Postmortem Studies in Schizophrenia - Schizophrenia Bulletin
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Carlson (7e) Chapter 17: Schizophrenia and
the Affective Disorders
Schizophrenia
Schizophrenia represents a disorder of thought and emotion but not a “split-personality” Thought disorder (e.g., loose associations) Hallucinations (e.g., auditory) Delusions (e.g., paranoia) Bizarre behaviors
The incidence of schizophrenia is about 1-2% No clear gender differences in incidence
17.2
Symptoms of Schizophrenia
Positive symptoms include delusions, hallucinations and thought disorder Delusions are beliefs that are contrary to reality
Delusions can involve control, grandeur, or persecution Hallucinations are perceptions that occur in the absence of
stimuli (often auditory and/or olfactory) Thought disorder: disorganized and irrational
Negative symptoms involve a loss of normal behaviors, such as Poverty of speech and low initiative Social withdrawal and diminished affect Anhedonia 17.3
Heritability of Schizophrenia
The heritability of schizophrenia is a strong indicator of a biological basis for schizophrenia Adoption studies
Adult schizophrenics that were adopted as children are likely to have schizophrenic biological relatives.
Twin studies Concordance rates for schizophrenia are higher for
identical than for fraternal twins: No single gene has been identified for schizophrenia
Genes may pass on a susceptibility to develop schizophrenia
17.4
The Dopamine Hypothesis of Schizophrenia
The “dopamine hypothesis” is that the positive symptoms of schizophrenia involve over activity of brain dopaminergic synapses Chlorpromazine (CPZ) was identified as an effective
antipsychotic (AP) agent CPZ was later found to block DA receptors (D2 receptors) D2 receptor blockade correlates with clinically effective dose
of typical antipsychotic medications Stimulants such as amphetamine that release DA can
produce the positive symptoms of schizophrenia in “normals” and relapse in schizophrenics 17.5
DA Activity in Schizophrenia
PET studies indicate greater activity of dopamine in the striatum of schizophrenics to a test dose of amphetamine Amount of dopamine activity was related to the increase in
positive schizophrenia symptoms Studies of dopamine receptors in schizophrenic brain have
provided mixed results (but generally supportive) Postmortem studies suggest increased numbers of D2 receptors
in striatum (but may be due to exposure to antipsychotic drugs) The striatum is a motor control region Schizophrenia may be related to D4 or D3 receptors
Clozapine is an effective (atypical) antipsychotic drug that interacts with D4 and not D2 receptors
strong effect on mesolimbic/mesocortical dopamine system (A10) little effect on nigrostriatal dopamine system (A9) 17.6
Dopamine Augmentation & Schizophrenia
Psychomotor stimulants (e.g., amphetamine) ‘normals’ develop paranoid psychosis schizophrenics release -- subjectively indistinguishable
for worsening of endogenous illness (cf. LSD) L-DOPA (precursor loading)
little or no effect in ‘normals’ worsening of psychotic symptoms in schizophrenics schizophrenic symptoms in some Parkinson’s patients
Stress (increased dopaminergic activity) precipitate relapse & perhaps even initiate disorder
Dopamine Attenuation & Schizophrenia
DA synthesis inhibitors (e.g., AMPT) abate schizophrenia
DA storage depleters (e.g., reserpine) abate schizophrenia
D2 receptor blockers (e.g., typical antipsychotics) abate schizophrenia
Even atypical antipsychotics (which do not effectively block D2 receptors) influence mesolimbic DA activity
Antipsychotic Medications
Antipsychotic medications diminish the thought disorder & disruptive behavior evident in schizophrenia
Side effects of antipsychotic medications include Major
Extrapyramidal (Parkinsonism-like) side effects due to blockade of DA receptors
Tardive dyskinesia: facial tics and gestures due to an over stimulation of DA receptors (may be related to CNS sensitization and relapse)
Minor Autonomic problems (dry mouth) Skin-eye pigmentation Breast development (increased prolactin release after blockade of
dopamine neurons) 17.9
Brain Damage and Schizophrenia
The negative symptoms of schizophrenia may be related to brain damage The neurological signs evident in schizophrenia include
Eye tracking problems Catatonia Problems with blinking, eye focusing, and visual pursuit
Schizophrenics exhibit enlarged brain ventricles, which suggests loss of brain cells
Regions of schizophrenic brain that are abnormal include Prefrontal cortex Medial temporal lobes Medial diencephalon
17.10
Causes of Brain Damage in Schizophrenia
The neurological symptoms of schizophrenia may be caused by Birth trauma (obstetrical issues) Viral infections that impair neural development during the
second trimester Seasonality effects (schizophrenia is more likely for winter births)
Nutritional issues (Hunger Winter: female offspring were more likely to exhibit schizophrenia than male offspring)
Maternal stress may compromise the immune system of the mother and lead to a greater chance of contracting a viral infection
17.11
Seasonality and Schizophrenia
Children born during the late winter and early spring are more likely to develop schizophrenia Seasonality effect occurs in
cities but not the countryside Seasonality effect may be
related to the mother contracting a viral infection during the second trimester of fetal development (or astrological sign?)
17.12
Hypofrontality and Schizophrenia
Hypofrontality refers to the decreased activity of the frontal lobe (dorsolateral prefrontal cortex). Damage to the prefrontal cortex
impairs behavioral flexibility (card sorting task) may disinhibit mesolimbic dopamine system
Schizophrenics show decreased activity in the prefrontal cortex Abuse of PCP produces positive and negative symptoms
of schizophrenia Positive: related to indirect actions of PCP on accumbens DA Negative: related to decreased DA utilization in prefrontal
cortex following PCP treatment Data are less compelling that dopamine-agonist effect 17.13
Major Affective Disorders
Affect refers to emotions, moods, and feelings Our affect is usually a reflection of our experiences In the major affective disorders, our emotional
reactions are at the extremes and may not be related to our actual experiences
The major affective disorders include Bipolar disorder - alternating cycles of
Mania: euphoria, delusions Depression: profound sadness, guilt, suicide risk
Unipolar depression: continuous, episodic
17.16
Biological Bases of Affective Disorder
Heritability of affective disorder (AD) has been established in twin studies and family studies Bipolar disorder may be related to a single gene
Depression is amenable to physical treatments including Pharmacological treatments
MAO inhibitors (e.g. iproniazid) Noradrenergic reuptake inhibitors (desmethylimipramine) Serotonin reuptake inhibitors (e.g. Prozac)
Electroconvulsive shock therapy (ECS) Sleep deprivation
17.17
Monoamine Hypothesis of Depression
Depression results from reduced activity of brain monoamines Reserpine depletes monoamines--> depression Suicidal depression is related to a low level of
5-HIAA (metabolite of serotonin) Antidepressant medications increase either NE or
5-HT (serotonin) Usually via blockade of monoamine reuptake
Tryptophan (precursor to 5-HT) deletion procedure: Reduces brain 5-HT levels Reinstates depression in former depressed patients
17.18
REM Sleep and Depression
Sleep pattern is disrupted in depressed persons Reduced REM latency (duration of sleep, from sleep onset to
the onset of the first REM sleep period) reduced stages 3 and 4 sleep
REM deprivation improves mood Antidepressant drugs suppress REM sleep, and
increase slow-wave sleep Persons who have short REM sleep latency are more
likely to develop depression REM sleep deprivation is more effective than is total
sleep deprivation (effects last longer) 17.19
Seasonal Affective Disorder
SAD is a form of depression evident in winter months (short days/long nights)
SAD involves Mood and sleep disturbances Carbohydrate cravings and weight gain
Phototherapy for SAD: increased exposure to light improves mood in SAD (and also for unipolar depression)
17.20
Anxiety Disorders, Autistic Disorder, Attention-Deficit/Hyperactivity Disorder, and Stress Disorders
Chapter 17
Lecture Preview
Anxiety Disorders Autistic Disorder Attention-Deficit/Hyperactivity Disorder Stress Disorders
Anxiety Disorders
Panic Disorder, Generalized Anxiety Disorder, and Social Anxiety Disorder Description
Panic Disorder – a disorder characterized by episodic periods of symptoms such as shortness of breath, irregularities in heartbeat, and other autonomic symptoms, accompanied by intense fear.
Anticipatory Anxiety – a fear of having a panic attack; may lead to the development of agoraphobia.
Anxiety Disorders (Continued)
Generalized Anxiety Disorder – characterized by excessive anxiety and worry serous enough to cause disruption to one’s life.
Social Anxiety Disorder – characterized by excessive fear of being exposed to the scrutiny of other people that leads to avoidance of social situations in which the person is called on to perform.
Possible Causes May involved alleles of the 5-HTT.
Anxiety Disorders (Continued)
Obsessive-Compulsive Disorder Description
A mental disorder characterized by obsessions and compulsions.
Obsessions – unwanted thought or idea with which a person is preoccupied.
Compulsion – feel that one is obliged to perform a behavior, even if one prefers not to do so.
Possible Causes Tourette’s Syndrome Streptococcal Hemolytic Infection
Autism
Autism: impairments of Social relations with others Ability to communicate Imaginative ability
Incidence of autism is 4/10,000 Males are 3 times more likely to develop autism
Autistic Disorder
Description A chronic disorder whose symptoms include
failure to develop normal social relations with other people, impaired development of communicative ability, lack of imaginative ability, and repetitive, stereotyped movements.
Possible Causes Heritability Brain Pathology
Biological Bases of Autism
Heritability: MZ twins exhibit a 96% concordance rate for autism
Autism is associated with neurological disorders: Phenylketonuria (PKU) Tourette’s syndrome Fragile X syndrome (mental retardation)
Factors that impair development lead to autism: Rubella, hydroencephalus Drugs such as Thalidomide
Attention-Deficit/Hyperactivity Disorder
Description A disorder characterized by uninhibited
responses, lack of sustained attention, and hyperactivity.
Possible Causes Delays in reinforcement render reinforcement
relatively ineffective, but immediate reinforcement is highly effective.
Figure 17.9 Delay of Reinforcement Gradients in ADHD
Stress
Stress – a general, imprecise term that can refer either to a stress response or to a situation that elicits a stress response.
Stress
Aversive stimuli can elicit emotional responses: Behavioral component: Fight or Flight response Autonomic component: Sympathetic activation Endocrine: secretion of epinephrine, NE
Physiological reactions to chronic aversive stimuli/situations can be damaging Stressors: the aversive stimuli Stress Response: our reaction to stressors
Hormone Secretion during Stress
Stressors evoke activity in sympathetic N.S. Adrenal glands release
Epinephrine: biases energy flow to muscles, increases blood pressure and blood flow to heart
Norepinephrine: increases blood flow and pressure Glucocorticoids: break down protein and fats to glucose
Physiology of the Stress Response
Glucocorticoid – one of a group of hormones of the adrenal cortex that are important in protein and carbohydrate metabolism, secreted especially in times of stress.
Physiology of the Stress Response(Continued)
The process involved in the production of glucocorticoids:
Corticotropin-Releasing Hormone (CRH) – hypothalamic hormone that stimulates the anterior pituitary gland to secrete ACTH.
Adrenocorticotropic Hormone (ACTH) – hormone released by the anterior pituitary gland in response to CRH; stimulates the adrenal cortex to produce glucocorticoids.
Figure 17.12 Control of Secretion of Stress Hormones
Stress Disorders (Continued)
Effects of Stress on the Brain Elevates glucocorticoid levels. Impairs development of primed-burst
potentiation. Disrupts learning. Prenatal Stress:
Increases size of the lateral nucleus of the amygdala. Elevates glucocorticoid response to stress.
Hippocampal Damage
Chronic Exposure to Stressors
Chronic stress is damaging to health Air traffic controllers: more likely to develop
High blood pressure Ulcers and diabetes
Chronic secretion of glucocorticoids leads to: Increased blood pressure (--> stroke, heart attacks) Loss of neurons in brain (e.g. hippocampal field CA1) Suppression of the immune system (--> illness) Suppression of the inflammatory system (delays healing)
Stress Disorders (Continued)
Health Effects of Long-Term Stress Hypertension – stress causes an increase in
hypertension. Wound Healing – stress causes an increase in
the time to heal wounds.
Posttraumatic Stress Disorder
Posttraumatic Stress Disorder (PTSD): Acute exposure to intense stressors can have delayed
effects (Air disasters, war, assault) Dreams, recall of trauma event Flashback episodes of event Intense distress
Stress Disorders (Continued)
Posttraumatic Stress Disorder A psychological disorder caused by exposure to
a situation of extreme danger and stress; symptoms include recurrent dreams or recollections; can interfere with social activities and cause a feeling of hopelessness.
Involves many brain regions, including the amygdala and prefrontal cortex.
Predisposing Factors for PTSD
Personality variables that predispose to PTSD: Tendency to brood about feelings Vietnam Veterans study:
Family financial difficulty History of drug abuse/dependence History of affective disorders History of childhood behavior problems
Genetic factors for PTSD: Vietnam PTSD soldiers were more likely to possess an allele of the
dopamine D2 receptor
Coping Responses and Stress
Stress reflects our reaction to stressors Coping implies modifying our responses:
Exerting control over aversive stimuli can reduce stress responses
Weiss study: rats that avoid shock show fewer ulcers Coping may involve an increase in the level of benzodiazepines in
brain (would act via GABA sites to reduce anxiety)
Psychoneuroimmunology
Psychoneuroimmunology: Study of the interactions between the immune system and behavior.
The branch of neuroscience involved with interactions between environmental stimuli, the nervous system, and the immune system.
Stress responses can impair the immune system Leading to illness and potential death
Psychoneuroimmunology
Antigen – protein present on a microorganism that permits the immune system to recognize the microorganism as an invader.
Antibody – protein produced by a cell of the immune system that recognizes antigens present on invading microorganisms
Stress Disorders (Continued)
B-Lymphocyte – a white blood cell that originates in the bone marrow.
Immunoglobulin – an antibody released by B-lymphocytes that bind with antigens and help destroy invading microorganisms.
T-Lymphocyte – a white blood cell that originates in the thymus gland.
Overview of the Immune System
Immune system destroys foreign organisms (viruses, bacteria, fungi) Nonspecific reaction: act to destroy organisms or infected
cells Inflammatory reaction: damaged cells leak substances that increase
blood flow Phagocytotic white blood cells: destroy damaged cells Cell infection --> interferon secretion (reduces viral replication Natural killer cells: detect and destroy infected cells
Immune System Overview, continued
Specific Immune reactions: Chemically-mediated: immune system produces antibodies
that recognize the antigens present on surface of a foreign cell B-lymphocytes: produce immunoglobulin antibodies that destroy
foreign cells Cell-mediated: antibodies on exterior of T-lymphocytes detect
foreign antigens (viruses)
Stress and the Immune Response
Stress increases likelihood of infectious disease Students are more likely to be ill during exam times Death of a spouse leads to illness of survivor
Explanation: stress releases glucocorticoids that in turn impair the immune system
Supporting Evidence: Bereavement leads to reduced immune response Alzheimer’s caregivers have impaired immune response Inescapable shock in rats reduces T-cells, B-cells and natural killer cells
Stress Disorders (Continued)
Stress, Health, and Disease Stress decreases immune function. Stress increases the susceptibility to infection.