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.