Schizophrenia: NEUR 1202 Fall 2024 PDF

Schizophrenia Schizophrenia Schizophrenia is classified as a psychotic disorder. – Psychosis (from G. “psyche” – mind/soul and “-osis” – abnormal condition) means a loss of contact with reality. Schizophrenia affects approximately 1/100 people in North America. The annu...

Schizophrenia Schizophrenia Schizophrenia is classified as a psychotic disorder. – Psychosis (from G. “psyche” – mind/soul and “-osis” – abnormal condition) means a loss of contact with reality. Schizophrenia affects approximately 1/100 people in North America. The annual cost of schizophrenia in the US is estimated at around $60 billion, due largely to the cost of treatment and lost wages. Schizophrenia is a common disease with severe consequences for patients and their loved ones, and for this reason, it is an area that has received a lot of attention from researchers. Myths about schizophrenia 1. MYTH: People who have schizophrenia are violent and dangerous. – FACT: Individuals who are being treated for schizophrenia are not more violent than anyone else. For those living with untreated schizophrenia, they are the greatest danger to themselves - the greatest risk is self-harm or suicide. 2. MYTH: People who have schizophrenia have multiple personalities. – FACT: Schizophrenia is not the same as multiple personality disorder (aka dissociative identity disorder.) 3. MYTH: People who have schizophrenia see things that aren’t there. – FACT: Schizophrenia is characterized mostly by auditory hallucinations (voices, etc.,.) Visual hallucinations are possible, but much less common. Characteristics of schizophrenia The symptoms experienced by people with schizophrenia can be divided into three basic groups. 1. Positive symptoms are symptoms that go beyond normally occurring experiences. – hallucinations (auditory most common) – delusions (irrational beliefs or paranoia that misrepresents reality), e.g., erotomanic delusions 2. Negative symptoms are characterized by a deficit or absence in a normal behavior. – E.g. apathy, limited thought/speech, emotional and social withdrawal. 3. Cognitive symptoms (also called disorganized symptoms) are symptoms that are characterized by erratic changes in speech, motor behavior, and emotions. – E.g. disorganized speech, inappropriate emotional reactions DSM-5 diagnostic criteria Key points: Individual must have at least one of: delusions, hallucinations, or disorganized speech. Diminished level of function. Long-lasting symptoms. Not due to drugs or some other medical condition. Development Schizophrenia is usually diagnosed in late adolescence or early adulthood. – It strikes right as people enter the world and begin to gain independence, it is a cruel surprise that deprives people of the chance of a normal life. – There is usually a lag of 1-2 years between the first onset of symptoms and diagnosis. In 85% of people, full-blown schizophrenia is preceded by a Mental illnesses like schizophrenia often prodromal stage – a 1–2-year period appear during university. The stress of moving, school, and possible drug/alcohol where subdued symptoms begin to abuse probably makes it worse. appear. – Magical thinking, minor illusions (feeling of a presence when one is alone, etc.,), and ideas of reference are common prodromal symptoms. Development and prognosis Complete remission is rare: most people (~78%) being treated for schizophrenia go through a pattern of relapse and recovery. The prognosis for schizophrenia is poorer than for most other disorders, but recovery/remission is more likely given the following factors: – Good social adjustment prior to onset of schizophrenia. – A low proportion of negative symptoms. – A good social support system for patients. The symptoms of schizophrenia may decrease with age, or at least “level out”. Development and prognosis Illustration from Barlow & Durand, Abnormal Psychology, 6th ed. Etiology - genetics There is clear evidence for a genetic link to schizophrenia. – This can be shown by looking at how the relative risk of developing the illness changes depending on whether other people in one’s family have schizophrenia. Monozygotic (identical) twins share 100% of their genes. – Therefore, if schizophrenia was 100% caused by genetics, both twins would always have schizophrenia. – In reality, the risk is only 48%. Dizygotic (fraternal) twins only share 50% of their genes. – If schizophrenia was 100% genetic, then you’d expect 50% of fraternal twins to have schizophrenia if the other does. Genes implicated are to do with dopamine functioning (as well as GABA, glutamate) Illustration from Barlow & Durand, Abnormal Psychology, 6th ed. Etiology – perinatal factors There is evidence that problems before and shortly after birth (the perinatal period) can increase the risk of developing schizophrenia. – These environmental stressors can unlock the predisposition for schizophrenia, aka, “the two-hit hypothesis” Fetal exposure to influenza and other virus- like diseases may subtly damage the fetal brain in a way that causes the symptoms of schizophrenia later in life. – Toxoplasmosis gondii (t.gondii) Pregnancy and delivery complications are also correlated with the development of schizophrenia. Prenatal nutrition / stress also implicated – Dutch Hunger winter Anatomical basis of schizophrenia Anatomical studies of brains from people with schizophrenia show enlarged lateral ventricles. Ventricle size on its own is not a problem, but since ventricles are empty space, it suggests that nearby parts of the brain either did not develop properly or have atrophied. MRI image of healthy and schizophrenic (right) brain. Note the enlarged lateral ventricles in the person with schizophrenia. The empty space left behind fills with CSF. It is difficult to tell whether this observation causes schizophrenia, or if it’s simply a consequence of the disease. – Genetic studies suggest that enlarged ventricles are an inherited risk factor, present in both people with schizophrenia and their healthy siblings. Anatomical basis of schizophrenia In addition to gross structural pathologies, several subtle microscopic pathologies have been characterized. Post-mortem brains from people with schizophrenia show reduced dendritic spine density in the prefrontal cortex. – Dendritic spines are small knobs located on dendrites. Each dendritic spine represents Photomicrograph of Golgi-Cox stained a post-synaptic terminal. dendrites. Note the reduced spine density in the dendrite in the right photo (from a patient with schizophrenia). Anatomical basis of schizophrenia Patients with schizophrenia often show reductions in the size of the hippocampus. This can be measured in living patients by techniques such as structural MRI. Based on comparisons between young and old patients, reductions in hippocampal volume are due to degradation. Young patients who are just showing symptoms for the first time have normal sized hippocampi. Structural MRI of human brain, showing areas of reduced hippocampal volume. The degree of hippocampal degradation is correlated with illness severity – people with worse symptoms have smaller hippocampal volume. Post-mortem samples show disorganized neurons in the hippocampus of schizophrenia brains. Illustration from Kolb & Wishaw, An Introduction to Brain and Behavior. But wait, what causes these changes? Antipsychotic drugs A major advance in the treatment of schizophrenia came with the discovery of chlorpromazine (trade name: Thorazine) in the early 1950s. Chlorpromazine was tried as an anesthetic and for various other purposes, but it produced amazing success when given to psychotic patients. – Patients were said to be “ready to return to normal life”, often after years of crippling psychosis. Because of its effects on psychosis, Vintage chlorpromazine chlorpromazine and related drugs are called (Thorazine) ad. Thorazine was offered as a cure not only antipsychotics. for psychosis, but also for – Chlorpromazine is the first discovered member of dementia, nausea, rowdiness, hiccups, menopause, etc., the phenothiazine family of first-generation antipsychotics. Antipsychotic drugs What makes the antipsychotics unique is that they reduce psychotic symptoms without producing too much general sedation. – Psychotic patients had been sedated for years, but chlorpromazine relieved them of symptoms without making them hopelessly sleepy… This breakthrough allowed patients to finally leave their institutions and resume normal life. – The deinstitutionalization movement was kick-started by the discovery of chlorpromazine. – For this reason, the discovery of chlorpromazine was one of the most important breakthroughs in the history of The number of patients in mental institutions began to decline rapidly psychiatry. following the discovery of chlorpromazine and other similar drugs. Illustration from Kolb & Wishaw, An Introduction to Brain and Behavior. How do antipsychotics work? If antipsychotic drugs like chlorpromazine can reduce the symptoms of schizophrenia, then learning how they work can help us understand the disorder Dopamin itself. Chlorpromazine e It turns out that chlorpromazine affects many neurotransmitter systems, but its effects on dopamine are the most important for treating psychosis. Chlorpromazine, and all other Dopamine receptor antipsychotics work primarily by blocking dopamine receptors, specifically the D2 variety. – They are D2 ANTAGONISTS Methods minute: Positron Emission Tomography (PET) PET is an imaging technique that detects changes in blood flow by measuring changes in the uptake of compounds such as oxygen or glucose – Radioactive molecules are injected into the bloodstream – Used to analyze the metabolic activity of neurons Very expensive Good TEMPORAL resolution Anatomy Minute: The Striatum Striatum is part of the basal ganglia Dorsal striatum is involved in habit learning, motor and action planning Ventral striatum (aka “nucleus accumbens) involved in reward learning, motivation Symptoms of Schizophrenia relate to overstimulation of D2 receptors Dopamine D2 receptors are found in a number of places, but it seems that the striatum is the most important for schizophrenia. The positive symptoms of schizophrenia seem to be caused by excessive stimulation of dopamine D2 receptors in the striatum. – In image, you can see that radioactive dopamine ligand (11C-NMSP) is binding a lot in the striatum (“hot spots”); after haloperidol, this occupies the receptor and Images of D2 receptor binding in the prevents dopamine from binding to it. striatum of a patient with schizophrenia before and after haloperidol treatment So, blocking dopamine D2 receptors (haloperidol is another kind of first- generation antipsychotic). in the striatum with drugs like chlorpromazine relieves the positive, psychotic symptoms of schizophrenia. Further evidence for dopamine’s role We’ve seen how blocking dopamine receptors improves psychotic symptoms. A great way to expand upon this finding would be to see if excess dopamine stimulation causes psychotic symptoms. It turns out that stimulant drugs such as cocaine and amphetamine can, when taken in high doses, produce psychosis in drug users. – As detailed previously, cocaine (and amphetamine) works by increasing dopamine release in the brain. So in general, drugs that decrease dopamine signaling reduce psychosis, drugs that increase dopamine signaling cause psychosis. – This all adds up to some fairly strong evidence for the role of dopamine in schizophrenia… More about dopamine It turns out that schizophrenia may also involve under-stimulation of dopamine D1 receptors in the prefrontal cortex. This condition is called hypofrontality, and it can explain why people with schizophrenia often struggle with planning, problem solving, and high- level reasoning. The ideal drug would be able to block D2 receptors, but activate D1 receptors. Unfortunately, no such drug has been discovered yet. But wait, there’s more… Glutamate Hypofunction: Schizophrenia may involve reduced activity of glutamate neurons, linked to cognitive and negative symptoms. Glutamate = Go! GABA’s Role: GABA (inhibitory) balances excitatory activity from glutamate; disruptions in this balance can contribute to the disorganized thinking and behavior seen in schizophrenia. GABA = STOP! Synaptic Pruning: Abnormal synaptic pruning (removal of extra synapses) in adolescence, influenced by glutamate and immune factors, may underlie schizophrenia’s neurodevelopmental DO NOT MEMORIZE THIS FIGURE! aspects. Summary – Neuroscience of Schizophrenia Genetic Basis: Schizophrenia has a strong genetic component (~40% heritability), with numerous risk genes affecting neurodevelopment, immune responses, and neurotransmitter systems (e.g., dopamine, glutamate). Dopamine Dysregulation: Excess dopamine activity in subcortical regions is linked to positive symptoms (hallucinations, delusions), while reduced dopamine in the frontal cortex contributes to cognitive deficits. Glutamate and GABA Imbalance: Insufficient glutamate activity at NMDA receptors and disrupted GABA regulation contribute to cognitive symptoms and negative symptoms (e.g., reduced motivation, emotional expression). Neurodevelopmental Factors: Abnormal brain development, particularly excessive synaptic pruning in adolescence, may underlie schizophrenia’s onset. Environmental stressors can interact with genetic risk, aligning with the "two-hit" hypothesis.