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ScienceWeek
MEDICAL BIOLOGY: SCHIZOPHRENIA
The following points are made by Robert Freedman (New Engl. J. Med. 2003 349:1738):
1) Schizophrenia is a chronic, debilitating psychotic mental disorder that affects approximately 1 percent of people. A new generation of medications and recent developments in neuropathology, brain imaging, and molecular genetics have led to a greater understanding of the pathophysiology of schizophrenia and to improved treatment. Nonetheless, it remains an enigmatic illness that places a substantial burden on patients, their families, and society.
2) Schizophrenia has varied and ominous symptoms that generally begin in late adolescence or early adulthood and usually continue throughout life.(1) Most patients have a history of behavioral dysfunction -- primarily social and learning difficulties.(2) Diagnostic features of schizophrenia include auditory hallucinations (generally voices that converse with or about the patient) and delusions (often the paranoid belief that external forces are conspiring against the patient). Patients may have some insight that the voices are internal thoughts and that the delusions cannot possibly be true, but these phenomena remain persistent and troubling.
3) In addition to these overt psychotic (or "positive") symptoms, various deficits (or "negative" symptoms) occur, including an inability to pay attention, the loss of a sense of pleasure, the loss of will or drive, disorganization or impoverishment of thoughts and speech, flattening of affect, and social withdrawal. Positive and negative symptoms vary in intensity over time; patients may have predominantly one type at any particular time. Cognitive dysfunction, including a decreased ability to focus attention and deficiencies in short-term verbal and nonverbal memory, is also a core feature of the illness, which predicts vocational and social disabilities for patients.(3) Criminal behavior per se is not a concomitant of schizophrenia, but patients may commit violent acts in response to hallucinations or delusions or because of frustration in social interactions.(4) The lifetime prevalence of suicide is about 10 percent among patients with schizophrenia.(5)
4) Schizophrenia is a uniquely human illness. Although none of us know to what extent our perception of the world is merely a construct of our own minds, persons with schizophrenia are confronted with this existential dilemma throughout most of their lives. Their struggle to decide if the voices or suspicions they experience are real is part of their inability to discern relevant information from their surroundings. Indeed, the hallucinations and delusions, which initially seem mysterious, can often be traced to misprocessed information. Persons with schizophrenia are hypervigilant, responding to extraneous stimuli as well as to internal thoughts that most other persons can ignore. In addition to this deficit in sensory gating, patients have difficulty processing information in short-term memory to assess its significance. For example, a college student who is becoming psychotic may report that he hears strange people who are hiding in the walls, whispering about his appearance. This symptom demonstrates his inability to filter out the noise of the dormitory and his lack of the skills necessary to learn the identity of the other students around him -- both of which heighten his insecurity about himself.
5) The conceptualization by biomedical researchers of schizophrenia as the manifestation of deficits in elementary brain processes was facilitated by observations of certain drug effects. Many drugs that cause psychoses resembling schizophrenia (e.g., stimulants) increase dopaminergic neurotransmission. All currently available antipsychotic drugs that alleviate symptoms of schizophrenia decrease dopaminergic neurotransmission. Decreased dopaminergic neurotransmission, in turn, diminishes the distractibility that characterizes patients with schizophrenia and improves their perceptual abilities. Patients treated with such drugs concomitantly experience a decrease in the intensity of their hallucinations and delusions, and the patients are therefore better able to manage their behavior.
6) The dopamine theory of schizophrenia has several flaws, however. First, blockade of dopaminergic neurotransmission does not fully alleviate symptoms of schizophrenia. Second, although positive symptoms of schizophrenia are diminished when dopaminergic neurotransmission is decreased by antipsychotic medications, levels of dopamine metabolites and receptors, when measured in patients before and after treatment, are still generally within the wide range of normal values. Third, the role of dopamine in the brain is more complex than that of acting as a simple switch for psychotic symptoms. During acute psychotic episodes, many persons with schizophrenia appear to have increased occupancy of receptors in the basal ganglia by dopamine, as measured by the displacement of radioactive ligands on single-photon-emission computed tomography. However, decreased dopaminergic activity in the cerebral cortex of the frontal lobe may also be one of the factors contributing to the cognitive impairment commonly found in persons with schizophrenia.
References (abridged):
1. Diagnostic and statistical manual of mental disorders, 4th ed.: DSM-IV. Washington, D.C.: American Psychiatric Association, 1994
2, Erlenmeyer-Kimling L. Early neurobehavioral deficits as phenotypic indicators of the schizophrenia genotype and predictors of later psychosis. Am J Med Genet 2001;105:23-24
3. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996;153:321-330
4. Swanson JW, Holzer CE III, Ganju VK, Jono RT. Violence and psychiatric disorder in the community. Hosp. Comm. Psych. 1990;41:761-770.
5. Siris SG. Suicide and schizophrenia. J Psychopharmacol 2001;15:127-135
New Engl. J. Med. http://www.nejm.org
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ON THE ETIOLOGY AND TREATMENT OF SCHIZOPHRENIA
The diagnoses of various behavioral disorders are for the most part made in the absence of defined etiology, and because of this there is a necessary focus on symptoms rather than causes, and the diagnostic categories are consequently often ambiguous and labile. Schizophrenia is a serious mental disease (or complex of mental diseases) that occurs worldwide with a prevalence ranging from 0.2% to 1%. Its chief characteristic is a chronic impairment of function involving disturbances of thought, perception, feelings, and behavior, particularly the appearance of the classical psychotic symptoms of delusions, hallucinations, and logic dysfunction. A major worldwide mental health problem, schizophrenia has been the focus of an enormous number of research studies during the past century, and nearly every possible etiology has been proposed to explain its pathogenesis, including genetic mutations and viruses.
The following points are made by A. Sawa and S.H. Snyder (Science 2002 296:692):
1) Most psychiatric disorders are classified as complex in origin -- i.e., they cannot be easily explained by a single genetic or environmental component. One of the most debilitating of these disorders is schizophrenia, which affects approximately 1% of the population. Once the symptoms of schizophrenia occur (usually in young adulthood), they persist for the entire lifetime of the patient and are almost totally disabling.
2) How do we define schizophrenia? In the absence of a known molecular abnormality, the diagnosis is based on the simultaneous presentation of two types of symptoms that reflect a psychotic disturbance: "positive" symptoms that include delusions, hallucinations, and bizarre thoughts, and negative symptoms that include social withdrawal with affective flattening, poor motivation, and apathy. Patients with affective disorders such as bipolar disorder may exhibit a subset of the psychotic symptoms associated with schizophrenia, such as hallucinations, but these disorders generally have a distinct constellation of symptoms and familial incidence (1).
3) Efforts to identify the underlying disturbances in schizophrenia are currently focused on three general lines of inquiry: (i) examination of the mechanism of action of the drugs that alleviate the symptoms of schizophrenia, (ii) examination of neuroanatomical abnormalities in the brains of schizophrenia patients, and (iii) examination of candidate genes that confer susceptibility to schizophrenia.
4) There was no truly efficacious treatment for schizophrenia until the early 1950s, when the beneficial effects of chlorpromazine were discovered. This drug revolutionized patient treatment: Besides calming down hyperactive patients, it ameliorated the positive symptoms of the disorder, enabling patients to leave mental hospitals and function moderately well in society at large. Chlorpromazine and its successor drugs were designated "neuroleptics," from the Greek term meaning "to clasp the neuron." This designation was based on the pioneering work of Jean Delay and Pierre Deniker, who observed that the effective dose of chlorpromazine varied widely among patients. Beneficial responses generally occurred at doses that elicited neurologic side effects resembling Parkinson's disease. Parkinson's disease is associated with degeneration of dopamine neurons that project to the caudate putamen of the brain. Through studies of dopamine turnover and direct measurements of dopamine receptors, it was established that neuroleptics block the D2 subtype of dopamine receptor (2,3)
5) Blockade of receptors in the caudate putamen was found to cause the neurologic side effects of the neuroleptics, and blockade of receptors in limbic areas such as the nucleus accumbens and prefrontal cerebral cortex of the brain -- which regulate emotional behavior -- was found to account for the antipsychotic effects of the drugs. Administration of amphetamines, which act by releasing dopamine, was found to exacerbate schizophrenia symptoms. These drug effects led to a "dopamine hypothesis" for the modulation of schizophrenia symptoms, with excess dopamine accentuating and decreased dopamine alleviating the symptoms (2-4). Although the great majority of neuroleptics relieve only the positive symptoms of schizophrenia, clozapine also relieves the negative symptoms and can cause substantial improvement in patients who fail to respond to other neuroleptics (5). The great success of clozapine led to the development of several "atypical" neuroleptics whose pharmacologic profile resembled that of clozapine.
References (abridged):
1. N. C. Andreasen, Neuron 6, 697 (1996)
2. I. Creese, D. R. Burt, S. H. Snyder, Science 192, 481 (1976)
3. P. Seeman, T. Lee, M. Chau-Wong, K. Wong, Nature 261, 717 (1976)
4. A. Carlson, Neuropsychopharmacology 1, 179 (1988)
5. H. Y. Meltzer, in Psychopharmacology: The Fourth Generation of Progress, F. E. Bloom, D. J. Kupfer, Eds. (Raven, New York, 1995), pp. 1277-1286
Science http://www.sciencemag.org
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ACCELERATED GRAY MATTER LOSS IN EARLY-ONSET SCHIZOPHRENIA
The following points are made by P.M. Thompson et al (Proc. Nat. Acad. Sci. 2001 98:11650):
1) Little is known about the profile of brain change in adolescence and its modulation in diseases with adolescent onset. Schizophrenia, for example, has typical onset in late adolescence or early adulthood, and cases occurring in childhood or early adolescence present unique opportunities to study disease development during adolescence. Childhood-onset schizophrenia is a severe form of the disorder that appears to be clinically and neurobiologically continuous with the later onset illness. The causes of schizophrenia are not known, but it is increasingly considered a neurodevelopmental disorder. Both early (prenatal) and later abnormalities of brain development have been proposed, but neither the anatomical pattern nor the timing of these developmental events has been established.
2) The authors report that with the use of brain mapping algorithms, they detected striking anatomical profiles of accelerated gray matter loss in very early-onset schizophrenia. Surprisingly, deficits moved in a dynamic pattern, enveloping increasing amounts of cortex throughout adolescence. The earliest deficits were found in parietal brain regions supporting visuospatial and associative thinking. In temporal regions, gray matter loss was completely absent early in the disease but became pervasive later. The authors suggest their results reveal a shifting pattern of tissue loss in schizophrenia, a changing profile that implicates both genetic and non-genetic patterns of deficits.
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SCHIZOPHRENIA GENETICS RESEARCH
The following points are made by Sanders and Gejman (J. Am. Med. Assoc. 2001 285:2831):
1) Schizophrenia is a devastating disorder affecting 1 percent of the population worldwide, and the elucidation of the biology of schizophrenia will constitute a development of great medical and historic importance. The study of familial schizophrenia was instrumental in opening the field of psychiatry to genetic inquiry, and together with twin and adoption studies helped forge the field of psychiatric genetics. Over the past century, studies have consistently demonstrated that both genetic and non-genetic factors play a significant role in the etiology of schizophrenia.
2) Currently, a large number of molecular and genomic database tools, an understanding of complex genetics, and a convergence of results from genetic mapping of several chromosomal regions all contribute to optimism that genes involved in the pathogenesis of schizophrenia will be characterized in the near future.
3) Identification of susceptibility genes, their products, and interacting proteins will likely illuminate pathways to illness, provide more specific pharmacological targets, and lead to improved understanding of environmental contributions to susceptibility. The hope is that this knowledge will further advance clinical progress in treatment and even prevention of schizophrenia.
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ON RETROVIRUSES AND THE PATHOGENESIS OF SCHIZOPHRENIA
The diagnoses of various behavioral disorders are for the most part made in the absence of defined etiology, and because of this there is a necessary focus on symptoms rather than causes, and the diagnostic categories are consequently often ambiguous and labile. Schizophrenia is a serious mental disease (or complex of mental diseases) that occurs worldwide with a prevalence ranging from 0.2% to 1%. Its chief characteristic is a chronic impairment of function involving disturbances of thought, perception, feelings, and behavior, particularly the appearance of the classical psychotic symptoms of delusions, hallucinations, and logic dysfunction.
A major worldwide mental health problem, schizophrenia has been the focus of an enormous number of research studies during the past century, and nearly every possible etiology has been proposed to explain its pathogenesis. The idea that viruses may be involved in the etiology of schizophrenia is not new, but as molecular biology continues to advance in techniques and insights, evidence and considerations of a virus involvement in schizophrenia continue to recur.
When viruses are categorized in terms of their genomes, there are two general types: a) viruses with a DNA genome (DNA viruses), and b) viruses with an RNA genome (RNA viruses). RNA viruses are unique: only in these viruses do we find genomes consisting of RNA; all other biological entities, DNA viruses, bacteria, plant cells, animal cells, etc., contain DNA genomes.
There are more than 2500 groups of different viruses now recognized and at least partially characterized. In each case, for both DNA and RNA viruses, once it enters the host cell, the general challenge for the virus is the same: directly or indirectly, the viral genome must bring about the production of the *messenger RNAs needed by the host ribosomes to produce the specific proteins necessary for replication of the complete virus.
With DNA viruses, the DNA genome acts as the template for the production of messenger RNA. With RNA viruses, however, the process is more complicated.
In general, with some types of RNA viruses, the RNA genome ("plus-sense"; "positive-strand") can itself act as messenger RNA for host *ribosomes; while other types of RNA viruses, the RNA genome ("minus-sense"; negative-strand) must first produce a complementary RNA, which then acts as messenger RNA for the host ribosomes. The replication process in minus-sense RNA viruses is complex, since host cells do not carry enzymes that can polymerize complementary RNA from an RNA template, and such viruses therefore must carry their own special enzymes ("RNA-dependent transcriptases") to achieve this synthesis.
A third and special type of RNA virus is the so-called "retrovirus", of which there are many versions. Retroviruses are single-stranded RNA viruses that have an enzyme called reverse transcriptase, and with this enzyme the viral RNA is used as a template to produce viral DNA from host-cellular material. This DNA is then incorporated into the host cell's genome, where it codes for the production of messenger RNA and the ultimate synthesis of viral components. The HIV virus, for example, is a retrovirus.
Concerning retroviruses, if the incorporation of the viral DNA into the host cell DNA takes place in *germ-line cells (oocytes) or early embryos, then the retroviral genes become "endogenous" -- they become a permanent part of the organismic genome and are reproduced from generation to generation. It is believed by some researchers that all vertebrates, for example, have endogenous retroviruses that are the "footprints" of ancient retroviral infections. For the most part, the significance of endogenous retroviruses is unclear, but there is some evidence suggesting they may contribute to the development of diseases in several animal species and possibly also in humans.
It is important to emphasize that the nomenclature here is not rigorous, since an endogenous retrovirus is not an actual virus, but one or more pieces (complete or incomplete genes) of a retroviral genome embedded in a host genome. These endogenous retroviral genes may be eternally dormant, sporadically activated and repressed, or always operational. A disease related to the activation of an endogenous retrovirus is therefore not an "infectious" disease in the classical sense, although the original introduction into the host germ-line of the retroviral genetic material may indeed have involved an infection. As a further complication, there is evidence that in some diseases interactions of endogenous retroviral genes and infectious (exogenous) retroviral genes may occur.
David A. Lewis (Proc. Nat. Acad. Sci. 2001 98:4293) presents a commentary on some recent work (H. Karlsson et al: Proc. Natl. Acad. Sci. US 2001 98:4634) connecting retroviruses to schizophrenia, the author (Lewis) making the following points:
1) The author (Lewis) points out that the contribution of genetic factors to the risk of developing schizophrenia has been demonstrated in family, twin, and adoption studies. In contrast to the 1 percent lifetime incidence of schizophrenia in the general population, the incidence of schizophrenia in the relatives of affected individuals is approximately 2 percent in 3rd-degree relatives, 2 to 6 percent in 2nd-degree relatives, and 6 to 17 percent in 1st-degree relatives. When one member of a twin pair has the illness, the risk of schizophrenia in the other twin is approximately 17 percent for fraternal twins and approaches 50 percent for identical twins. Furthermore, in adoption studies, the risk of schizophrenia is related to the presence of the illness in the biological but not in the adoptive parents. Although regions on a number of chromosomes have been implicated as sites of potential susceptibility genes, the specific genes (or combination of genes) that confer risk for schizophrenia have not yet been identified.
2) The author (Lewis) points out that a number of environmental factors, usually factors occurring early in life, also seem to increase the risk for schizophrenia. For example, severe maternal malnutrition during the first trimester or maternal influenza during the second trimester of pregnancy are apparently associated with a doubling of the relative risk of schizophrenia, and *perinatal brain damage or maternal *preeclampsia may increase the risk by 7- to 9-fold.
3) The author (Lewis) points out that retroviruses have been considered possible etiological agents in schizophrenia for some time, at least since 1984, because retroviruses could apparently explain some of the enigmatic aspects of the illness. For example, the differential activation and reintegration of endogenous retroviruses during early development may lead to altered brain function later in life, providing a potential link between risk factors identified in utero and perinatal risk factors on the one hand, and the onset of clinical schizophrenia during the late second and third decades of life on the other hand. In addition, an endogenous retroviral etiology could provide explanation for the continued prevalence of schizophrenia despite the reduced fecundity associated with the illness, and for the relatively uniform incidence of schizophrenia throughout the world.
4) Although evidence of an association between retroviruses and schizophrenia has not been available, Karlsson et al (2001) now report the identification of nucleotide sequences homologous to retroviral "pol" (polymerase) genes in the cerebrospinal fluid of 28.6 percent of subjects with schizophrenia of recent onset (N = 35), and in 5 percent of subjects with chronic schizophrenia (N = 20). In contrast, such retroviral sequences were not found in any individual with non-inflammatory neurological illness (N = 22) or in normal control subjects (N = 30).
5) The author (Lewis) states: "Although the observations of the study of Karlsson et al are interesting, their potential significance for our understanding of the etiopathogenesis of schizophrenia rests on the replication of these findings in other cohorts of subjects. Independent replication is an axiom in all areas of medicine, but it is particularly important in studies of schizophrenia, where the history of the field includes many examples of exciting findings that subsequently either failed to be confirmed in other cohorts of subjects with the disorder or proved to lack specificity to the illness."
Proc. Nat. Acad. Sci. http://www.pnas.org
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Notes:
messenger RNA: (mRNA) The ribonucleic acid molecule transcribed from DNA that carries the coded information specifying the sequence of amino acids in a protein.
ribosomes: A ribosome (not to be confused with riboZYME) is a small particle, a complex of various ribonucleic acid component subunits and proteins that functions as the site of protein synthesis. In general, ribosomes read the messenger RNA template to produce specific polypeptide sequences by polymerizing amino acids.
germ-line cells: In general, "germ-line" cells are reproductive cells, or any cells giving rise to reproductive cells such as oocytes (egg cells) or spermatocytes (sperm cells). All other cells are called "somatic cells". Mutations (or introduction of foreign genes) in germ-line cells are carried from the parent generation to the offspring generation, while mutations in somatic cells are not transferred to the next generation.
perinatal: Refers to the time-frame before, during, and immediately after birth.
preeclampsia: In general, the development of hypertension during pregnancy.
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