine interactions leading to clinical efficacy not observed with D2-receptor blockade alone.

Atypical antipsychotics are not without adverse effects, most notably metabolic abnormalities including regulation of glucose and lipid levels and weight gain. For example, long-term clozapine or olazapine treatment increases body weight gain, which becomes a risk factor for diabetes and cardiovascular disease. Schizophrenics treated with clozapine also are at risk of developing agranulocytosis, a potentially lethal blood disorder involving the loss of white blood cells and a compromised immune system.

In conjunction with antipsychotic medication, psychosocial therapy can facilitate the management of schizophrenia. Psychosocial relationships assist the individual in developing coping strategies and in identifying stressors and relapse symptoms. Cognitive-behavioral therapy (CBT), a talking therapy that initiates cognitive and behavioral change based on an individualized reappraisal of the person’s faulty beliefs, is effective in treating schizophrenics with stabilized antipsychotic medications.15 An important benefit of psychosocial and family support is the encouragement of compliance with antipsychotic medication that requires a period before the emergence of clinical efficacy.

Mood Disorders: Depression and Bipolar Disorder

Mood refers to a sustained emotional state as opposed to brief emotional feelings, which are termed affective states. Healthy individuals are normally capable of experiencing a variety of affective states including euphoria, joy, surprise, fear, sadness, anxiety, and depression. When emotional states, such as sadness, become chronic and uncontrollable, individuals may be diagnosed with a mood disorder called depression. The two major classifications of mood disorder are: (1) unipolar or major depressive disorder, also known as major depression or clinical depression, which consists of episodes of depression; and (2) bipolar disorder, which is further classified into bipolar I and bipolar II disorders. Bipolar I disorder features manic episodes and at least one major depressive episode and bipolar II disorder is characterized by recurrent major depressive episodes with one or more hypomanic (milder than manic) episodes. Box 19-3 presents the major criteria of depression and bipolar disorder according to the American Psychiatric Association’s DSM-IV-TR.13

BOX 19-3   MAJOR SYMPTOMS OF DEPRESSION AND MANIA

Symptoms of Depression∗

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Sep 9, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Neurobiology of Schizophrenia, Mood Disorders, and Anxiety Disorders

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