Posts Tagged ‘dopamine’

Brain Biochemistry and Brain Disorders

Brain Biochemistry and Brain Disorders

Philip G. Strange

Oxford, New York, Tokyo: Oxford University Press, 342 pp, 1992

I read and re-read this book several times — it is easy to read. On my first survey, I noted numerous excusable and many unforgiveable omissions (for example, only a brief mention of the dopamine D-3 receptors on page 239 and not even a word on the D-4 receptors that had been described by then). But I came to the realization that one cannot be an excessively critical judge. Any book of this size that comprises biochemistry, structure, research methodology and a wide range of pathologies of the brain can only be somewhat of a smorgasbord. There is nothing wrong with a neuroscience buffet, however, provided it is nutritious and served with style. And this must be recognized about this book, including the extremley well chosen cover illustration of Edward Munch’s “The Dance of Life”.

The first seven chapters provide sufficient amounts of basic information and neuroscience facts that are required for the grasp of the second part of the book, which focuses on six different disorders.

The author discusses artfully and, for purposes of psychiatric residents and practitioners, sufficiently the cellular aspects of the brain tissue, the chemical and electrical signalling, the neurotransmitter and receptor systems as well as some research technologies, although the description of the restriction-fragment length polymorphism (RFLP) could have been made clearer.

The author chose six diverse pathologies that are connected along the mesostriatal, mesolimbic and mesofrontal tracts. The totality of these six pathologies, and some others mentioned en passant, provides a base not only for the understanding of these illnesses but also for the comprehension of these brain parts. The discussion of Parkinson’s disease, including the MPTP, genetic aspects, rationale of tissue transplant, etc. is fairly complete, as is the chapter on Huntington’s disease and Alzheimer’s disease. The chapter on schizophrenia, as a brain disease, competently deals with the subject, although the contribution of Weinberger (mentioned briefly on page 256) could have been more extensive. The chapter on depression, although thorough and interesting, is too speculative in relation to the septohippocampal system. The last chapter, on anxiety, is probably the weakest.

The illustrations, including the CT scans, are of good quality. There are aspects of the quotations of original contributors where one could disagree with the author. Considering that books rapidly become outdated, this book has a certain philosophy and appeal — not to mention a modest price — that will assure a measure of longevity.

Novel Antipsychotic Drugs

Novel Antipsychotic Drugs

H. Y. Meltzer

New York, NY: Raven Press, 288 pp., 1992

Traditionally, the development of antipsychotic drugs has entailed looking for agents that produced catalepsy and blocked amphetamine-induced stereotypic movements in rodents. This produced a generation of drugs that were therapeutically antipsychotic but produced unacceptably high rates of neurological adverse effects. The atypical antipsychotics are a new generation of drugs that, through novel pharmacological properties, promise a lower rate of extrapyramidal side-effects and, in some cases, therapeutic superiority over the typical agents.

This volume, edited by psychiatrist and psychopharmacologist Herbert Meltzer, represents the proceedings of a symposium held in late 1990 which detailed the atypical agents being developed. For the most part, the volume is a status report on agents in various stages of development. These include clozapine and the related drug amperozide, the substituted benzamides remoxipride and raclopride, a number of dopamine agonists; drugs that mediate glutamine, “sigma” receptor antagonists, and serotonin antagonists such as respiridone and ondansetron. There are also three conceptual articles: Meltzer’s review of research into the efficacy and favorable extrapyramidal side-effect profile of clozapine, Philip Seeman’s review of receptor selectivities, which unfortunately predates the work on the D4 receptor, and Daniel Casey’s review of classification and directions for future research.

Although some of the articles appear to have been updated with material and references more recent than 1990, most of the book suffers from being a step out of date. Despite this, I found the volume more helpful than I anticipated, particularly the articles by Casey and Meltzer. This volume may be most significant as a historical work, since it heralds a welcome turning point in the pharmacotherapy of schizophrenia. For the first time, there is the promise of agents that offer novel therapeutic profiles, without the disabling neurologic effects we and our patients have had to learn to live with. Not only do these agents offer optimism, they also lead us to new models of pathophysiology for understanding schizophrenia and related disorders.

Schizophrenia Research, Advances in Neuropsychiatry and Psychopharmacology

Schizophrenia Research, Advances in Neuropsychiatry and Psychopharmacology Volume 1

Carol A. Tamminga, S. Charles Schulz

New York, NY: Raven Press, 391 pp., 1991

Because it is a human trait to be beguiled by the mysterious, it is fitting that the first volume in this new neuroscience series be devoted to schizophrenia, a disease which the editors characterize in the Preface as “. . . clinical. . . (with) no verified biologic criteria . . . whose basic pathophysiology remains unknown”. This ambitious overview is timely because emerging techniques in brain imaging, molecular biology, and neurochemistry are energizing the field and creating new knowledge at so fast a pace that psychiatrists cannot easily digest it or incorporate it into their clinical understanding and practice.

What is Schizophrenia?

Several chapters are devoted to defining the boundaries of the schizophrenia concept. For reasons that are not self-evident, these chapters come in Part IV, but should be read first.

One approach to specifying the nosologic border between schizophrenia and non-schizophrenia is to study schizotypal personality disorder. The derivation of this particular cluster of personality traits is instructive: in the course of the Danish adoptive studies of Kety et al, certain individuals, both subjects and blood relatives of subjects, were found to possess schizophrenia-like traits to a degree “affected” or “not affected” category. These traits were catalogued and refined by Spitzer et al during the assembly of DSM III and now constitute the Axis II category called “schizotypal.” Therefore, as noted by Larry Siever, schizotypal personality disorder is the first to be empirically defined, at least in part, on the basis of a genetic relationship to schizophrenia. It is thus not surprising that a close relationship exists between schizophrenia and schizotypal personality disorder with respect to family segregation patterns, biologic markers, and course of illness.

Family History of Schizotypal Disorder

The consensus among several family studies using DSM III criteria is that schizotypal personality disorder is transmitted familially as one of several schizophrenia-related disorders which include chronic schizophrenia, chronic schizoaffective disorder, and unspecified psychosis. Family segregation patterns support such a genetically determined schizophrenia spectrum concept.

Biologic Markers of Schizotypal Disorder

Currently, one of the best biological markers for schizophrenia is impairment of smooth-pursuit eye movements (SPEM). This has been reported in 52% to 86% of schizophrenia subjects, as compared to 6% to 8% of “normal” subjects and 21 % of psychiatric patients suffering from non-psychotic disorders. These findings have now been consistently replicated in different laboratories and are convincing in that they bear no relations to neuroleptic medication and are observed with equal frequency when acute schizophrenic symptoms are in remission. SPEM are also abnormal in 30% to 50% of affective disorder patients, particularly those who have been psychotic. Other data suggest a relationship with psychosis severity. Philip Holzman, SPEM’s discoverer, suggests that impairment of SPEM underlies a disturbance in attention and information processing which may reflect a dysfunction of the frontal cortex. He and his colleagues have twin and family data that establishes SPEM impairment as heritable, sometimes phenotypically expressed with schizophrenia, sometimes expressed alone or instead of schizophrenia.

Importantly for the schizotypal concept, a relationship between SPEM impairment and schizotypal features has been reported both in nonclinical populations and in clinically identified schizotypal patients. The schizotypal patients in those studies evidenced eye-tracking deficits comparable in magnitude to these of chronic schizophrenic controls.

Increased ventricle to brain ratio (VBR) is a second well-replicated biologic marker, reported in this volume by Cazzullo et al. In their hands, VBR was increased over controls not only in a schizophrenia sample but also in schizophreniform disorder and in schizotypal disorder (but not in paranoid disorder). Taken together, biologic marker studies, which include psychological, structural, and neurochemical measures, tend to support a schizophrenia spectrum concept which incorporates within it schizotypal personality disorder.

Course of Illness in Schizotypal Disorder

In the Chestnut Lodge long-term follow-up study, reported here by Tom McGlashan, the global function outcome of the schizotypal sample consistently emerged as intermediate between Axis I schizophrenia and Axis II borderline groups. The sex differences found in schizophrenia (women faring better than men) were “echoed, to a muted degree” by the schizotypal group.

It seems clear from this overview that schizotypal personality disorder constitutes an integral part of what is meant by “Schizophrenia”. The status of other possibly related disorders is only cursorily discussed. Psychotic mood disorders are not seriously considered for candidacy within the spectrum. McGlashan gives definite membership status to schizophrenia, delusional disorder, and schizotypal personality. According to him, schizophreniform disorder, schizoaffective disorder, paranoid personality disorder, and schizoid personality disorder probably qualify. He accords possible status to a potpourri of other disorders, including affective disorder with mood-incongruent delusions and certain types of brief reactive psychoses.

What Lessons Do Molecular Biology Teach about Schizophrenia?

Tentative answers to this question are offered in Parts 1 and 2 of the book which are somewhat arbitrarily divided into biochemistry, neurobiology, and physiology — distinctions which seem outmoded. Two of the most interesting chapters are on molecular genetics — one on linkage studies, written by Jim Kennedy and Luis Giuffra, and the other on gene expression, by Edward Ginns.

The Kennedy/Giuffra chapter summarizes the family linkage studies initiated to date, explains the difference between genome scans and attempted linkage to candidate regions or genes, and suggests possible sources of error in these techniques. Correct diagnosis, especially of a person in the older generation of the family, is a crucial factor. False positives are especially problematic. The authors remind us that the candidate gene strategy works only if good guesses exist to explain the biochemical manifestations of a disease. In the absence of informed serendipity, virtually any gene that influences brain development or function could be considered as a candidate schizophrenia gene. There are a possible 50,000 to 70,000 such genes in the human genome! The authors further suggest that the implication of a single gene in schizophrenia is unlikely because, in such an instance, the monozygotic to dizygotic twin ratio (MZ/DZ) of concordance would have to be 2:1 for an autosomal dominant disorder and the expected “decay” in the incidence of the disease from first- to second- to third-degree relatives would have to be close to 1:2. These ratios hold true in principle, regardless of “penetrance” or variable expression of a genotype. They also hold true regardless of the presence of “phenocopies” or non-genetic variants of the disease. In schizophrenia, family and twin studies results show an MZ/DZ ratio greater than 2:1 and a rate of decay with each degree of relationship far faster than 1:2. Mathematical modelling of these ratios is consistent with a two to three gene model, with genes on different chromosomes interacting to produce the disease through a process called “epistasis”.

Another possibility is what Matthysse, Holzman and Lange refer to as the single gene latent trait model. This involves the SPEM impairment described earlier. The idea is that a single gene is expressed either as schizophrenia or as impaired eye movements or both. The MZ/DZ ratio for impaired SPEM among twins discordant for schizophrenia is consistent with a single major locus of transmission for SPEM; 77% of the MZ twins versus 39% of the DZ twins are concordant for eye movement impairment.

The chapter on gene expression explains that clinical heterogeneity such as is found in schizophrenia can be the consequence of different mutations either in the same gene or indifferent genes, each mutation affecting the biological activity and influencing the processing, cellular compartmentalization, and/or stability of a protein. A mutant gene can act on its own or it can be influenced by modifier genes. Most mutations appear to be single base substitutions which may or may not result in amino acid substitutions (because the same amino acid can derive from more than one combination of base triplets). Many of these substitutions result in silent polymorphism. Rarer events such as frameshift mutations or deletions are more likely to affect the actual activity of a protein. This, in turn, may result in receptor or membrane defects. Abnormal cellular structure or function of several proteins can be disturbed by a mutation in a single amino acid chain. From examples of other diseases, it appears as if different allelic mutations in the same gene can lead to different functional consequences and a clinically heterogeneous clinical picture. In other words, clinical heterogeneity does not necessarily imply more than one defective gene, but it may suggest different mutations within the same gene.

What is the Role of Neurodevelopment in Schizophrenia?

In a chapter on the neuroplasticity of dopamine neurons, Fuxe et al remind us that epigenetic influences may trigger the onset of schizophrenia in genetically predisposed individuals. Animal experiments show that a developmental lesion leads not only to an overall decrease of the brain mass in the area of the lesion but also to substantial alterations in the amount and distribution of selective transmitter-identified nerve cell populations. Thus, a variety of prenatal influences in humans could lead to the existence of discrete alterations in the neuronal circuitry of specific brain areas which, in turn, would explain the observed multiplicity of schizophrenia symptoms.

Tamminga et al articulate a similar hypothesis, that schizophrenia may not be a single disease but, rather, a collection of symptoms with “multiple etiologies and multiple pathophysiologies.” They postulate “a nidus of dysfunctions” located in the limbic system (eg. hippocampus, amygdala, or cingulate gyrus). The limbic system (particularly the hippocampus) is known to be highly vulnerable to hypoxia and developmental accident. A perinatal insult to this region could permanently alter its function, leading to psychotic symptoms and clinical schizophrenia.

The authors represented in this volume do not address the intriguing question of whether genes are responsible for the susceptibility to insult (hypoxia, for example) in specific brain regions or at specific neurodevelopmental periods. Or whether, in contrast, protective factors which normally modify genetic instruction are lost as a result of injury. Or whether genetic predisposition and environmental stress, pre- or post-natally, act in concert to initiate a process which leads to schizophrenia spectrum disease.

How do Cognitive Functions Elucidate Schizophrenia?

Gur et al address the important issue of appropriate control populations for cognitive studies in schizophrenia. Matching patients and controls for IQ, educational level or socioeconomic status leads to error since the disease itself is responsible for the “downward drift” in these parameters. Further methodological difficulties include patient sampling, comparability of psychiatric diagnosis, inadequate neurological evaluation, and failure to control for past and concurrent treatment. The Gur et al chapter provides the reader with a neuropsychological battery to assess specific cognitive functions (p. 159) and recommends integration of neuropsychological and imaging techniques in order to test hypotheses about regional brain dysfunction. This field is still in its infancy and preliminary findings need to be replicated.

What Can be Learned from Treatment Response?

Breier et al review studies that demonstrate the beneficial effects of stress reduction in schizophrenia. Whether behavioral or pharmacologic techniques of reducing anxiety are applied, positive results accrue, suggesting abnormal stress mediation as a core schizophrenia deficit. These authors postulate a functional impairment in 4GABA-dopamine indirection during stress as an explanation for individual episodes of acute psychosis. Test et al emphasize that long term comprehensive treatment (which can be conceptualized as stress reduction) needs to be continued indefinitely. Patients which schizophrenia cannot generalize from prior lessons learned in this area, which supports the hypothesis of a fundamental impairment.

Specific treatment aimed at other hypothesized schizophrenia deficits (higher-level conceptualization, social appropriateness, abstraction, initiative, judgement) also seem to produce worthwhile results as described in an interesting chapter by Trzepacz and Starratt. These experimental programs need to be replicated. The lesson learned from neuroleptic medication is that response to treatment can lead backwards to a better understanding of disease mechanisms.

“Atypical” neuroleptics, such as clozapine, can be invaluable in clarifying which neurotransmitters, other than dopamine, are involved in the production and resolution of schizophrenia symptoms. Several chapters are devoted to this issue. As best explained in the Lieberman et al chapter, clozapine has been shown to have superior antipsychotic efficacy in treatment-refractory patients; it may have therapeutic effects on negative symptoms; it appears to diminish impairment in social and vocational functions; it does not cause acute extrapyramidal symptoms; it has a reduced capacity to produce tardive dyskinesia; and, it may even have therapeutic effects against preexisting tardive dyskinesia. Not only does this make it an attractive therapeutic agent, but it also opens a new area of enquiry into antipsychotic response, extrapyramidal effects, and tardive dyskinesia mechanisms.

An excellent chapter on neuroleptic noncompliance by Weiden et al is, again, not only therapeutically useful but, in addition, addresses theoretical issues on the importance of illness-denial and health beliefs in schizophrenia patients.

Several chapters mention, in passing, the intriguing role of sex differences in schizophrenia. For instances, does clozapine act on the dopamine system? It does not alter prolactin levels, it does not increase CSF homovanillic acid, it does not increase extrapyramidal symptoms, except in females (Lieberman et al). Test et al mention gender differences in their long-term follow-up (to be described, they assure the reader, in a separate paper). Berner presents nosologic sex differences in a special Figure (p. 223). Sex differences are not mentioned in the Cazzullo et al chapter on cerebral structural abnormalities in schizophrenia, but an expanding literature exists on this subject. A large literature also exists on personality disorders and sex. It is alluded to in the McGlashan chapter. He further refers to premorbid and outcome differences in schizophrenia between men and women. The Gur et al chapter does not mention sex, although Rachel Gur has published important work on sex differences in male and female schizophrenics. Breier et al point out that, for reasons that are not understood, male schizophrenics are more susceptible than females to the psychotogenic effects of familial criticism. The autoimmunity chapter (by MaAllister et al) does not mention sex, although immune functions are well known to be distinct in the two sexes. Neuroplasticity, prenatal brain development, genetic mechanisms of DNA recombination , all profoundly affected by sex, are justifiably emphasized in this volume, without exploring the possibility that these basic mechanisms are influencing sex differences in the clinical expression of schizophrenic illness. This is, of course, a personal bias of the reviewer. Other reviewers would have wanted to see other important areas highlighted.

Altogether, this volume consists of a few excellent chapters interspersed among others which are overly technical for most psychiatrists. The divisions into parts are somewhat arbitrary and the conceptual linkages have to be supplied by the reader. Nonetheless, this is a solid reference book for 1991 in a field which is rapidly changing.