psychologist-student


+ biopsychology of stress- part۳

This text is a summary of 17th part of the book "biopsychology" writen by John P. J. Pinel and translated into persian (Farsi) By S.Hani Mosavi(myself), student of psychology courses in Imam Qomeini institute for education and research as a work of phsiologic psychology class by M.K Khoda Panahi Ph.D

Lecture 17c   

THE BIOPSYCHOLOGY OF SCHIZOPHRENIA, AFFECTIVE DISORDERS and ANXIETY

Outline
     1.     Schizophrenia
          a) The First Antischizophrenic Drugs
          b) Dopamine Theory of Schizophrenia
          c)  The Dopamine Theory: Unanswered Questions
     2.     Affective Disorders
          a) Symptoms and Etiology
          b) Antidepressant Drugs
          c)      Monoamine Theory of Depression
          d) Hypothalamic-Pituitary-Adrenal Theory of Depression
          e) Diathesis-Stress Model of Depression
          f) Neural Mechanisms of Depression: Unanswered Questions
     3.     Anxiety Disorders

 Lecture Notes

1.     Schizophrenia

-     schizophrenia literally means a splitting of psychic function (“the shattered mind”); it is characterized by a complex and diverse set of symptoms that often overlap with other forms of mental illness and may change with time

-     individuals with any of the following symptoms are diagnosed as schizophrenic: bizarre delusions, hallucinations, inappropriate affect, incoherent thought, or odd behavior (e.g., catatonia)

-     about 1% of the population is schizophrenic; another 2 or 3% display marginal symptoms; the incidence appears to be about the same in all parts of the world

-     a genetic basis for the disease emerged when it was recognized that the concordance rate of schizophrenia in identical twins is about 45%; in fraternal twins it is about 10%

-     in addition to a genetic predisposition, experiences such as prenatal trauma, infection, and stress may all be susceptibility factors

-     clearly schizophrenia is influenced by both genetics and experience

a) The First Antischizophrenic Drugs

-     chlorpromazine was initially developed by a drug company as a new antihistamine; in 1950, a French physician wrote the company because he was trying to find an antihistamine that would prevent the swelling associated with surgery; they sent him a few that were in the developmental stages, including chlorpromazine; he tried them and by chance noticed that chlorpromazine, although not an effective antihistamine, seemed to calm his patients down

-     the French physician recommended that his psychiatrist colleagues try it as a sedative in difficult-to-manage psychiatric cases; in most cases it didn't seem to work; however, one of the psychiatrists administered large doses of chlorpromazine for several weeks, and he noticed a marked improvement in several schizophrenic patients after 3 weeks

-     amazingly the chlorpromazine seemed to calm agitated schizophrenic patients and to activate catatonic ones; therefore the effect seemed specifically antischizophrenic, not just sedative (sleep-inducing)

-     also in the early 1950s, an American psychiatrist became interested in reports that the snake root plant had been used for centuries in India as a cure for various psychiatric disturbances

-     reserpine, the active ingredient of the snakeroot plant, had been isolated so he gave it to some of his schizophrenic patients

-     it proved to be an effective antischizophrenic; however, it is no longer used for treatment of schizophrenia due to its effects of dangerously lowering blood pressure

b)  Dopamine Theory of Schizophrenia

-     given the dissimilarity of the structure of chlorpromazine and reserpine, the similarity of their effects was remarkable; their therapeutic effects did not occur until 2 or 3 weeks after the beginning of therapy, and at that time both drugs started to produce side effects; mild tremors that were most obvious when the patient was inactive, muscular rigidity, and a decrease in voluntary movement

-     you should recognize these symptoms as the symptoms of Parkinson's disease; it seemed that the same neurochemical changes that were the basis of these drugs' antischizophrenic action were inducing the Parkinson's symptoms

-     in 1960, it was discovered that there was a deficiency of dopamine in the brains of Parkinson's patients; thus it seemed that both chlorpromazine and reserpine reduced brain dopamine levels and that this reduction was alleviating the symptoms of schizophrenia; on the basis of these two inferences it was proposed that schizophrenia is associated with excessive activity in dopaminergic systems in the brain

-     two previous findings lent support to this theory:
          (1) reserpine was known to be a dopamine antagonist (it depleted the brain of dopamine and other monoamines by causing them to leak from their vesicles); and
          (2) stimulants, which are agonists of dopamine and other monoamines, trigger schizophrenic episodes in healthy subjects at high doses (e.g., amphetamine psychosis)

-     in 1963, Carlsson and Lindqvist tested the dopamine theory; they expected to show that chlorpromazine, like reserpine, depletes the brain of dopamine--but they didn't; they found instead that chlorpromazine left dopamine levels unchanged, but that it produced a great increase in dopamine metabolites

-     they concluded that, like reserpine, chlorpromazine is a dopamine antagonist, but that it antagonizes dopamine in a different way

-     they suggested that chlorpromazine is a false transmitter at dopamine synapses; that a feedback signal produced by the inactivity of the postsynaptic neurons causes the presynaptic neurons to release more dopamine; that this excess of dopamine is immediately broken down by enzymes in the synapse because all of the binding sites are taken up by chlorpromazine; and that as a result dopamine levels stay about the same but metabolite levels increase

-     a technique developed in the mid 1970s allowed Snyder and his colleagues to measure the degree to which various antischizophrenic drugs bind to dopamine receptors, and to relate this binding affinity to the potency with which each drug alleviated schizophrenic symptoms in human patients

-     the correlation was positive, but there were some disturbing exceptions; for example, haloperidol, one of the most potent antischizophrenic drugs, bound only weakly to dopamine receptors

-     the answer to this puzzle was suggested by the discovery that there are two dopamine receptor subtypes: D1 and D2

-     it turned out that chlorpromazine and all other antischizophrenic drugs of the same chemical class (i.e., the phenothiazines) bind with equal affinity to both D1 and D2 receptors; in contrast, haloperidol and the other butyrophenones bind with highest affinity to D2 receptors

-     this suggested a modification to the dopamine theory of schizophrenia, as schizophrenia could now be viewed as being caused by excess activity at D2 receptors and alleviated by drugs that block activity at D2 receptors (use Digital Image Archive Figure CH17F14.BMP)

c)  The Dopamine Theory of Schizophrenia:  Unanswered Questions

-     there are still five questions about the dopamine theory of schizophrenia that have yet to be resolved:
          1) Why is clozapine, an atypical neuroleptic that binds poorly to D2 receptors, effective against schizophrenia?  The discovery of new dopamine receptors provides the possible answer; clozapine and conventional neuroleptics bind to D1 and D4 receptors and some serotonin receptors; perhaps these are critical receptors in schizophrenia.
          2) Why does it take 2 or 3 weeks for antischizophrenic drugs to take effect when they block receptors almost immediately? It appears that the therapeutic effect of blockade is mediated by neural adaptation (slow developing compensatory changes) to the blockade rather than by the blockade.  One hypothesis is that prolongued neuroleptic treatment eventually produces depolarization blockade in dopamine neurons, and it is this decrease in activity that is related to the drug's therapeutic effect.

          3)  What brain regions are involved in schizophrenia?  Imaging studies have revealed many changes, including small cerebral cortices and large ventricles.  To date, no pathology in brain dopaminergic systems has been reported.

          4) Why do antischizophrenic drugs help only some patients? The current hypothesis is that cases dominated by positive symptoms (hallucinations, delusions, incoherence) are caused by excess dopamine activity and are helped; those cases dominated by negative symptoms (catatonia, blunt affect, poverty of speech) have brain damage and are not helped.

          5)  In what way does stress activate schizophrenic symptoms?  One possibility is that stress activation of dopaminergic projections to the prefrontal cortex areas that may have abnormal development in schizophrenics

 2.     Affective Disorders

a) Symptoms and Etiology

-     all of us have experienced depression; people in whom depression is so severe and so frequent, often without obvious cause, are said to be suffering from the psychiatric disorder of depression; depression can be reactive (triggered by negative experiences) or endogenous, (no apparent external triggers)

-     40% of clinically depressed people also experience periods of mania (talkative, energetic, impulsive, confident, distractible, unrealistic); these people are said to suffer from bipolar affective disorder; the 60% of depressed people who do not experience periods of mania are said to suffer from unipolar affective disorder

-     about 6% of people suffer from unipolar affective disorder and 1% from bipolar affective disorder at some point in their lives

-     the concordance rate of bipolar affective disorder for identical twins is about 60%; for fraternal twins it is about 15%; thus, there is a strong genetic component

-     like schizophrenia, stress plays a major role in the etiology of affective disorders; stress can trigger attacks of depression, and there is some indication that early exposure to stress increases the likelihood of developing depression in adulthood

b.     Antidepressant Drugs

-     the first antidepressant drug, iproniazid, was developed as a treatment for tuberculosis; it had no effect on tuberculosis, but it did leave the patients less depressed about their condition and its clinical usefulness in this regard was soon exploited

-      iproniazid is an MAO inhibitor; MAO inhibitors are no longer used for depression because they block the metabolism of tyramine by the liver; MAO inhibitors in combination with tyramine-rich foods (e.g., cheese, wine, or pickles) cause life-threatening surges in blood pressure; this is called the cheese effect

-     imipramine, the first tricyclic antidepressant, was initially developed as an antischizophrenic drug; when it was tried on a mixed group of psychiatric patients, it was found to be ineffective against schizophrenia but affective against depression

-     lithium chloride is affective against mania as well as depression; it was discovered when an Australian psychiatrist attempted to induce experimental mania in guinea pigs by injecting the urine of manic patients, mixed with lithium chloride to form an injectable salt; the guinea pigs became very inactive, even those in the lithium-chloride control group; thus, he concluded that lithium had calmed the guinea pigs; he was wrong, the lithium merely made them ill; nevertheless, this study encouraged some clinical trials; it was found to be effective against both mania and depression and today is the treatment of choice for bipolar affective disorder

-     Prozac, a selective serotonin-selective reuptake inhibitor, is a variation of tricyclic antidepressants which selectively blocks serotonin uptake (use Digital Image Archive Figure CH17F14.BMP).  It is not more effective than imipramine against depression but it has fewer side effects and has benefited those with forms of depression expressed in a lack of self esteem, fear of failure etc.

c) Monoamine Theory of Depression

-     MAO inhibitors are monoamine agonists; all clinically effective tricyclic antidepressants are serotonin and norepinephrine agonists, they block reuptake from synapses

-     thus, it was suggested that depression is caused by underactivity at serotonin and norepinephrine synapses; there is evidence that certain norepinephrine and serotonin receptors are elevated in untreated depressed patients.

d) Hypothalamic-Pituitary-Adrenal Theory of Depression

-     this is based on the observation that depressed patients synthesize more corticotrophin-releasing hormone from their hypothalamus, which causes a greater release of adrenocorticotropic hormone from the anterior pituitary, which caused increased glucocorticoid release from the adrenal cortex.  The elevated glucocorticoid levels may play a role in the development of depression, an idea supported by the fact that injections of corticotrophin-releasing hormone can induce signs of depression.

e) Diathesis-Stress Model of Depression

-     this theory is based on the idea that some people inherit a predisposition for depression-possibly because of insufficient monaminergic neurotransmission, or because of their hypothalamic-pituitary-adrenal axis is hyperactive, or because of both sets of neural dysfunctions.

-     this predisposition is not itself sufficient for the development of depression; however, if the individual is stressed early in life their systems become altered so that they are hypersensitive to stress for the rest of their lives.  This leads to the development of depression.

f) Neural Mechanisms of Depression: Unanswered Questions

-  there are many questions still left about the neural bases of affective disorders; here are 4 of them:
          1) Why does it take weeks for antidepressant drugs to be clinically effective?  This suggests that it is some slow-developing response to elevated monoamine levels, rather than the elevated transmitter levels themselves, that produce the antidepressant effeect.
          2) How do antidepressant drugs that do not directly affect monoaminergic systems elicit their antidepressant effect?
          3) Why do some monoamine agonists (the notable examples being cocaine and amphetamine) not produce antidepressant effects? 
          4) How does sleep deprivation induce its antidepressant effect? 

3.     Anxiety Disorders

-     Anxiety is a fear that disrupts normal functioning and persists in the absence of a direct threat; these are the most prevalent of all psychiactric disorders; there are four major classes of anxiety:

-     generalized anxiety is a stress response in the absence of an obvious stimulus

-       phobic anxiety is caused by exposure to a specific object or      situation (snakes, height etc.)

-       panic disorders are rapid onset attacks characterized by extreme fear and stress symptoms (tachycardia, choking etc. )

-       obsessive-compulsive disorders are frequently recurring, uncontrollable anxiety-producing thoughts and compensatory responses

-     treatment often includes benzodiazepines (Librium, Valium) that increase the binding of GABA to the receptor; problematic side effects include tremors, nausea, and addiction;

-     the efficacy of the new anxiolytic buspirone, which is an agonist at  serotonin type 1-A receptors, suggests that serotonergic systems may also be involved in anxiety

-     attention is being focused on brain structures such as the amygdala, due to the role that the amygdala plays in conditional fear, the amygdala's high concentration of GABAA receptors, and the fact that local infusions of benzodiazepines into the amygdala-producing anxiolytic effects in animals, and demonstrations that local injections of GABA antagonists into the amygdala can block the anxiolytic effects of systemic injections of benzodiazepines

Suggested Websites for Lecture 17c:

Anxiety Disorders: http://anxiety.mentalhelp.net/

          A page briefly explaining the symptoms and treatment of anxiety, with links to related sites.

     National Anxiety Foundation: http://lexington-on-line.com/naf.html

          Home page for the National Anxiety Foundation; information on anxiety, panic attacks, OCD.

Neural Bases of Depression: http://www.sciam.com/1998/0698issue/0698nemeroff.html

          From Scientific American, an article by Dr. Charles Nemeroff on the neural bases of depression; includes information about norepinephrine, serotonin, corticotropin-releasing hormone and the contribution of new imagin techniques in the study of depression. 

      Shock Therapy: http://www.epub.org.br/cm/n04/historia/shock_i.htm

          From the Brain and Mind site and the State University of Campinas in Brazil, an examination of the role of ECT, insulin shock, convulsions and other forms of “shock therapy”; interesting historical overview of a controversial topic.

The Discovery of Antipsychotics:http://www.pbs.org/wgbh/aso/databank/entries/dh52dr.html

          From the Public Broadcasting System's A Science Odyssey, a description of Laborit's discovery of chlopromazine.

Mental Illness: http://www.latimes.com/HOME/NEWS/SCIENCE/REPORTS/THEBRAIN/mental.htm

          Another good page from the LA Times' The Brain site, looking at current thought on schizophrenia.

 

نویسنده : S.Hani M.M ; ساعت ۱:٤٩ ‎ق.ظ ; یکشنبه ٢٩ خرداد ،۱۳۸٤
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