Chapter 14: Psychological Disorders Substance Abuse Addiction applies to far more situations than just alcohol and drugs Drug Mechanisms - Most commonly abused drugs derive from plants. - Why do our brains respond to plant chemicals? Or, why do plants produce chemicals that affect our brains? o Nearly all neurotransmitters and hormones are the same in humans as in other species o If a plant evolves a chemical to attract bees, repel caterpillars, etc., that chemical is likely to affect humans also - Drugs can either facilitate or inhibit transmission at synapses - Antagonist – a drug that blocks the effects of a neurotransmitter - Agonist – a drug that mimics or increases the effects - A drug has an affinity for a receptor if it binds to it (like a key in a lock) - Efficacy – a drug’s tendency to activate the receptor - Effectiveness and side effects of drugs vary from person to person. Why? o People vary in their abundance of each kind of receptor Predispositions - With alcohol, some people drink in moderation, whereas others develop a habit of abuse. - Seen with other substances as well. - Study by Ersche et al., 2012) - Certain aspects of brain and behavior are present from the start in people with a predisposition to addiction, regardless of their later substance abuse Genetic Influences - Probability of abusing alcohol or other drugs depends on both genetic and environmental factors - Probability of substance use or abuse rises for children who grow up in an unstable environment. Probability is magnified if they also have particular gene that affects serotonin synapses - Gene that controls metabolism of alcohol o After drinking ethyl alcohol, enzymes in liver metabolize it to acetaldehyde (toxic) o Enzyme acetaldehyde dehydrogenase then converts acetaldehyde to acetic acid (chemical that body uses for energy) o People with gene for producing less acetaldehyde dehydrogenase metabolize acetaldehyde more slowly - Result – More than a third of people in China and Japan have gene that slow acetaldehyde metabolism. What is the result of this? Environmental Influences - The prenatal environment contributes to the risk for alcoholism - Mothers who drink during pregnancy - Experiments with rats – prenatal exposure to alcohol increases alcohol consumption after birth - Childhood environment is critical also – the effect careful parental supervision on impulse problems Behavioral Predictors of Abuse - How do we identify young people who are at risk of later substance abuse? - Large scale studies have found that alcoholism is more likely among those who were described in childhood as: Impulsive Risk-taking Easily bored Sensation-seeking Outgoing - Other research follows this design: o First, identify young men who are not yet problem drinkers o Compare men whose fathers had alcoholism to men who have no close relative with an alcohol problem o Expectation – that many of the sons of alcoholics are future alcoholics themselves (see fig, 14.2) - Most robust finding: o Sons of alcoholics show less than average intoxication after drinking moderate amount of alcohol, report feeling less drunk, and show less body sway o Men who report low intoxication after moderate drinking are more likely than others to abuse alcohol throughout their lives o Similar results for women o “Holding your liquor” well is not something to brag about, but something to worry about Synaptic Mechanisms - Drugs affect synapses in different stages of someone’s experiences The Role of Dopamine - Olds and Milner (1954) – examined stimulation of brains of rats - Self-stimulation of the brain – - Researchers have found many brain areas that rats will work to stimulate - All of these areas have axons that increase release of dopamine in nucleus accumbens – area is important for many types of reinforcing experiences - Stimulants (e.g., cocaine, amphetamine) increase or prolong release of dopamine in nucleus accumbens o o o o o Sexual excitement Music Imagining something pleasant Gambling for habitual gamblers Video games for habitual video game players - Results suggested that dopamine release might be essential for all addictions and all substance abuse - However, growing evidence indicates that role of dopamine has been overemphasized o Alcohol, nicotine, opiates do generally increase dopamine release, but not by much o Amount of release does not correlate strongly with pleasantness of experience or probability of addiction o Pharmaceutical companies have failed to find drugs that alleviate addictions via effects on dopamine – drugs that block dopamine synapses do not reduce reward properties of opiate drugs and they do not decrease use Cravings - Some evidence indicates that people with addictions have trouble breaking any habit, not just a drug habit - A learned habit craving can persist long after the behavior has ceased to be rewarding (compare to people with prefrontal cortex damage) - Craving – an insistent search for the substance and a defining feature of addiction o After long period of abstinence, cues associated with the substance trigger a renewed craving o Brain mechanism of craving differs from response to original activity - Research with rats – exposure to addictive substances (e.g., cocaine) alters neuronal structure and gene expression in several brain areas (especially if exposure begins early in life) o Effects of repeated cocaine use on the nucleus accumbens o Everyday pleasures become less intense – users can still achieve pleasurable state by increasing dose or frequency of cocaine use o Cues (reminders) become sensitized – attract greater attention - Craving increases during early stage of abstinence, and slightly declines later - Increased response to drug cues traced to facilitated glutamate synapses in nucleus accumbens (for cocaine and nicotine) - Can a drug that desensitizes glutamate synapses in nucleus accumbens reduce cravings for certain drugs? Tolerance and Withdrawal - As addiction develops, many of its effects, especially enjoyable ones, decrease - Tolerance – reduction in pleasurable effects o Leads to greater dosage of drug and greater frequency of use o A complex phenomenon that is learned - In rats, receiving drugs in distinctive location show more tolerance in that location than elsewhere Cues associated with receiving drug activate learned mechanisms that counteract effects of drug Learned tolerance can be weakened through extinction Withdrawal – body reacts strongly when drug is absent o Withdrawal symptoms after one quits heroin or other opiates Anxiety Sweating Vomiting Diarrhea o Withdrawal symptoms of quitting alcohol - Irritability Fatigue Shaking Sweating Nausea In severe cases, progresses to hallucinations, convulsions, fever, and cardiovascular problem Hypothesis – addictive behavior is attempt to avoid withdrawal symptoms o Why is this hypothesis problematic? - Modified explanation – someone with addiction learns to use the substance (or gambling behavior) to cope with stress o Receiving an addictive drug during withdrawal period is a powerful experience – users learn that that the drug relieves the distress caused by drug withdrawal o That learning can generalize to other situations – users crave drug during other kinds of distress Berridge and Robinson (1998) – dopamine in nucleus accumbens relates to how much you want something, not how much you like it Addictive drugs and attention Treatments - Some people can decrease their use without help - For those who cannot solve the problem on their own o Alcoholics Anonymous, Narcotics Anonymous o Therapy, particularly cognitive behavioral therapy Contingency management – includes rewards for remaining drug-free Medications to Combat Alcohol Abuse - Disulfiram (Antabuse) – antagonizes enzyme that metabolizes acetaldehyde o Anyone taking Antabuse becomes nauseated after drinking alcohol o Antabuse is about equal to a placebo – threat of becoming ill discourages any attempt to drink alcohol o Taking daily pill reaffirms pledge to avoid alcohol - Related idea is to have people drink alcohol and then immediately take a drug that produces nausea – forms learned aversion to taste of alcohol o Quick and effective treatment, but use has never been popular - Naloxone (Revia) and Naltrexone are other medications – block opiate receptors and thereby decrease pleasure from alcohol Medications to Combat Opiate Abuse - Heroin – artificial substance invented in 1800s as supposedly safer alternative for those trying to quit morphine - Methadone – similar to heroin and morphine – activates same brain receptors and produces same effects o Advantages - Can be taken orally – gradually enters blood and then the brain, so its effects rise slowly (avoids “rush” experience) Metabolized slowly and leaves brain slowly – withdrawal symptoms are gradual Buprenorphine and levomethadyl acetate (LAAM) are similar to methadone and also use to treat opiate addiction o LAAM has long-lasting effect, reducing frequency of clinic visits - People using these drugs live longer and healthier on average than heroin or morphine users - These drugs do not end the addiction, but merely satisfy craving in less dangerous way Mood Disorders Major Depressive Disorder - People with major depressive disorder feel sad and helpless every day for weeks at a time and can hardly imagine enjoying anything - Their nucleus accumbens becomes less responsive to reward - Feel worthless, contemplate suicide, and have trouble sleeping - Have cognitive problems o Low motivation o Attention problems o Impaired memory o Impaired sense of smell - Absence of happiness is more reliable symptom than increased sadness o How do people with depression react to funny or pleasant stimuli? - About 5-6% of adults in U.S. and Canada have a clinically significant depression within a given year and more than 10% do at some point in life - More common in women than in men during reproductive era, but about equal before puberty and after menopause - Some people suffer from long-term depression - More common to have episodes of depression separated by periods of normal mood - Some people have shorter episodes of depression, and possibly more of them, than other people do. Genetics - Depression has moderate degree of heritability, according to studies of twins and adopted children - Genetic factors are not the only cause o Several studies have found: Increased activity of immune system (can arise from injury) Highly stressful experiences Poor diet Other causes - Many studies have identified one or more genes associate with depression, but results vary from one study to another - - Likely explanation – differenent genetic variations occur in different populations Another reason it is hard to find a gene linked to depression - There are at least two distinguishable syndromes 1. People with early-onset depression (before age 30) Have high probability of other relatives with depression Also have high probability of relatives with: o Anxiety disorders o Neuroticism o Attention-deficit disorder o Alcohol or marijuana abuse o Obsessive-compulsive disorder o Bulimia, o Migraine headaches o Irritable bowel syndrome Early-onset depression tends to be more severe, more longlasting, and more associated with suicidal tendencies 2. People with late-onset depression (especially after age 45 to 50) - Have high probability of relatives with circulatory problems Researchers have begun looking for genes that might be associated specifically with early-onset or late-onset depression - Another issue: the effect of a gene varies with the environment - One gene controls the serotonin transporter protein o Protein regulates ability of an axon to reabsorb serotonin after its release (to recycle it for further use) - Have identified two types of genes: “short” type and “long” type - Caspi et al. study showed that for people with two short forms of the genes, increasing numbers of stressful experiences led to big increase in probability of depression o For those with two long forms, stressful events only slightly increased risk of depression o Those with one short and one long gene were immediate - Not all studies have replicated this result o However, review of literature confirms that short form of serotonin transporter gene increases risk of a depressive reaction to major stressors, especially stress of early childhood maltreatment o We should not think of this gene as “risk for depression” gene – the same gene increases smiles, laughter, or anger, depending on the event - Short form of serotonin transporter gene increases emotional reactivity of almost any type, good or bad Possibility raised by evolutionary psychologists o Our ancestors evolved a tendency to become depressed under certain conditions (e.g., to conserve energy after a defeat) Abnormalities of Hemispheric Dominance - Strong relationship between happy mood and increased activity in left prefrontal cortex - Depression associated with increased activity in the right prefrontal cortex o Stable over years despite changes in symptoms of depression o Probably represents predisposition to depression rather than reaction to it Antidepressant Drugs - Like many other psychiatric drugs, early antidepressants discovered by accident (e.g., Iproniazid) Types of Antidepressants - Four major categories o Tricyclics o Selective serotonin reuptake inhibitors (SSRIs) o MAOIs o Atypical antidepressants - Tricyclics (e.g., imipramide, trade name Tofranil) o Operate by blocking transporter proteins that reabsorb serotonin, dopamine, and norepinephrine into the presynaptic neuron after their release (see Fig. 14.7) o Result – Prolongs presence of the neurotransmitters in synaptic cleft, where they continue stimulating postsynaptic cell o Also block histamine receptors, acetylcholine receptors, and certain sodium channels - Blocking histamine produces drowsiness Blocking acetylcholine leads to dry mouth and problems urinating Blocking sodium channels causes heart irregularities and other problems Selective serotonin reuptake inhibitors (SSRIs) – e.g., fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), and paroxetine (Paxil or Seroxat) - - - Similar to tricyclics, but specific to serotonin - Attach to the center of the serotonin transporter protein and lock it into a shape that prevents serotonin from binding to it - Block reuptake of serotonin – prolongs presence of serotonin in the presynaptic cleft, where it continues to stimulate the postsynaptic cell - Produce milder side effects than the tricyclics, but about the same in effectiveness Serotonin norepinephrine reuptake inhibitors (SNRIs) – e.g., duloxetine (Cymbalta), venlafaxine (Effexor) - Block reuptake up both serotonin and norepinephrine - Improve certain aspects of memory - Many patients now take two or more drugs with different modes of action Monoamine oxidase inhibitors (MAOIs) – e.g., phenelzone (Nardil) - The earliest antidepressants, bit no longer first choice for treatment - Block the enzyme monoamine oxidase (MAO), a presynaptic terminal enzyme that metabolizes catecholamines and serotonin into inactive forms - When MAOIs block enzyme, presynaptic terminal has more of its transmitter available for release - People taking MAOIs must avoid foods containing tyramine New antidepressant – Ketamine – antagonizes NMDA-glutamate receptors and also increases formation of new synapses - o Produces rapid antidepressant effects in patients who don’t respond to other medications o Often produces hallucinations and delusions, and benefits are not long lasting - Atypical antidepressants – miscellaneous group containing everything other than the other three types - e.g., bupropion (Wellbutrin) o inhibits reuptake of dopamine and to some extent norepinephrine but not serotonin o St. John’s wort – an herb o Marketed as nutritional supplement and not regulated by U.S. Food and Drug Administration o Purity varies from one bottle too another o Less expensive than antidepressant drugs o Available without prescription o Effectiveness seems to be comparable to that of standard antidepressants o Has potentially dangerous side effect – increases the effectiveness of a liver enzyme that breaks down plant toxins, but enzyme also breaks down most medicines – decreases effectiveness of other drugs one is taking How Are Antidepressants Effective? - Commonly used antidepressants increase presence of serotonin and other neurotransmitters at the synapse - Is depression due simply to having too little of the neurotransmitters? o People with depression have approximately normal levels of release of neurotransmitters and some studies have found increased serotonin release o Possible to decrease serotonin levels suddenly by a special diet (eliminate tryptophan, the precursor to serotonin) o This does not provoke feelings of depression - Major theoretical difficulty – Antidepressant drugs produce effects within hours, but mood elevation does not occur for two or more weeks - Much current research focuses on neurotrophins o Most people with depression have lower than average levels of brainderived neurptrophic factor (BDNF) BDNF is important for synaptic plasticity, learning, and proliferation of new neurons in hippocampus Therefore, most people with depression have smaller than average hippocampus, impaired learning, and reduced production of new hippocampal neurons Prolonged use of antidepressant drugs generally increases BDNP production and improves learning and formation of new neurons (process takes weeks) Procedures that block neuron production also block behavioral benefits of antidepressant drugs BDNF by itself does not automatically elevate mood Antidepressants elevate mood in depressed people but not in normal people o Formation of new neurons is not the whole explanation for antidepressant drugs – drugs also exert essential effects on mature hippocampal neurons How Effective Are Antidepressants? o Most controlled studies find that antidepressants are at least moderately more effective than placebos o Effect of placebos is strong and apparently increasing in recent years o Antidepressants may have only slight advantage over placebos in a clinical sense o Antidepressants have apparently little effect on suicide rate o See Fig. 14.9 o Many people respond well on placebos, either because of spontaneous recovery or expectations from taking a pill o Point remains that antidepressant drugs are only moderately helpful for most patients with depression, and not helpful at all in many cases o Many patients are prescribed different drugs in a trial and error process – cannot predict which drug will work best for a given o Eventually, most patients show favorable response to one of the drugs o How can we be sure that the drug is responsible for the improved mood? Depression occurs in episodes – even without treatment, most people recover in a few months - Even without treatment, many people recover within a few months Alternatives to Antidepressant Drugs - Alternative to antidepressant drugs is psychotherapy (cognitive behavioral and other forms) - Brain scans show that antidepressants and psychotherapy increase metabolism in the same brain areas o Not surprising if we accept mind-body monism - Advantage of psychotherapy is that its effects are more likely to last – relapse into depression more likely after antidepressant drug treatment than after psychotherapy - What about a combination of antidepressant drugs and psychotherapy? People receiving both treatments show more rapid improvement than those receiving either one alone – but percentage of those showing improvement increases only slightly Evidently, not many respond to one treatment and not the other Electroconvulsive Therapy (ECT) - Treatment for depression through an electrically induced seizure - Sometimes used for patients with severe depression who do not respond to drugs and is effective in most cases – sometimes ordered for suicidal patients - ECT is usually applied every other day for about 2 weeks - Has several side effects o Memory loss, although if applied to only right hemisphere, memory impairment is minimal o A high risk of relapsing into another episode of depression within a few months o Compared to psychotherapy or antidepressant drugs, ECT generally acts faster, but its benefits are less likely to persist o To prevent relapse, patient usually returns for additional ECT treatments - After ECT has relieved depression, usual strategy is to try to prevent relapse through drugs, psychotherapy, or periodic ECT treatments - No one is sure how ECT works o ECT increases proliferation of new neurons in hippocampus o Also increases BDNF levels Exercise and Diet - Simplest and least expensive treatment is program of regular, moderate intensity exercise - Provides modest antidepressant benefits, especially for those over 60 - Even simple walking improves positive mood - Best used as supplement to other treatments rather than stand-alone therapy - Some value seen in consumption of omega-3 fatty acids (important for neuron membranes), and vitamins B6, B9, and B12 (research not extensive and not conclusive) Altered Sleep Patterns - Almost everyone with depression has sleep problems - People who have trouble sleeping are at high risk for later depression - Usual pattern – fall asleep at proper time but enter REM earlier and awaken early (see fig. 14.11) - Total night of sleep deprivation can relieve depression – but benefits are brief - One approach is to alter the sleep schedule – go to bed hours earlier than usual o Procedure usually relieves depression quickly and benefits last for week or more o Eventually, circadian rhythm shifts again o Phase-advancing sleep schedule is not a popular therapy - Seasonal Affective Disorder (SAD) - Depression that recurs during a particular season (e.g., winter) - SAD is most prevalent near the poles (winter nights are long) - Patients with SAD have phase-delayed rhythms o Many have mutation in one of the genes responsible for regulating circadian rhythm - Treatments include very bright lights for a couple of hours each morning o Benefits are substantial o Researchers have tested bright-light therapy for nonseasonal depression – results as least as good as those for antidepressant drugs, with quicker benefits, lower cost, and much less risk of side effects Deep Brain Stimulation - Physician implants battery-powered device into the brain to deliver periodic simulation to certain brain areas - Still in experimental stage, but results have been encouraging - Refinement of procedure is to use optogenetic stimulation (from Chapter 3) – can control individual connections, rather than all the axons going from one area to another Bipolar Disorder - Depression can be either unipolar or bipolar - Unipolar depression – people vary between normality and depression - Bipolar depression (formerly known as manic-depressive disorder – people alternate between two poles – depression and its opposite, mania - Mania – characterized by restless activity, excitement, laughter, self-confidence, rambling speech, and loss of inhibitions - Bipolar I disorder – people have full-blown episodes of mania - Bipolar II disorder – people have milder manic phases (hypomania), which are characterized mostly by agitation or anxiety - Bipolar disorder usually has onset in teenage years or early 20s About equally common for men and women – men more likely to have severe (bipolar I), but women more likely to get treatment - Brian increases its use of glucose during mania and decreases use during depression (see Fig. 14.13) - Disorder linked to many genes, but none specific to disorder Treatments - First successful treatment and still most common one is lithium salts o Lithium stabilizes mood, preventing a relapse into either mania or depression o Dose must be regulated carefully o Mechanism of effect evidently related to cells in hippocampus - Hippocampus forms new neurons throughout life and some than form in bipolar patients are hyperexcitable Lithium relieve bipolar disorder only if it alleviates hyperexcitability Other effective drugs are anticonvulsants valproate (Depakene or Depakote) and carbamazepine o If not effective, physicians sometimes supplement them with antidepressants drugs or antipsychotics - Antidepressant drugs are risky - Supplementary strategies include diet and sleep o Omega-3 fatty acids, such as those in seafood, reduce risk of bipolar disorder o Because of poor sleep quality, getting consistent, adequate sleep helps stabilize mood and decrease risk of new episode Schizophrenia Diagnosis - Was originally called dementia praecox - 1911 – Eugene Bleuler introduced term schizophrenia – term is Greek for “split mind” - Schizophrenia is not dissociative identity disorder - Bleuler meant a split between emotional and intellectual aspects of experience - Diagnosis is sometimes difficult - According to DSM - 5 o Someone must have deteriorated in ability to function in everyday life, and by for at least 6 months for reasons not attributable to other disorders. Must also have at least two of the following, including at least one from the first three: Delusions – unfounded beliefs Hallucinations – false sensory experiences (e.g., hearing voices) Disorganized speech Grossly disorganized behavior Weak or absent signs of emotion, speech and socialization - Probably a family of disorders rather than a single disorder - Positive symptoms – behaviors that are present that should be absent (first four items on list) - Negative symptoms – behaviors that are absent that should be present (number five on list) - - Usually stable over time and difficult to treat Cognitive symptoms – limitations of thought and reasoning that are common in schizophrenia, even in people with normal or above normal intelligence o Most typical type of thought disorder in schizophrenia is difficulty understanding and using abstract concepts – they interpret sayings too literally o Also have trouble maintaining and focusing attention o Memory impairments are common – related to reduced connectivity between sensory areas of the cortex and hippocampus - One hypothesis – impairments of attention and working memory are central problem o Can we make normal, healthy people talk or behave in incoherent ways if we overtax their working memory? (Read demonstration on p. 481) Differential Diagnosis of Schizophrenia - Therapist must make a differential diagnosis – one that rules out other conditions - Conditions that resemble schizophrenia: o Substance abuse – use of certain drugs can produce hallucinations and delusions o Brain damage – damage or tumors in temporal or prefrontal cortex o Undetected hearing deficits – can lead to delusions of persecution o Huntington’s disease – symptoms include hallucinations, delusions, and disorganized thinking Catatonic schizophrenia – uncommon type that includes motor abnormalities o Nutritional problems – niacin deficiency can produce hallucinations and delusions ( so can deficiency of vitamin C or allergy to milk proteins Demographic Data - About half of one percent of people suffer from schizophrenia at some point in life - Occurs in all ethnic groups and all parts of world o More common in cities than in rural areas, especially for people who have lived in large cities since early childhood Reasons? - More common in men than in women by ratio of about 7:5 - More severe in men and has earlier onset – usually in early 20s for men and mid-to late 20s for women - There are a number of unexplained oddities about schizophrenia (see p. 481) Genetics - Although schizophrenia has a genetic basis, it does not depend on any single gene Family Studies - The more closely you are biologically related to someone with schizophrenia, the greater your own probability of the disorder (see fig. 14.14) - Monozygotic twins have much higher concordance rate than do dizygotic twins o But concordance rate in monozygotic twins is still only about 50% o Note greater similarity between dizygotic twins than between siblings Dizygotic twins have same genetic resemblance as siblings, but greater environmental similarity (includes prenatal environment) Adopted Children Who Develop Schizophrenia - Studies of adopted children suggest a genetic basis o But, are also consistent with a prenatal influence - Studies on adopted children also support role for environmental influences o Study of adopted children in Finland (see fig. 14.15) Efforts to Locate a Gene - Researchers have identified more than a hundred genetic loci that differ on average between people with or without schizophrenia o Few of these genes actually change structure of any protein o Mostly, they control amount of production of proteins that are important for brain function o Many of these genes also increase probability of other psychological disorders - No common gene produces more than a small increase in probability of schizophrenia o DISCI (disrupted in schizophrenia 1) controls differentiation and migration of neurons in brain development, production of dendritic spines and generation of new neurons in the hippocampus - Certain variants in DISCI gene are more common in people with schizophrenia than in the rest of the population No common gene has strong effect, but certain rare mutations do – especially mutations that alter the structure of proteins at synapses, or mutations that interfere with major histocompatibility complex (part of the immune system) o Mutation in one gene is rare event, but mutation in any of several hundred genes is not so rare o Another contributor is microdeletion – deletion of a small part of the chromosome – microdeletions are more common among people with schizophrenia than in other people New mutation or deletion of any of hundreds of genes disrupts brain development and increases probability of schizophrenia The Neurodevelopmental Hypothesis - Hypothesis that schizophrenia is based on abnormalities in the prenatal or neonatal development of the brain – influences can be genetic, environmental, or both o Abnormalities by themselves do not cause schizophrenia, but leave the brain vulnerable to other disturbances at critical periods in childhood or adolescence o Supporting evidence includes: Several kinds of prenatal or neonatal difficulties are linked to later schizophrenia People with schizophrenia have minor brain abnormalities that apparently originate early in life Abnormalities of early development could impair behavior in adulthood Prenatal and Neonatal Environment - Torrey and colleagues – schizophrenia results from combination of genetic and environmental influences – distinguished between intermediate and low risk factors - Intermediate risk factors o Living in a crowded city o Prenatal or childhood infection with Toxoplasma gondi – parasite from cats that can infect humans – impairs brain development if the parasite infects the brain of an infant or child - Low risk factors - Risk is mildly elevated among people who had problems that could have affected their brain development. Includes” o Poor nutrition of mother during pregnancy o Premature birth o Low birth weight o Complications during delivery o Exposure of mother to extreme stress early in pregnancy o Prolonged illness during pregnancy – illness triggers the immune system o Head injuries in early childhood - If mother is Rh-negative and baby is Rh-positive, baby’s Rh-positive blood factor may trigger an immunological rejection by the mother o Second-and later-born babies have about twice the usual probability of schizophrenia - Another prenatal influence is the season-of-birth effect – tendency for people born in the winter to have slightly greater risk of developing schizophrenia that people born at other times of the year o Tendency greater for latitudes far from the equator o Leading hypothesis for effect is viral infections Influenza and viral epidemics are common in the fall Pregnant women become infected in the fall with a virus that impairs crucial stage of brain development in a baby who will be born in the winter Cause excessive cytokines in brain of fetus, impairing brain development (cytokines cross the blood-brain barrier) Cause fever, which slows division of fetal neurons Mild Brain Abnormalities - Some people with schizophrenia show mild abnormalities of brain anatomy - On average, people with schizophrenia have less than average gray matter, especially in the hippocampus, amygdala, and thalamus - Reduced white matter and larger than average ventricles - Consistent abnormality found in areas that mature slowly (e.g., dorsolateral prefrontal cortex) o Weaker than average connections from dorsolateral prefrontal cortex to other brain areas o Less than normal activity in this areas during tasks requiring attention and memory o People with schizophrenia perform poorly at tasks that depend on prefrontal cortex o Most patients with disorder show deficits of memory and attention similar to those of people with temporal or prefrontal cortex damage - Wisconsin Card Sorting Test (p. 485) Long-Term Course - People with schizophrenia vary in their long-term outcome o Up to one-fourth show serious disorder throughout life and possibly deteriorate o Perhaps 10-20% recover from first episode and do well from then on o The others (the majority) have one or more remissions and one or more relapses - Some studies report that a few brain areas deteriorate over age slightly more than is typical for people of their age - However, most of the abnormality of brain and behavior is present at first diagnosis, with some further impairment in next couple of years, but only slight deterioration after that in most patients - At microscopic level, cell bodies are smaller than normal, especially in the hippocampus and prefrontal cortex - Lateralization differences: o Right planum temporale is either the same size or larger than the left (it is larger in the left for most people) o Lower than normal overall activity in the left hemisphere, suggesting a subtle change in brain development - Abnormalities in people with schizophrenia are small and variable - Reasons for abnormalities are uncertain o May be due to substance abuse - Results are inconsistent as to whether brain damage associated with schizophrenia is progressive o Brains of people with schizophrenia do not show signs of neuron death Early Development and Later Psychopathology - Abnormalities are found in early development, but disorder is usually not diagnosed until after age 20 - Many people with schizophrenia had shown other problems since childhood o Attention deficits o Memory deficits o Problems with impulse control - Dorsolateral prefrontal cortex (DLPFC) is area that show consistent signs of deficit in schizophrenia -- matures slowly and damage may not show up until later o One of the slowest brain areas to mature o Researchers damaged area in monkeys and tested monkeys later Results at age 1 versus age 2 o DLPFC may not do too much at a very early age Treatments - Before antipsychotic drugs became available in mid-1950s, most people with schizophrenia were confined to mental hospitals. Today, mental hospitals are far less crowded Antipsychotic Drugs and Dopamine - Chlorpromazine (Thorazine) – discovered in 1950s; relieves positive symptoms for most patients - Antipsychotic or neuroleptic drugs – drugs that tend to relieve schizophrenia and similar conditions o Belong to two chemical families phenothiazines – includes chlorpromazine butyrophenones – includes haloperidol (Haldol) o Each of these drugs blocks dopamine receptors, specifically dopamine type D2 receptors (see Fig. 14.18) – drugs that are most effective against schizophrenia are the most effective at blocking dopamine receptors - The dopamine hypothesis of schizophrenia – holds that schizophrenia results from excess activity at dopamine synapses in certain brain areas o Dopamine release is increased in the basal ganglia o Further support for hypothesis – Substance-induced psychotic disorder – characterized by hallucinations and delusions – results from repeated doses of amphetamine, methamphetamine, cocaine, and LSD Drugs increase or prolong activity at dopamine synapses Second-Generation Antipsychotic Drugs - Drugs that block dopamine synapses produce their benefits by acting on neurons in the mesolimbocortical system o Set of neurons that project from the midbrain to the limbic system and prefrontal cortex - Drugs also block dopamine neurons in the mesotriatal system, which projects to the basal ganglia o Results in tardive dyskinesia – characterized by tremors and other involuntary movements - Best strategy is to prevent tardive dyskinesia from ever starting o Second-generation antipsychotics (aka atypical antipsychotics) – reduce the risk of movement problems from 30% to 20% o Most common are clozapine, amisulpride, risperidone, olanzapine, and aripiprazole o Second-generation antipsychotics have less effect on dopamine type D2 receptors but more strongly antagonize serotonin type 5-HT2 receptors o Also increase release of glutamate o Produce other side effects (weight gain and impairment of immune system) - Second-generation antipsychotics do not differ by much in their effectiveness o Results of drug studies sponsored by one of the competing drugs Role of Glutamate - About one-third of all patients fail to respond to the drugs that block dopamine – dopamine hypothesis is at best incomplete - The glutamate hypothesis of schizophrenia – the problem relates in part to deficient activity at glutamate synapses, especially in prefrontal cortex - In many brain areas, dopamine inhibits glutamate release, or glutamate stimulates neurons that inhibit glutamate release - Therefore, increased dopamine could produce same effects as decreased glutamate - Schizophrenia is associated with lower than normal release of glutamate in prefrontal cortex - Further support for hypothesis comes from effects of phencyclidine (PCP or “angel dust”) o Low doses produce intoxication and slurred speech o Larger doses produce both positive and negative symptoms of schizophrenia o PCP and related drug Ketamine produce little if any psychotic response in preadolescents o LSD, amphetamine, and cocaine produce temporary symptoms of schizophrenia in almost anyone. However, PCP produces relapse for someone who has recovered from schizophrenia o It is difficult to test the glutamate hypothesis of schizophrenia Autism Spectrum Disorders - Once considered rare condition - Today, estimates of its incidence vary considerably - Median estimate of about one in 160 people worldwide o Part of increase is due to greater awareness and greater likelihood of using autism label, but it is possible that condition has become more common Symptoms and Characteristics - Asperger’s syndrome – term for people with mild impairment similar to autism, but term is no longer used. Autism spectrum disorder combines the two - Four times more common in boys than in girls - When it does occur in females, tends to be more severe - Occurs throughout the world - APA identifies following characteristics of ASD o Deficits in social and emotional exchange o Deficits in gestures, facial expressions, and other nonverbal communication o Stereotyped behaviors (e.g., repetitive movements) o Resistance to change in routine o Unusually weak or strong responses to stimuli (e.g., indifference to pain or panicked reaction to a sound) - Most people with autism have additional problems (e.g., epilepsy, anxiety, poor coordination, deficits in attention) - Many have abnormalities in cerebellum – results in clumsiness and impaired voluntary eye movements - Parents often notice a problem from the start, and other problems increase over time (e.g., eye contact after about 2 months gradually declines over next two years) - Problem is not aversion to eye contact – they maintain eye contact as much as normal children do – problem is that eyes and other social cues do not readily attract their attention - Certain strengths occur – many develop narrow skills at which they excel o They also tend to be substantially better than average at detecting visual motion Genetics and Other Causes - Many genes have been linked to autism, but no common gene exerts a large effect - Number of possible mutations of genes relevant to autism is large, but their effects converge onto just a few chemical pathways that affect early development of the brain – exploring those pathways can help illuminate basis of autism - Most mutations occur on chromosomes inherited from the father, and oldest fathers slightly more likely to have children with autism than younger fathers are (same is true for schizophrenia) o What is explanation for older-father effect? - Prenatal environment can also contribute to autism – pregnant mother’s exposure to pesticides, solvents, perfumes, air pollutants - Some mothers of children with ASD (about 12%) have antibodies that attack certain brain proteins – few if any mothers of unaffected children have these antibodies o Identifying women with those antibodies may make it possible to intervene pharmacologically to prevent disorder - Another contributing factor: Folic acid (vitamin B9) is important for development of nervous system – women who take folic acid pills during pregnancy have about half the probability of having child with autism compared to other women - Children with autism have brain abnormalities that vary from one to another o Notable feature is a large head – at age one, mean head size for ASD children is 10% greater than average o For next several years, much of cerebral cortex is larger than average o Some connections within the brain are stronger than average and some are weaker o By young adulthood, brain size is only 1% greater than average o Brain development is progressing in an unusual way, but unknown how this relates to symptoms Treatments - No medical treatments can help with central problem of decreased social behavior and communication o - Risperidone (2nd generation antipsychotic drug) sometime reduce stereotyped behaviors, but has serious side effects Behavioral treatments address deficits in social behavior and communication o Focus on eliciting child’s attention and reinforcing favorable behaviors o Successful with many children but not all o Cognitive behavioral therapy provides moderate benefits according to parents and therapists – but not according to the people with autism o A number of fad treatments have arisen – can become popular despite supporting evidence
