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Lecture 19 - Psychopathology… • Schizophrenia •...

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Unformatted text preview: Psychopathology… • Schizophrenia • Depression • Bipolar disorder • Anxiety disorders Panic attack PTSD Psychopathologies are widespread Psychopathologies • Psychopathologies affect hundreds of millions of people worldwide worldwide Common • Common disorders are schizophrenia and bipolar disorder bipolar And • And even more common… depression, anxiety disorders disorders Biology of psychopathology Understanding • Understanding the biology of psychopathology can help make life better for millions millions Recent • Recent discoveries have allowed millions of people’s lives to be greatly improved But • But still a great deal of work left… as many as 1/3 of Americans report psychiatric disorders psychiatric Biology of psychopathology biological • A biological perspective for psychiatry grew in the early 20th century when it early was discovered that a very large number of patients in mental hospital with delusions (false beliefs strongly held in spite of contrary evidence) where suffering from brains damaged by syphilis damaged Antibiotics that kill the Antibiotics bacteria that causes syphilis, eliminated ‘syphilitic psychosis’ ‘syphilitic • Schizophrenia Delusions • Delusions (false beliefs) are still extremely common common Schizophrenia has Schizophrenia ‘positive’ and ‘negative’ symptoms symptoms The positive symptoms The include delusions and hallucinations hallucinations The negative symptoms The include emotional withdrawal and impoverished thought impoverished • • • Schizophrenia and public health About • About 1-2% of people (across cultures) have schizophrenia schizophrenia About 2.2 million About Americans have it Americans Appears in adolescence Appears and young adulthood and Schizophrenia is a ‘public’ Schizophrenia disorder because many end up on the streets (consumes a disproportionate share of community health resources) resources) • • • Schizophrenia: positive symptoms Positive • Positive symptoms refer to abnormal behavioral states that have been gained gained Hallucinations (hearing Hallucinations voices that aren’t there is the most common type of delusion) delusion) Delusions (usually highly Delusions personalized… they’re coming to get me, etc) coming Excited motor behavior • • • Schizophrenia: negative symptoms Negative • Negative symptoms refer to abnormalities that result in a normal function that has been lost that For example, slow and For impoverished thought and speech speech Emotional and social Emotional withdrawal withdrawal Blunted affect (emotions) … more specifically, more blunted expression of emotions emotions • • • Schizophrenia and heritability Schizophrenia • Schizophrenia is extremely • • • • complex complex There are many types There are environmental and There developmental influences These influence genetic These predispositions predispositions So, we can never understand So, something as complex as behavior (especially an extremely complicated abnormality involving behavior) by just genes or just environment just Schizophrenia and heritability The • The more closely related a person is to a schzophrenic, the more likely her or she is to developing the disease developing Therefore, schizophrenia Therefore, is inherited is But, it is not simple But, genetic determinism (like Huntington's) Huntington's) There appears to be There multiple genes involved multiple • • • Schizophrenia: twin studies Monozygotic • Monozygotic twins: twins derived from a single fertilized egg (also referred to as identical twins) to Monozygotic twins have the Monozygotic same genome (so called identical twins) identical Dizygotic twins: twins Dizygotic derived from two different eggs eggs Also called dizygotic twins Also or fraternal twins (have half their genes in common… like non-twin siblings like • • • Schizophrenia: twin studies f • IIf both twins have a trait (in this case, schizophrenia) they are said to be concordant for this trait concordant If only one twin has If schizophrenia, they are ‘discordant’ for the disease ‘discordant’ 50% of monozygotic twins 50% are concordant for schizophrenia schizophrenia In sets of twins that are In discordant for schizophrenia they often differ in other traits (such as differences in motor coordination) motor • • • Schizophrenia Patients • Patients with schizophrenia have greater difficulty making smooth-pursuit movements with their eyes than non-schizophrenics (people with schizophrenia have jerky eye movements) have Schizophrenia: adoption studies For • For people with schizophrenia that were adopted… their biological parents are much more likely to have the disease than their adoptive parents their But genetic nature of But the disease is extremely complicated and poorly understood and Genes important for Genes schizophrenia are located on at least 15 or 23 chromosomes • • Schizophrenia: brain abnormalities People • People with schizophrenia have enlarged lateral ventricles ventricles Ventricular • Ventricular enlargement is not related to the length of illness illness Patients • Patients with larger ventricles don’t respond as well to medication medication Schizophrenia: brain abnormalities Twins • Twins that are discordant for schizophrenia show differences in their limbic systems systems The twins with The schizophrenia have smaller limbic structures (hippocampus and amygdala) amygdala) Since these regions are Since near the ventricles… enlarged ventricular systems may be due to atrophy of limbic structures atrophy • • Schizophrenia: brain abnormalities The • The hippocampal pyramidal cells of chronic sufferers of schizophrenia exhibit a characteristic disorganization disorganization The • The more impaired the person… the more disorganized the cellular structure of the hippocampus hippocampus Schizophrenia: brain abnormalities Those • Those with early onset schizophrenia have a thicker corpus callosum callosum There • There is also a loss of gray mattter in schizophrenia patients schizophrenia There • There is a significant loss of cortical gray matter during adolescence in those with early onset schizophrenia schizophrenia Schizophrenia: brain abnormalities Patients • Patients with schizophrenia show impairments in neuropsychological tests that indicate damage to frontal cortex Schizophrenia: brain abnormalities Patients • Patients with schizophrenia show decreased activity within frontal cortex frontal Hypofrontality hypothesis Hypofrontality suggests that underactivation of the fronal lobes is important for schizophrenia schizophrenia In discordant identical twins, In low blood flow in frontal cortex is only seen in the twin that has schizophrenia schizophrenia Drugs that improve symptoms, Drugs increase blood flow in frontal lobes • • • Schizophrenia: neurochemistry Drugs • Drugs can cause hallucinations… • • • • for example LSD for But LSD causes visual But hallucination and hallucinations with schizophrenia are primarily auditory auditory Chronic amphetamine users have Chronic symptoms similar to patients with schizophrenia (amphetamine psychosis) psychosis) Experience paranoia, auditory Experience hallucinations, bizarre motor behavior behavior This leads to the idea the dopamine This is important for schizophrenia (dopamine hypothesis) (dopamine Schizophrenia: neurochemistry The • The symptoms of amphetamine psychosis are eliminated by the dopamine receptor antagonist thorazine (chlorpromazine) (chlorpromazine) Chlorpromazine also Chlorpromazine alleviates symptoms of schizophrenia schizophrenia Also called a neuroleptic Also or antipsychotic or These drugs block These postsynaptic D2 dopamine receptors • • • Schizophrenia: neurochemistry f • IIf a schizophrenia medication acts by blocking D2 receptors it is called a ‘typical neuroleptic’ Dopamine hypothesis- the Dopamine idea that schizophrenia results from either excessive levels of dopamine or highly sensitive dopamine receptors receptors Boosting dopamine levels in Boosting parkinson’s patients can induce symptoms of schizophrenia schizophrenia • • Schizophrenia: neurochemistry Dopamine • Dopamine is only part of the • • • • schizophrenia story schizophrenia There are inconsistent results And while dopamine receptors And are blocked rapidly by drugs, it takes weeks for symptoms to go away go Atypical neuroleptics are Atypical drugs that treat schizophrenia but do not primarily block D2 receptors receptors For example, clozapine mildly For blocks D2 but primarily blocks serotonin (5HT2A receptors) serotonin Schizophrenia: neurochemistry • The glutamate hypothesis Just • Just like the dopamine hypothesis comes from a drug induced state similar to that seen in schizophrenia (amphetamine psychosis) (amphetamine The glutamate hypothesis was The derived from observing what people are like when they take PCP PCP Psychotomimetic (a state Psychotomimetic resembling schizophrenia) resembling PCP (phencyclidine) is also PCP known as angle dust known • • • NMDA receptor Schizophrenia: neurochemistry PCP • PCP causes auditory • • • hallucinations hallucinations PCP is an NMDA antagonist PCP (blocks the central calcium channel) channel) Give monkeys PCP for two Give weeks and they show frontal cortex deficits similar to humans with schizophrenia humans These data have led some These scientist to suggest that there is an under activation of glutamate receptors in schizophrenia schizophrenia NMDA receptor Schizophrenia: interaction of many factors One • One view of schizophrenia is that it is an outcome of complex interactions between genetic, developmental, and stress factors and Each component is Each associated with its own features important for impacting the vulnerability in developing schizophrenia developing • Schizophrenia: interaction of many factors The • The emergence of schizophrenia depends on whether a compromised brain is subjected to environmental stressors environmental If pregnant mother gets If the flu during first trimester… then odds of baby getting schizophrenia go up schizophrenia • Depression: a common mood disorder We • We need to distinguish between low mood and major depression major Low mood is just a Low normal passing malaise (i.e. you just feel crappy for a bit couple days or even a couple weeks… but then it goes away and you are ok) you Depression is a Depression psychiatric condition that persists and should be treated treated • • Depression: a common mood disorder Clinically, • Clinically, depression is not characterized by sadness but by an unhappy mood (loss of interests, energy, and appetite; difficulty concentrating, restless agitation) agitation) Depressive bouts can Depressive occur without any apparent environmental cause and last for months cause Can afflict up to 20% of Can the population the • • Depression: a common mood disorder f • IIf there are bouts of euphoria and extremely positive mood mixed in… this is called bipolar disorder disorder ~ 80% of all suicides are 80% believed to have been profoundly depressed profoundly Over the last two Over decades, pharmaceutical companies have greatly increased the number of drug treatments drug • • Depression: inheritance Concordance • Concordance rate for depressive disorders in monozygotic twins is ~ 60% (and this is similar if twins are reared apart or together) together) Whereas it is only about Whereas 20% for dizygotic twins 20% This suggests a strong This genetic component to depression depression Like schizophrenia, many Like genes involved (very complex) complex) • • • Depression: Neural signaling Patients • Patients with depression show increases in blood flow (which suggests increases in activation) of the frontal cortex and the amygdala Blood flow in amygdala Blood can be normalized with anti-depressants anti-depressants Conversely, blood flow is Conversely, decreased in parietal and posterior temporal cortex and anterior cingulate… systems important for attention and language attention • • Depression: Neurochemistry • The monoamine hypothesis Drugs • Drugs that increase • • • monoamine signaling alleviate depressive symptoms symptoms The earliest antidepressants were depressants monoamine oxidase (MAO) inhibitors inhibitors These drugs prevent the These breakdown of monoamines and therefore increase their signaling signaling Serotonin & norepinephrine Depression: Neurochemistry Reserpine • Reserpine reduces norepinephrine and serotonin release in the brain This drug causes profound This depression depression Electroconvulsive shock Electroconvulsive therapy (ECT) also alleviate symptoms of major depression and is still used in patients that are resistant to drug treatment to Believed to work by causing Believed monoamine release monoamine • • • Depression: Neurochemistry Serotonin • Serotonin is especially important for depression important Suicide victims have Suicide reduced serotonin metabolites in the brain metabolites Suicide attempters that have Suicide very low levels of serotonin are 10 X more likely to eventually commit suicide than attempters with normal levels of serotonin levels Specific variants of Specific serotonin receptor genes are associated with depression and suicide and • • • Depression: Neurochemistry • The most popular anti• • • • depressants are the depressants selective serotonin reuptake inhibitors (SSRIs) reuptake Prozac is an SSRI SSRIs work better than SSRIs MAO inhibitors and have fewer side effects fewer In rats, SSRIs increase In neurogenesis in the hippocampus SSRI treatment works SSRI better with therapy better Depression: Neurochemistry Blocking • Blocking serotonin transporters increases serotonin levels rapidly… but it takes weeks depressive symptoms to be improved be So, there must be other So, things going on things In some people, SSRIs In don’t work at all don’t There is a massive There placebo effect (~33%) and there is not evidence that SSRIs help kids SSRIs • • • Depression: Neurochemistry Blocking • Blocking serotonin transporters increases serotonin levels rapidly… but it takes weeks depressive symptoms to be improved be So, there must be other So, things going on things In some people, SSRIs In don’t work at all don’t There is a massive There placebo effect (~33%) and there is no evidence that SSRIs help kids SSRIs • • • Depression: HPA axis HPA • HPA axis – hypothalamic pituitary adrenal axis pituitary Cushing’s syndromeCushing’s depression resulting from very high levels of circulating glucocorticoids (such as cortisol) cortisol) In hypothalamus, CRH In producing cells project to portal system and is released into portal veins that travel to anterior pituitary • • Depression: HPA axis Anterior • Anterior pituitary produces ACTH produces ACTH is released when ACTH stimulated by CRH stimulated ACTH travels to adrenal ACTH gland gland ACTH stimulation of ACTH adrenal gland causes glucocoritcoid release into the blood stream into This feeds back into the brain and decreases CRH release release • • • • Depression: HPA axis • Causes of Cushing’s 1) • 1) pituitary tumor that • • • results in excessive ACTH production ACTH 2) tumor in the adrenal 2) gland that results in hypersecretion of cortisol hypersecretion 3) cortisol replacement 3) therapy therapy The majority of patients The with Cushing’s get depression sooner than other symptoms (obesity) other Depression: HPA axis Dexamethasone • Dexamethasone suppression test suppression Dexamethasone is a Dexamethasone potent synthetic glucocorticoid the suppresses the natural rise in cortisol levels first thing in the morning thing In depressed patients, In dexamethasone fails to suppress early morning rise in serum cortisol rise After treatment, it starts After to work normally • • • Depression: HPA axis Dexamethasone • Dexamethasone data suggest depressed people have CRH neurons that are abnormally excited excited This causes ACTH to be This released too easily Or, depressed people Or, may have impaired negative feedback regulation of this system (such as too few or insensitive brain glucocorticoid receptors) glucocorticoid • • Sex differences in depression More • More women suffer from • • • • depression than men depression Women are twice as likely to Women have depression in the US but this difference hold worldwide this One possibility is there is One more discrimination of women more …or hormonal differences or (such as postpartum depression) depression) … or men are just as depressed but more likely to be alcoholics be Bipolar disorder Characterized • Characterized by periods of depression that alternate with periods of highly elevated mood highly Some people cycle only 4 Some times a year… some cycle multiple times a day cycle The most common The treatment is lithium treatment The mechanism of The lithium’s effects are poorly understood poorly • • • Anxiety disorders Normal • Normal anxiety is critical for survival for But there are some that But experience irrational fears, sense of terror, trouble breathing, and feeling of loosing control feeling So, anxiety can come as So, an onslaught of panic (panic attack) (panic These are dangerous… These higher rates of cardiovascular disease and suicide and • • • Anxiety disorders Phobic • Phobic disorders- intense irrational fears that become centered on a specific object, activity, or situation or Anxiety disordersAnxiety (including panic disorder… recurrent transient attacks of intense fearfulness) intense And generalized anxiety And disorder … persistent excessive anxiety and worry experience for months months • • Anxiety disorders Patients • Patients with panic attacks have temporal lobe abnormalities lobe Benzodiazepines are Benzodiazepines used to treat anxiety (these are called anxiolytics) anxiolytics) Valium is a Valium benzodiazepine and is one of the most prescribed drugs in history history Benzodiazepines are Benzodiazepines GABA agonists GABA • • • PTSD and fear conditioning Posttraumatic • Posttraumatic stress disorder (PTSD) – memories of an unpleasant episode repeatedly plague the victim victim Comprehensive Comprehensive psychobiological model of the development of PTSD PTSD Fear conditioning, Fear behavioral sensitization, and extinction • • PTSD and fear conditioning ntense • IIntense trauma will activate brainstem systems that sensitize subject to future stimuli sensitize PTSD and fear conditioning And • And also more rostral brain system (especially the amygdala) that conditions a long-term fear response amygdala) ...
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