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PSYCHOLOGICAL DISORDERS CHAPTER 14 Schizophrenia Affective disorders Anxiety disorders Schizophrenia • Mental disorders are common and disabling, affecting 1 in 3 people over their lifetime. • Schizophrenia is a psychosis that is characterized by perceptual, emotional, and intellectual deficits; loss of contact with reality; and inability to function in life. – The term means “split-mind,” a distortion of thought and emotion; it is not the same as multiple personality. • Schizophrenia is currently divided into diagnostic subtypes, such as paranoid schizophrenia, but these are now more often considered symptoms rather than separate disease processes. Schizophrenia • Schizophrenia afflicts men and women about equally often. – Men usually show the first symptoms during the teens or twenties, while the onset for women ordinarily comes about a decade later. • Acute symptoms develop suddenly and are typically more responsive to treatment. – The prognosis is reasonably good in spite of brief relapses. • Symptoms that develop gradually and persist for a long time with poor prognosis are called chronic. Schizophrenia • Schizophrenia is a familial disorder—incidence is higher among the relatives of schizophrenics. – Heritability for schizophrenia has been estimated at between .60 and .90. – Identical twins of schizophrenics are three times as likely to be schizophrenic as the fraternal twins of schizophrenics. Concordance for Schizophrenia Among Relatives Figure 14.5 Schizophrenia • Adopting a child out of a schizophrenic home provides no protection from developing the disorder. • Discordance in identical twins means that some other factor must play a role. – However, risk is the same in the offspring of the affected and unaffected members of a discordant pair. – This suggests that the genes are not expressed in the unaffected twins. ◊ Risk in Offspring of Normal & Schizophrenic Twins Figure 14.6 Schizophrenia • Various problems make the identification of candidate genes difficult. – Not all studies include the spectrum diagnosis. – The effects of multiple genes are small and cumulative. – A significant cause is rare copy number variations. • The genes that have been identified play a role in: – – – – Neurotransmission and transmitter deactivation Neural development, such as axon guidance Neurodegeneration Immune factors and the inflammatory response ◊ Schizophrenia • The Vulnerability Model – Some threshold of causal forces must be exceeded in order for the illness to occur. – Environmental challenges combine with a person’s genetic vulnerability to exceed that threshold. • Environmental influences work in part by epigenetic means, by upregulating and downregulating gene functioning. ◊ Schizophrenia • Positive symptoms involve the presence or exaggeration of behaviors, such as delusions, hallucinations, thought disorder, and bizarre behavior. • Positive symptoms – are more often acute and – are more likely to respond to antipsychotic medications. ◊ Schizophrenia • Negative symptoms are characterized by the absence or insufficiency of normal behaviors, and include – lack of affect (emotion); – inability to experience pleasure; lack of motivation, poverty of speech, and impaired attention. Negative symptoms tend to be chronic. Patients typically have: poorer adjustment prior to onset; poorer prognosis after diagnosis; tissue deficits and intellectual and cognitive deficits. Schizophrenia • The dopamine hypothesis states that schizophrenia is caused by excess dopamine activity in the brain. – Amphetamine, a dopamine agonist, can cause hallucinations and delusions that look very much like those in schizophrenia. – Drugs that block dopamine receptors are useful in treating schizophrenia, particularly the positive symptoms. – Schizophrenics typically have higher dopamine activity in the striatum. – However, some schizophrenics are deficient in dopamine, and 30% to 40% are not helped by anti-dopamine drugs. Schizophrenia • The effectiveness of new drugs has supported alternative explanations for schizophrenia. – Atypical or second generation antipsychotics • are as effective as older drugs; • are more effective in 15-25% of cases; • help treatment-resistant schizophrenics. – Atypical antipsychotics increase glutamate levels. – They affect serotonin levels, and several block 5-HT2 serotonin receptors. – They also target D2 receptors less and produce less tardive dyskinesia. Schizophrenia The glutamate theory states that schizophrenia is due to reduced glutamate activity. PCP blocks NMDA glutamate receptors and can cause a type of psychosis that resembles schizophrenia. Glycine activates the NMDA receptor, and improves negative and cognitive symptoms. Atypical antipsychotics downregulate the transporter gene, hence decreasing reuptake. There is evidence that the dopamine imbalance may be a result of reduced glutamate activity in the prefrontal cortex. Schizophrenia • Some schizophrenics have enlarged ventricles, indicating brain tissue deficits. – Most schizophrenics have normal-sized ventricles. – The changes in ventricle size are small. Figure 14.8: The brain on the left is from a schizophrenic patient. Schizophrenia Hypofrontality, a decline in frontal lobe function, is characteristic of schizophrenia. The Wisconsin Card Sorting Test, which requires reversing strategies, is used to assess hypofrontality. Schizophrenics perform poorly on the task. Their hypofrontality involves a dopamine deficiency in the dorsolateral prefrontal cortex. Amphetamine, which increases dopamine, improves prefrontal blood flow and performance. Dorsolateral prefrontal damage causes symptoms seen in schizophrenia, including flat affect, social withdrawal, and cognitive impairments. Blood Flow During Card Sorting Task Figure 14.9 (a) During the task, blood flow is greater in the control brain (above) than in the brain of a schizophrenic (below). Schizophrenia Recent attention is shifting from localized deficits to disrupted coordination of neural activity. In schizophrenics, the normal coordination of activity between the hippocampus and prefrontal cortex during a working memory task is absent. This is at least partly due to decreased white matter in the frontal and temporal areas. Lack of coordination probably explains hypofrontality. Abnormal synchronization in sensory areas may explain visual and auditory hallucinations. Impaired auditory gating, the inability to suppress environmental sounds, is associated with synchrony deficits across wide areas. Schizophrenia • Some of the brain defects in schizophrenia apparently stem from problems during pregnancy or at the time of birth. • Winter Birth Effect: More schizophrenics are born during the winter and spring. – Infants born during this time would have been in the second trimester in the fall or early winter, when there is a high incidence of infectious diseases. – Incidence of schizophrenia is higher in individuals born following influenza epidemics. – The effect is likely caused by the immune reaction to the virus rather than by the virus itself. Schizophrenic Births, Season, & Influenza Figure 14.12 Schizophrenia • At least some of the prenatal effects are likely epigenetic. – Schizophrenic births doubled following the 1944-1945 food blockade of the Netherlands. – This effect was confirmed in a larger study of famine in China. (See Chapter 6 for epigenetic effects of starvation.) – Risk for schizophrenia increases if the father is older than 25 at the time of conception; beyond age 50 the risk increases by two-thirds. ◊ Schizophrenia Most researchers agree that schizophrenia is a disorder of early development. Brains show problems in migration of cells in the temporal and frontal lobes; a deficiency of Reelin, a protein that functions as a “stop” signal for migrating cells, particularly in the hippocampus and prefrontal areas; gray matter deficits and ventricular enlargement at the time of diagnosis. Behavioral evidence from home movies suggest that symptoms are present long before diagnosis is made. There is also evidence for severe pruning of synapses during adolescence involving both dopamine and glutamate pathways. Gray Matter Loss During Adolescence Figure 14.14 Schizophrenic adolescents show much more gray matter loss during circuit pruning. Affective Disorders One in five people will experience a mood disorder in their lifetime. The financial cost is almost $19 billion a year in the U.S. In major depression a person often feels sad to the point of hopelessness for weeks at a time; loses the ability to enjoy life, relationships, and sex; and experiences loss of energy and appetite, slowness of thought, and sleep disturbance. Mania involves excess energy and confidence that often lead to grandiose schemes. Decreased need to sleep, increased sexual drive, and abuse of drugs are common. Affective Disorders • Depression alone is called unipolar depression. – Females are three times more likely to be depressed than males. – Risk for men increases with age; women are most vulnerable between the ages of 35 and 45. • In bipolar disorder, the individual alternates between periods of depression and mania. – Mania can occur alone, but this is rare. – Bipolar patients often show psychotic symptoms such as delusions, hallucinations, paranoia, or bizarre behavior. – Bipolar disorder occurs equally in males and females, usually in the early 20s to age 30. Affective Disorders • Concordance for affective disorders is about 69% in identical twins, compared to 13% in fraternal twins. • In depression, heritability is somewhere around .37, with the number somewhat higher for women than for men. • Different genes may be involved in depression in males and females. • This genetic difference may explain why females more often suffer from depression whereas males are more likely to commit suicide. ◊ Affective Disorders People with the short allele for the 5-HTTLPR serotonin transporter gene are more vulnerable to depression. They show tissue loss in the amygdala and the subgenual anterior cingulate cortex. Their amygdala is hyperreactive to stress, apparently due to lack of damping by the subgenual anterior cingulate cortex. An allele of the gene for brain-derived neurotrophic factor, which encourages neuron survival, protects against the effects of the short 5-HTTLPR allele. ◊ Depression and the Serotonin Transporter Gene Figure 14.15 People with the short allele had more depressive episodes as stress increased. Affective Disorders • The heritability for bipolar disorder has been estimated between 85% and 93%. • In one study that examined large sets of data, 69 genes for bipolar disorder were identified. • Many of these genes overlap with those that play a role in substance abuse. • Some mutations found in bipolar disorder are also involved in the control of circadian rhythms. ◊ Affective Disorders • The monoamine hypothesis states that depression involves reduced activity at norepinephrine and serotonin synapses. – All the effective antidepressant drugs increase the activity of one or both transmitters at the synapses. • Monoamine oxidase inhibitors block the destruction of excess monoamines in the terminals. • Tricyclic antidepressants block reuptake at the synapse. • Atypical or second-generation antidepressants affect a single transmitter; fluoxetine (Prozac) is a selective serotonin reuptake inhibitor. Synaptic effects take hours; improvement takes weeks. Affective Disorders Electroconvulsive Therapy (ECT) A convulsive seizure is produced by applying 70 to 130 volts of electricity to the head of an anesthetized patient. Therapeutic effect is rapid, a benefit for suicidal patients. ECT is usually reserved for patients who do not respond to the medications or who cannot take them. Like the drugs, ECT increases the sensitivity of postsynaptic serotonin receptors. Sensitivity of presynaptic autoreceptors is reduced, increasing norepinephrine and dopamine release. Brain excitability decreases, probably due to an increase in diminished GABA. Affective Disorders • Other types of electrical stimulation have also been used to treat depression. – Fast TMS (transmagnetic stimulation) produces effects similar to traditional ECT. – Deep brain stimulation of the subgenual anterior cingulate gyrus is another approach that can produce immediate effects. – Stimulation of the vagus nerve relieves depression, probably because it increases GABA levels in the cortex. ◊ Affective Disorders • Antidepressants, ECT, and Neural Plasticity – Treatment increases neurogenesis in the hippocampus. New cells are thought to be more plastic. – The time required for the new neurons to form connections matches the delay in symptom improvement. – There is evidence that treatment increases plasticity and synaptic enhancement even when neurogenesis is blocked. – Antidepressants and ECT modify genes that contribute to neurogenesis, neuron survival, and plasticity. ◊ Neurogenesis During Antidepressant Treatment Figure 14.18 (a) Fluoxetine (Prozac) increased neurogenesis. (b) Brown dots are new cells. Affective Disorders • The circadian rhythm – the one that is a day in length – tends to be phase advanced in affective disorder patients. • Patients also enter rapid eye movement sleep (REM) earlier in the night and spend more time in REM than normal. • Some patients who are unresponsive to medication can get relief from their depression by readjusting their circadian rhythm. • Some depressed patients also benefit from a reduction in REM sleep. Affective Disorders • Some people’s depression rises and falls with the seasons and is known as seasonal affective disorder (SAD). – Most SAD patients are more depressed during the fall and winter, then improve in the spring and summer. – A smaller number experience depression in the summer and improve during the cooler winter months. – A treatment for winter depression is phototherapy–having the patient sit in front of high-intensity lights for a couple of hours or more a day. – Winter depression involves low serotonin, which explains why carbohydrate craving is typical. Affective Disorders • In bipolar disorder, periods of depression typically last longer than mania. • Cycling is regular in some and unpredictable in others; cycle length varies from 48 hours to months. • Lithium is the drug of choice for bipolar disorder, and usually works best in the manic phase. – The belief has been that lithium works by stabilizing many transmitters. – Recent evidence is that lithium and valproate inhibit protein kinase C, an enzyme that regulates neuron excitability. ◊ Metabolism in a Rapid-Cycling Bipolar Patient Figure 14.22 Top: The patient during depression. Middle: A day later, during mania. Affective Disorders • Structural and Functional Alterations – There are volume deficits in the hippocampus, dorsolateral cortex, and subgenual prefrontal cortex. The amygdala is increased in volume. – Activity is reduced during depression, though unipolars have increases in the amygdala and ventral prefrontal cortex. – The ventral prefrontal cortex may be a “depression switch;” its activity varies with the mood state. – Activity increases in the subgenual prefrontal cortex at the start of a period of mania, so it may be a “bipolar switch”. Affective Disorders • Suicide is very common among people with psychiatric illnesses. – Mood disorders account for 60% of all completed suicides. – About 20% of people hospitalized for bipolar disorder commit suicide. Six chromosome sites have been associated with suicide risk. Psychiatric patients who attempt suicide are more likely to have a low level of the serotonin metabolite 5-HIAA. Selective serotonin reuptake inhibitors can increase risk, possibly because they increase agitation. Serotonin Levels and Suicide Figure 14.25 Anxiety Disorders • Generalized Anxiety, Panic Disorder, and Phobia – People with generalized anxiety disorder experience chronic unease and worry, overreacting to stressful conditions. – In panic disorder, the person has a sudden and intense attack of anxiety with rapid breathing, a high heart rate, and feelings of impending disaster. – Phobias refer to intense fear and avoidance of particular objects (for example, dogs) and situations (such as heights, crowds, or enclosed spaces). ◊ Anxiety Disorders Anxiety disorders involve deficits in GABA and serotonin, are often treated with antidepressants that modulate serotonin. Brain areas involved in anxiety include amygdala locus coeruleus parahippocampal gyrus ◊ Anxiety Disorders Posttraumatic Stress Disorder (PTSD) PTSD is characterized by recurring thoughts and images (flashbacks), nightmares, overreactivity to environmental stimuli, and lack of concentration. PTSD can be triggered by combat, sexual assault, and other traumatic experiences. More men are exposed to traumatic situations than females, but females are four times as likely to develop PTSD when they are exposed. – Vulnerability factors include: • a smaller hippocampus, apparently due to childhood abuse; a genetic predisposition; heritability is about 30%. Anxiety Disorders Treatments for PTSD Drugs & psychotherapy often do not work with PTSD. Exposure therapy, an extinction process, is an alternative. But people with the VAL66MET allele have hypoactive connections between the prefrontal cortex and the amygdala and are resistant to fear extinction. Fear erasure during reconsolidation shows some promise for relieving PTSD symptoms. – Virtual reality is another experimental treatment. • The patient uses relaxation techniques while controlling progress through a video simulation of the traumatic situation. • Success with this therapy is about 80%. ◊ Anxiety Disorders • Obsessive-compulsive disorder (OCD) consists of two behaviors, obsessions and compulsions. – An obsession is a recurring thought, such as an annoying tune or wishing harm to another person. – The compulsive individual is compelled to engage in repetitive behaviors such as hand washing, ritualistic touching, or checking appliances to make sure they are turned off. – Serotonin levels are high in OCD; antidepressants help, by reducing receptor sensitivity. – Antipsychotics and glutamate blockers help other patients. Anxiety Disorders OCD patients have increased activity in the orbital frontal cortex and in the caudate nuclei of the basal ganglia. This excess activity decreases following successful drug treatment and even after behavior therapy. Surgery is sometimes used to disconnect the orbitofrontal cortex from the anterior cingulate cortex or to deliver stimulation. OCD occurs with a number of diseases that cause basal ganglia damage. For example, streptococcus infections in children can cause an immune attack on the basal ganglia. Anxiety Disorders There are also white matter abnormalities in OCD They suggest a defect in connections of the cingulate gyrus with a circuit involving the basal ganglia, thalamus, and cortex. – This deficit has two apparent effects: • a loss of impulse control; • inability to activate the orbitofrontal cortex when a task requires switching choices. ◊ Anxiety Disorders Some researchers cite trichotillomania (hair pulling) as evidence OCD is a disorder of “excessive grooming.” Both are hereditary and hair pullers have a number of relatives with OCD. Both respond to serotonin reuptake inhibitors. Another condition similar to OCD is hoarding, though it may be a separate disorder. Tourette’s syndrome is also similar to OCD. This is a disorder of motor and phonic tics. Sufferers often have OCD as well and, like OCD, activity is increased in the basal ganglia. However, it is usually treated with dopamine antagonists. Caudate Nuclei Dopamine Activity in Tourette’s Figure 14.30 Anxiety Disorders Family and twin studies indicate that the anxiety disorders are genetically influenced, with heritabilities ranging between .20 and .43, depending on the disorder. Understanding the hereditary underpinnings of anxiety is difficult because of significant genetic overlap with other disorders. Over 90% of individuals with anxiety disorders have a history of other psychiatric problems. The overlap with affective disorders is particularly strong. 50-60% of patients with major depression also have a history of one or more anxiety disorders and panic disorder is found in 16% of bipolar patients.