PATHOPHYSIOLOGY MODULE #2: Alterations in Mental Health- Schizophrenia

Neurodevelopmental theory from prenatal period to adolescence: Again as a reminder here, these changes occur from a neurodevelopmental process of a combination of series of genes that are affected, obstetrical complications and prenatal stressors, changes in the brain and synaptic growth and pruning that occurs throughout childhood and particularly adolescence and then the switch seems to be turned on and symptoms appear in late adolescence to early adulthood, and the person's symptoms can be triggered earlier if they smoke cannabis containing large amounts of THC.

(SORRY LAME SLIDE) Brain development from prenatal periods through adolescence requires several coordinated molecular activities, including cell proliferation, cell migration, axonal outgrowth, pruning of neuronal connections, programmed cell death and myelination. All these activities require coordinated brain development, usually through activation and inactivation of proteins by genes. This is what happens in the non-schizophrenic brain.

Two (or more ) of the following, each present for a significant portion of time during a 1 month period (or less if successfully treated). At least one must be (1), (2), or (3): what are they?

1) Delusions 2) Hallucinations 3) Disorganized speech 4) Grossly disorganized or catatonic behaviour 5) Negative symptoms

______ a gene on chromosome 14 has been found to be a susceptibility gene in schizophrenia with reduced levels of it and one if its substrates in the hippocampus, frontal cortex of people with schizophrenia as well as reduced gray matter volume in the caudate and right prefrontal cortex and reduced cognitive performance. It has also been found to be implicated in proper dopaminergic neurotransmission.

AKT1

Describe acute dystonia.

Acute dystonia occur early in the course of pharmacotherapy and involve severe muscle spasms, particularly in the back, neck, tongue and face. Akathisia is an inability to rest or relax. the person may pace, have trouble sitting or remaining still and may have trouble sleeping.

Both _____________ and __________ use can mimic the symptoms of schizophrenia.

Amphetamine and cocaine These drugs block the reuptake of dopamine and foster symptoms of schizophrenia.

Which medications followed the discovery of the conventional medications and have a broader spectrum of action?

Atypical antipsychotics Controlling both positive and negative symptoms of psychosis and schizophrenia. They produce fewer EPS type side effects but do produce troubling side effects of their own.

All antipsychotic drugs act by entering the dopaminergic synapses and competing with dopamine for D2 receptors. By blocking about ____ % of D2-receptors, antipsychotics reduce the symptoms of schizophrenia. If ____ % are blocked, motor abnormalities begin to occur. A. 70%, 85% B. 65%, 80% C. 60%, 80% D. 65%, 95%

B. 65%, 80%

Genetic factors are thought to contribute to about ___ % of the liability to develop schizophrenia in the population and environmental factors are thought to contribute ___ % of the liability. A. 70%, 30% B. 80%, 20% C. 90%, 10% D. 60%, 40%

B. 80%, 20% Certain variations in genes, called polymorphisms may increase the risk for it. A polymorphism is an alteration in the sequence of DNA of the gene. Also from the depression module we talked about how genes help control the metabolism of neurotransmitters and their receptors the numbers of particular types of neurons and their synaptic connections, the intracellular transduction of neuronal signals and the speed with which all of these can change in response to environmental stressors. IT is thought that multiple genes are involved in the development of schizophrenia each appearing to have different regional brain expressions at different developmental stages. Research suggests the genes affecting brain development related to cognitive ability are operating more strongly in late adolescence, which correlates with the onset of schizophrenia. Important to note that the research is not conclusive and in the future large scale sequencing studies in large samples of people with schizophrenia need to occur to determine which genes prove to be of clinical importance.

Which drugs are first choice for treating schizophrenia? A. Typical antipsychotics B. Atypical antipsychotics C. Antiparkinsons D. Both A and B

B. Atypical Atypical are thought to have fewer and less distressing side effects and have been found to be equally or more effective than typical and for these reasons have become the first choice medications for those suffering form psychosis or schizophrenia. Side effects include little or no extra pyramidal side effects, but do include weight gain and obesity and its related risk factors, increased prolactin levels resulting in menstrual disorders, decreased libido and osteoporosis in women and lack of libido and impotence in men.

Which of the following genes is located on chromosome 2 and has been shown to be involved in anti-social or isolative aspects of schizophrenia? A. Dysbindin B. Calcineurin C. Neuroregulin D. AKT1

B. Calcineurin

Studies have shown _________ neuronal volume in the hippocampus. A. Increased B. Decreased C. Normal

B. Decreased As discussed the hippocampus plays important roles in the consolidation of information from short term memory to long term memory and spatial navigations. Again in MRI studies reduced neuronal volume has been found. Cellular disarray or a disorganization in nerve cells also occurs and can be seen in this slide (in module), and this disorganization in neuronal content can also be seen throughout the cortical or outermost layer or gray matter of the brain containing the neurons and their connections and the limbic system in person's with schizophrenia. Volume decreases have been evident on MRI findings of the thalamus. Its function includes relaying sensation, spatial sense, and motor signals to the cerebral cortex, along with the regulation of consciousness, sleep, and alertness.

Which non-pharmacological treatment is found to be effective in cases of severe psychosis? A. Meditation B. Electroconvulsive therapy C. Transcranial magnetic stimulation D. Antioxidants

B. Electroconvulsive therapy In combination with antipsychotics.

What dietary supplement has been used in small trials to improve the function of the NMDA receptor and has shown improvements with positive and negative symptoms? A. Omega-3 B. Glycine C. Calcium D. Vitamin D

B. Glycine (an amino acid) Omega-3 fish oils high in EPA, a type of Omega-3 fatty acid has been found to have some effect on reducing positive and negative symptoms.

Delusions are false fixed beliefs that usually involve a misinterpretation of an experience. A person states: "I will one day take over the world. I am the smartest human being on this planet". What type of delusion is this? A. Nihilistic B. Grandiose C. Persecutory D. Somatic

B. Grandiose Grandiose: person believes that they have exceptional powers, wealth, skill, influence or destiny. Nihilistic: person believes that they are dead or that a calamity is pending. Persecutory: person believes they are being watched, ridiculed, harmed or plotted against. Somatic: they believe they have abnormalities in their bodily functions or structures.

Which of the following is false? A. Schizophrenia has been described as a disconnection between thought and language. B. It is a complex disorder occurring in about 10.3 % of the population in Canada. C. It occurs in all countries and cultures, and is equally distributed amongst men and women. D. 10% of persons will commit suicide.

B. It is a complex disorder occurring in about 10.3 % of the population in Canada. This is FALSE. It is about 1.3 % of the population. A. is true... there is an interference with the filtering of stimuli from the environment, which affects a person's thoughts, feelings, perceptions and overall behaviours. C. is true... although there is a later onset in women because estrogen is believed to be a protective factor and delays onset of symptoms. And D is also true!

Antioxidants have an effect on which type of symptoms? A. Positive B. Negative C. Depressive

B. Negative Antioxidant vitamins have been shown to have a positive influence on the negative symptoms.

Which of the following candidate gene is involved in neuronal migration and connectivity, cell signalling and myelination? A. Calcineurin B. Neuroregulin C. AKT1 D. Dysbindin

B. Neuroregulin Short arm of chromosome 8 contains the gene neuroregulin which is involved in neuronal migration and connectivity, cell signalling and myelination. This gene is also related to a decreased activation of the temporal and frontal lobe regions and in mutant mouse research neuroregulin has also been found to be involved in structural brain abnormalities of lateral ventricle enlargement. Research also suggests that alterations in neuroregulin can also lead to altered neuronal signalling of dopamine during development, possibly leading to hyperdopaminergic states as an adult and to impact GABA and glutamingeric signalling.

To summarize here and to the best of our knowledge it is not clear whether genetic vulnerability is present in all cases. We know that heritability of it is high and genetic factors contribute to about 80% of liability for the illness but that no major gene locus has been found that can explain this disorder. Currently we believe that a large number of candidate genes likely contribute to liability for the illness.

BAM!

______ and variants in the gene that encodes it which are located on chromosome 11 have been implicated in schizophrenia.

BDNF (brain derived neurotrophic factor) As you may recall from depression module, BDNF is involved in the birth, survival and maturation of brain cells during development and the BDNF gene is also involved in production of the alleles "met" and "val". BDNF also plays a role in GABAergic transmission, regulation of glutamatergic transmission, intracellular signalling and transmission.

In the schizophrenic brain, any of these processes could be disrupted by inherited genes that place the individual at risk for schizophrenia, an allele of this gene that is activated in adolescence or early adulthood, or a genetic sensitizing that leaves the individual susceptible to environmental causes or lesioning during some adverse perinatal event. In addition, several maturational events normally occur during puberty that may affect brain development including changes in dopaminergic, serotonergic, adrenergic, glutamatergic, gamma-aminobutyric acid (GABA)-ergic and cholinergic neurotransmitter systems and substrates, a complex combination of synaptic pruning along with substantial brain growth in some areas of the cortex and changes in the steroid-hormonal environment.

BLAH BLAH BLAH!

Can a patient with schizophrenia lose the ability to recognize faces of family members?

Because of damage in these areas, a person may lose the ability to recognize faces of family members and believe that they have been replaced by imposters or may begin to recognize strangers as people they know, and they may become quite paranoid and frightened. A person may experience seeing and or hearing god or the devil who may be commanding them to take certain actions and these are called command hallucinations and they can be quite frightening and dangerous for the person. If the person experiences voices which seem to be coming from within their head they are thought to be less severely ill than a person who experiences voices coming from outside of their head. The most severe form of hallucinations is when the person experiences both voices and visual hallucinations which come form the external environment.

Damage to what area will result in hallucinations?

Broca's and Wernicke's area in the auditory processing center in the frontal and temporal lobe. You will remember that Broca's area is responsible for the production of and expression of speech and wernicke's area is responsible for the comprehension of written and spoken language, and it is believed that the person with schizophrenia may actually be hearing voices which don't actually exist which are stimulated in these damaged areas.

What are the chances of a monozygotic twin having schizophrenia if her twin has it? A. 20-30% B. 50% C. 40-50% D. 30-60%

C. 40-50% They share 100% of their genetic material. If both parents have it the risk of the child developing it is also about 40%.

Negative symptoms don't exist but should; lessening or absence of normal social and interpersonal behaviours. A patient that once found painting soothing enjoyed it very much has suddenly stopped and states that it just doesn't provide the same happiness it used to is showing what type of negative symptom? A. Alogia B. Apathy C. Anhedonia D. Ambivalence E. Avolition F. Affective

C. Anhedonia Alogia: reduced fluency and productivity of thought/speech Avolition: withdrawal and inability to initiate and persist in goal-directed activity Apathy: Decreased reaction to stimuli with diminished interest and desire Affective: flattening or blunting in range of emotion expressed; inappropriate affect Anhedonia: inability to experience pleasure in things that ordinarily are pleasurable Ambivalence: concurrent experience of equally opposing feelings making it impossible to make a decision * may also exhibit an increased tolerance to pain

The left globus pallidus is shown to have ____________ neuronal volume and is correlated with ____________ symptoms. A. Increased, positive B. Decreased, negative C. Increased, negative, D. Decreased, positive

C. Increased, negative This portion of the brain on PET scan has shown an abnormal function of excessive neuronal activity as the schizophrenia progresses and an increased neuronal volume. The left globus pallidus has been correlated with the negative symptoms including poor cognition, planning and social capabilities.

Which of the following is found to show some promise to treat auditory hallucinations? A. Meditation B. Electroconvulsive therapy C. Transcranial magnetic stimulation D. Antioxidants

C. Transcranial magnetic stimulation

Prodromal symptoms are early symptoms of schizophrenia which often appear in adolescence and marijuana use has been seen to trigger and exacerbate these early symptoms.

Oh snap... my little bro? perhaps ahhha

Which chromosome is related to Schizophrenia? Which of the following persons is most at risk for developing Schizophrenia? A. John a male with two met alleles who smokes cannabis. B. Jessica a female with one met and one val allele who smokes cannabis. C. Jennifer a female with two val alleles and smokes cannabis.

Chromosome 22 where a person can have the met or val allele. An allele is an alternative form of a gene or one member of a pair and occurs at loci on chromosomes and people have two pairs for each trait. Answer: C. Jennifer! If a person has the met and met allele and smokes cannabis there is no effect on the risk. If a person has one met and one val allele and smokes cannabis it doubles the risk and if a person has two vals and smokes cannabis it increases their risk five times. Brain imaging studies have also shown that the hippocampus and amygdala are smaller in cannabis users.

Which drug(s) can cause neuroleptic malignant syndrome? A. Haloperidol B. Congentin C. Chlorpromazine D. Both A and C

D. Both A and C Symptoms include an elevated temperature of >38, unstable BP, profuse sweating, dyspnea, muscle rigidity and incontinence. Elevated temperature is believed to be related to hypothalamic dopamine receptor blockage. There may be an increased white cell count and creatine phosphokinase (CPK) plasma concentration may be reported due to increased muscular activity and rhabdomyolysis (a destruction of muscle tissue). This is caused by an increased calcium release from muscle cells resulting in rigidity and eventual muscle cell breakdown. The person may also experience a hypertensive crisis and metabolic acidosis. A non-generalized slowing on an EEG is reported in around 50% of cases and may be related to changes in neuronal pathways as a result of blockage of dopamine pathways.

If there is a volume reduction in the temporal lobe as well as damage to this area of those with schizophrenia what do you expect to see? A. Formal thought disorders B. Anxiety C. Disconnection between thinking and language D. Both A and C

D. Both A and C The temporal lobe is responsible for processing auditory information and language, visual and spatial information, emotion and memory. Limbic system structures buried within the temporal lobe are responsible for our emotional responses. A volume reduction occurs in schizophrenia in the temporal lobe and results in formal thought disorders in this part of the brain. People with schizophrenia who have damage in the temporal lobe experience a disconnection between their thinking and their language, and this will be expressed in symptoms such as loosening of associated between thoughts as previously described, to absolute nonsensical expression which is called word salad.

Which medications are most affective for treating positive symptoms? A. Atypical antipsychotics B. Phenothiazines C. Non-phenothiazines D. Both B and C

D. Both B and C Conventional or first generation antipsychotic medications have been around for 50 years and are most affective for treating positive symptoms. They are sub-classified as phenothiazines and non-phenothiazines.

Which gene had been found to be related to visual processing deficits? A. AKT1 B. DISC1 and DISC2 C. BDNF D. Dysbindin

D. Dysbindin Gene of chromosome 6 found to be a risk gene for schizophrenia. Found to be related to visual processing deficits, cognitive functioning and reductions in volume in the prefrontal cortex in persons with schizophrenia. It has also been found to have a major role in neuroplasticity and in mice studies creating mutations in dysbindin results in deficits in social interaction and poor performance in memory tasks has been observed. Also a link between dysbindin and NMDA which is a glutamate receptor.

Which of the following is false with regards to anatomical changes in schizophrenia? A. The lateral and third ventricles are enlarged. B. A reduction in the frontal lobe and reduction in the temporal lobe particularly in the medial aspect. C. Whole brain volume reduction and diminished neuronal content in both the thalamus and hippocampus. D. Less prominent sulci and decreased activity in the limbic system.

D. Less prominent sulci and decreased activity in the limbic system. There is actually prominent sulci and increased activity in the limbic system and globus pallidus and an increase generally in D2 receptors (basal ganglia). The rest are correct!

_______ and _______ are located on chromosome 1. This gene leads to neuronal migration problems involved in the development of schizophrenia and may play an important role in hippocampal development.

DISC1 and DISC2 DISC stands for disrupted in schizophrenia. Further research has shown that DISC 1 may be linked with cognitive impairment and social anhedonia as well as reduced gray matter volume in the hippocampus and cortex seen in schizophrenia. Research has suggested that DISC 1 signalling during development could contribute to the alterations of dopaminergic and GABAergic signalling in the prefrontal cortex.

There is somewhat a __________ in serotonin activity in schizophrenia.

Decrease Serotonin is a neurotransmitter that works interdependently with dopamine to modulate dopamine. There is some evidence of a decrease in 5-HT2A (excitatory) and increase in 5-HT1A (inhibitory) receptor densities in schizophrenia. There are some similarities between the negative symptoms and depression and people with schizophrenia can also suffer symptoms of depression. With the newer atypical antipsychotic medications, it is believed that they more quickly bind to the D2 receptors and then rapidly dissociate, and some researchers believe that these newer drugs also block the serotonin receptor at the same time that they bock the dopamine receptors and that this somehow normalizes the serotonin-dopamine balance and effects the negative symptoms and depression symptoms.

Do we see increased or decreased blood flow and glucose metabolism in the prefrontal cortex of someone with schizophrenia?

Decreased! You may remember from the depression module that the prefrontal cortex is part of the cerebral cortex which is the most evolved portion of our brain. It is described as the "chief administrator" of the brain and is responsible for planning, problem solving, intellectual insight, judgement, and expression of emotion. The prefrontal cortex is part of the frontal lobe which contains most of the dopamine-sensitive neurons. The dopamine system is associated with reward, attention, short-term memory tasks, planning, and drive. Dopamine tends to limit and select sensory information arriving from the thalamus to the forebrain. A positron emission tomography or PET scan of the frontal lobe, in this slide, shows a hypofrontality or reduced blood flow and glucose metabolism in the prefrontal cortex of people with schizophrenia. Also MRI studies have shown a reduced neuronal volume in the frontal lobes.

Disorganized symptoms include what?

Disorganized thinking: disturbed speech and thinking patterns including thought content and process. Disorganized perceptions: oversensitivity to colours, shapes and background activities. Illusions: misperception or exaggeration of stimuli that exists in the external environment. Ancillary symptoms: anxiety, depression, hostility.

What is the chance of a dizygotic twin having schizophrenia if his twin has been diagnosed with it? A. 10-15% B. 15-20% C. 50% D. 20-30%

Dizygotic twins share 50% of their genetic material so the answer is... A. 10-15%

List the MANAGEABLE side effects of typical antipsychotics.

Dry mouth, tachycardia, blurred vision, sedation which usually diminishes with continued therapy, hypotension which is most severe when moving from recumbent to an upright position and sexual dysfunction ranging from impotence to a diminished libido.

Late adolescent is a time when the prefrontal cortex of the brain becomes fully myelinated and therefore functional.

During late adolescence, what happened in the brain related to genetics and neuronal development before adolescence becomes functional, the regulation of dopamine transmission becomes affected and the hyperdopaminergic positive symptoms manifest. Then during the course of schizophrenia, psychotic symptoms themselves may "sensitize" the brain and increase the pathology.

Environmental factors include which of the following: A. Prenatal stressors B. Adolescent brain changes C. Genetics D. Neurobiological challenges E. A,B, and D F. All of the above

E. A, B, and D Neurobiological changes involve some type of a lesion which causes anatomical and functional changes in the brain which are believed to begin in the prenatal period, continue to deteriorate during growth and development particularly in the adolescent period but remain silent and begin to be recognizable in late adolescence to early adulthood as behavioural changes and symptoms of schizophrenia.

Define positive symptoms.

Exist but should not; excess or distortion of normal functions. Delusions: grandiose, nihilistic, persecutory, somatic Hallucinations: involve 5 senses; auditory (most common), visual (2nd most common), tactile (touch), gustatory (tastes), olfactory (smell)

What is this? A neuronal network that is part of the motor system of the brain involved in the coordination of movement. It is differentiated from the tracts of the motor cortex that reach their targets by travelling through the pyramids of the medulla. This system is involved in reflexes, locomotion, complex movements and postural control.

Extrapyramidal system

Which neurotransmitters are believed to be involved in the development of schizophrenia? A. Dopamine B. Glutamate C. GABA D. NMDA receptor E. Serotonin F. All of the above

F. All of the above... duh easy

True or False? Second degree relatives are 10 times more likely to experience schizophrenia than those in the general population.

FALSE! First degree relatives including siblings and children are 10 times more likely to experience schizophrenia than those in the general population.

True or False? Hallucinations are perceptual experiences that occur with external sensory stimuli.

FALSE! Hallucinations are perceptual experiences that occur WITHOUT actual external sensory stimuli. Hallucinations involve any of the 5 senses, but are usually visual or auditory. The person may see or hear things that are not in the external world but nevertheless are very real to the person who is experiencing them. Auditory hallucinations range from simple to repetitive sounds, to many voices speaking at once and can be interpreted as pleasant to distressing by the person experiencing them. When visual hallucinations occur, they often occur in conjunction with auditory.

True or False? Schizophrenia is a single disorder.

FALSE! It has been shown to be not a single disorder but a family of disorders and different people have different therapeutic responses to medications.

True or False? Neuroanatomical changes are the result of progressive brain deterioration.

FALSE! Neuroanatomical changes are not the result of progressive brain deterioration or the effects of psychiatric medications, but are caused by abnormalities in neurodevelopment that occur in prenatal or early postnatal life. These anatomical changes continue to deteriorate through lifespan, particularly in late adolescence to early adulthood when the positive symptoms begin to occur and negative symptoms become enhanced.

True or False? Studies show narrowing of the sulci in schizophrenic patients.

FALSE! Studies examining healthy individuals matched to schizophrenia individuals show a widening of sulci in certain areas of the brain in schizophrenia people. These studies have shown a correlation between individuals with schizophrenia with widened sulci and impaired performance on tests of working memory and executive functioning.

True or False? Ancillary symptoms can be the main symptoms of Schizophrenia.

FALSE! They may accompany schizophrenia (anxiety, depression, hostility) but are by no means the main symptoms.

True or False? Total brain volume is reduced and lateral and third ventricle spaces are found to be smaller.

FALSE! Total brain volume is reduced but lateral and third ventricle spaces are found to be larger (see MRI images in module of monozygotic twins). Remember that the ventricular system is the part of the brain that houses the cerebral spinal fluid and that in increase in the size of the ventricular system is a result of a reduced overall brain volume reduction, so as the brain shrinks as a result of abnormal pruning and neuroplasticity, the ventricles enlarge.

True or False? Non-pharmacological treatments are best to treat schizophrenia to avoid harmful side effects of medications.

FALSE! Yes they show some promise but pharmacological treatments are essential and should always be used in treatment. Much more research is needed in this area of non-pharmacological treatments.

True or False? The neurodevelopmental model of Schizophrenia says it is influenced by a few factors.

FALSE! It is influenced by many factors. Rapoport in an update that he and his colleagues published in 2005 describes the model simply as the behavioural outcome of an aberration in or abnormal neurodevelopmental processes that begins long before the onset of clinical symptoms and is caused by a combination of environmental and genetic factors. In simple terms this means that patients with it have a biological predisposition or vulnerability that is exacerbated by environmental stressors.

True or False? The psychosocial theory is still used today. It blames dysfunctional parenting in early childhood as the cause of schizophrenia.

FALSE! It is no longer held valid. Social theories used to explain the etiology of schizophrenia focus on theories of family interaction. The theory of expressed emotion or (EE) correlates family communication patterns of negative comments about family members, when there are aspects of speech that connote criticism, hostility and negativity, and when families are emotionally "over involved", overprotective and self-sacrificing with an increase in symptoms and relapse in patients with schizophrenia. Research associated with emotional expressiveness related to schizophrenia is contradictory.

Where is the decreased cortical volume and widespread reduction in cortical thickness most pronounced?

Frontal and temporal lobes MRI findings indicate an overall reduction in gray (nerve cell) and white (axonal) matter in the brains of people diagnosed with schizophrenia. These volume reductions are not associated with a reduction in nerve cell numbers, but rather to changes in nerve cell density, to a decrease in the number of connections between nerve cells, to a decrease in axonal integrity and to a decrease in the number of synapses between nerve cells. Also the complexity of dendritic branching, total dendritic length, and dendritic spine sensitivity is decreased in the prefrontal cortex of people with schizophrenia. Research has shown greater negative symptom severity including greater interpersonal and cognitive impairment in persons with schizophrenia which correlates with these neuronal volume losses.

What is the relationship of GABA and schizophrenia?

Glutamate is alo a precursor to GABA production. GABA is the most widespread inhibitory neurotransmitter in the brain. GABA has an inverse relationship with dopamine, so the less GABA there is, the more dopamine and more psychosis.

Fun facts coming your way...

In diffusion tensor anisotropy studies water molecules movement within axons is studied, and this research has demonstrated a reduction in white matter integrity of the brain and a reduced connectivity between brain cells. In comparing those with first episode psychosis and those with chronic schizophrenia, white matter has been shown to become progressively more and more affected with repeated psychosis.

Fun facts again... you love it don't lie

In studies of hypofrontality using a PET scan to measure metabolic activity in the frontal lobe, people with schizophrenia were asked to do a Wisconsin Card Sort. A Wisconsin Card Sort is a neuropsychological test where the participant is given a number of cards with different numbers of shapes in different colours and they are asked to match the cards by colour, shape or quantity. This test measure prefrontal cortex activity in the area of executive functioning including attention, working memory and visual processing.

Is it too late now to say sorry...? Cuz I am throwing more lame facts at chuuuuuu oouuuuuu

People with schizophrenia have been found to fail in the task previously described because they were unable to activate their prefrontal cortex in this activity. In the area of cognitive recognition in people with schizophrenia, in the Gestalt recognition test, there has been shown to be a latency or delayed recognition in people with schizophrenia which may be indicative of the damage to the amygdala and hippocampus and the visual and verbal memory centres in the temporal lobe as has been discussed.

List the risk factors for Schizophrenia.

Include stressors in the prenatal period of the mother, for example starvation, poor nutrition and maternal infection which place added stressors on the developing fetus. Some research has shown that the risk for schizophrenia worldwide is 5-8% higher for those born during the winter and spring, when colds and viruses are more prevalent. The precise neurological mechanism in relation to maternal infections is not known but it is believed that cytokines and an abnormal immune response to these infections interfere with normal fetal brain development during this period. Obstetrical complications may cause fetal hypoxic or ischemic damage to the developing brain, where premature cortical synaptic pruning is from your depression module, but in general terms what this means is that the connections between brain cells or neurons becomes disconnected or pruned prematurely. Older parental age including both the mother and father's age has been found to double the risk in offspring and this is thought to be related to impaired formation of sperm cells leading to an increased risk of genetic mutations. The risk is higher in individuals born in urban settings and is thought perhaps because the city is more stressful. Infants who have been affected by the previously stated maternal stressors have conditions that include their own risk factors such as low birth weight, short gestation, and early developmental difficulties and in childhood central nervous infections. First degree relatives of persons with schizophrenia have be found to be at greater risk.

How does THC increase this risk?

It interacts with the cannabinoid system and disregulates the cannabinoid system. This system serves a regulatory function in controlling the release of glutamate and GABA has an effect on neuronal synaptic connections and on the dopamine system. Neuropruning or untangling of brain cells happens to teenagers in their normal brain development and THC is believed to interfere with this normal development neuropruning process.

The dopamine pathways include...

Mesolimbic tract, mesocortical tract, tuberoinfundicular tract, nigrostriatal tract

The left globus pallidus is involved with what?

Motor control A portion of the basal ganglia next to the putamen and connected to the substantia nigra in an area of the brain involved with motor control and richly dense with dopaminergic neurons.

_______ is a risk gene and has also been found in the receptor.

NMDA-R... also been found in the NMDA receptor (discussed later).

Hypoactivity of the mesocortical tract is thought to be associated with the ____________ symptoms of schizophrenia.

Negative The mesocortical pathway is a neural pathway that connects the ventral tegmentum to the cerebral cortex, particularly in the frontal lobes. The mesocortical pathway is essential to the functioning of the prefrontal cortex involved in motivation and emotional response. Dopamine hypoactivity in this region of the brain is thought to be associated with the negative symptoms of schizophrenia, for example alogia which refers to a reduced fluency and productivity of thought/speech, and avolition- the withdrawal and inability to initiate and persist in goal-directed activity as well as cognitive impairment. By its association with the prefrontal neocortex, the mesocortical tract contributes to motivation, planning, sequencing of behaviours in time, attention, and social behaviour- all of which are disrupted in schizophrenia.

Several types of dopamine receptors including D1 through 6 receptors and dopamine are found in four pathways in the brain and these pathways innervate different parts of the brain.

Neurobiologic changes in the dopaminergic system can be related to the symptoms of schizophrenia.

Which pathway is responsible for some motor symptoms such as stereotypic behaviour?

Nigrostriatal dopaminergic tract The pathway connecting the substantia nigra with the striatum. It modulates motor activity and is believed to be the site of the extrapyramidal side effects of antipsychotic drugs used to treat schizophrenia, such as pseudoparkinsonism and tardive dyskinesia because antipsychotic drugs are not selective and block dopamine in all four pathways.

Disorganized behaviours are coupled with disorganized speech and may for example include a slow, rhythmic and ritualistic movement coupled with disorganized speech.

Other examples include aggression which often occurs if the person believes someone is trying to harm them, agitation involving an inability to sit still or attend to others which is accompanied by heightened emotions and tension, catatonic excitement which involves a hyperactivity characterized by purposeless activities, abnormal movements such as grimacing and posturing, echopraxia which involves involuntary imitation of another person's movements and gestures, regressed behaviour involving childlike and immature behaviour, stereotypy involving repetitive purposeless movements that are idiosyncratic to the individual and somewhat out of their control, hypervigilence involving sustained attention to external stimuli as if expecting something important or frightening to happen, and waxy flexibility involving holding a posture in an odd or unusual fixed position for an extended period of time.

Disturbances in though processes include various types of delusions.

Other examples include depersonalization or the belief the one's self and one's body is strange or unreal and magical thinking which is a belief that one's own thoughts, words or actions have the power to cause or prevent things from happening.

Out of phenothiazines and non-phenothiazines which one was the first effective drugs used to treat schizophrenia?

Phenothiazines These medications revolutionized the treatment of mental illness, but they exhibit numerous adverse effects that can limit their pharmacotherapy. Non-phenothiazines were introduced shortly after and were initially expected to produce fewer side effects although unfortunately this proved not to be the case.

Which type of symptoms are thought to be caused by dopamine hyperactivity in the mesolimbic tract, which regulated memory and emotion?

Positive symptoms (hallucinations and delusions) It is hypothesized that this hyperactivity could result from an overactive modulation of neurotransmission from the nucleus accumbens.

In the past it was believed an excess in the amount of dopamine in the brain was the sole culprit for the symptoms. The dopamine hypothesis supports that it is likely an excess of the amount, sensitivity to and receptor number and affinity for dopamine that causes psychosis. What is the opposing argument?

Research has been conducted which shows that when large numbers of dopamine receptors are blocked, there was little reduction in patients who had psychosis for 10-30 years. Also high numbers of patients with first-episode psychosis responded to low dose antipsychotic medication with much less blockage of D2 receptors. Research has also shown that when dopamine receptors are blocked, it can take several days for an improvement in symptoms.

Pseudoparkinsonism

Symptoms include tremor, muscle rigidity, stooped posture and a shuffling gait. Benzotropine mesylate (congentin) an antiparkinson agent which blocks cholinergic activity is believed to restore the acetylcholine/dopamine doses of the antipsychotic medications.

Neuroplasticity is the concept of what? (hint: it was already mentioned in one of the answers)

Research suggests that heredity is a significant factor in this disease, but more research is still required in this area. The next idea is that neurobiological changes in the brain occur as a result of these genetic and environmental factors. Some type of a lesion in the brain occurs which causes anatomical and functional changes in the brain which are believed t begin in the prenatal period, continue to deteriorate during growth and development particularly in the adolescent period but remain silent and begin to be recognizable in late adolescence to early adulthood as behavioural changes and symptoms of schizophrenia. This is the concept of neuroplasticity which you may recall from depression module, can be defined as the ability of the brain to change its structure and function in response to internal and external pressures.

And more...

Scans of patients who are treated with antipsychotic medications, in particular atypical have shown a slowing down of ventricular enlargement and of hippocampal shrinkage. This research supports the idea that if patients are correctly identified and treated early with medication, for example before the hallucinations and paranoia become entrenched, then there is an increased likelihood that the patient will attain control over their condition and be able to have a decent quality of life. The flip side of this is that the longer the diagnosis takes, the worse the prognosis for the person, especially since those with full blown disease have greater challenges with medication compliance.

Further directions for research in the area could include better treatment for negative symptoms, developing ways to prevent the deteriorating progression of schizophrenia, antenatal diagnosis, better understanding of genotype-phenotype relationships or the genetic makeup of the person in relation to their symptoms and gene therapy.

TRUE DAT! Remember... early intervention means recovery is possible folks!

True or False? Another explanation for the dopaminergic hyperactivity in the mesolimbic tract is the hypoactivity of the mesocortical tract.

TRUE! Another explanation for dopaminergic hyperactivity in the mesolimbic tract is hypoactivity of the mesocortical tract, which normally inhibits dopamine activity in the mesolimbic tract by some feedback systems. In schizophrenia the primary defect may be in the mesocortical tract, where dopaminergic function is diminished, thereby decreasing the inhibitory effects on the mesolimbic tract. This disinhibition may be responsible for the overactivity of dopamine in the mesolimbic tract, resulting in the positive symptom cluster. The interconnection between these tracts has been demonstrated in animal studies.

True or False? The tuberoinfundicular tract is not heavily implicated in schizophrenia.

TRUE! It is active in the area of the hypothalamus of the brain. Dopamine released in the tract regulates the secretion of prolactin from the anterior pituitary gland. Some antipsychotic drugs block the action of dopamine in this path, causing an increase in blood prolactin levels and disruptions in women's menstrual cycles, visual problems, headache and sexual dysfunction.

True or False? You can tell by MRI images which twin would have schizophrenia.

TRUE! Research in studies of monozygotic twins where only one of the twins was diagnosed with schizophrenia has demonstrated that you could pick out the affected twin through an MRI image as the twin who had a somewhat bigger third ventricle. Three-dimensional image studies have also shown a lateral and third ventricle enlargement and other cortical shrinkage.

True or False? There can be overstimulation of the amygdala and limbic system with a schizophrenic patient?

TRUE! The amygdala is constantly scanning the environment and assigns emotional significance to everything you see, hear and feel. The amygdala helps us to recognize emotional, social, and sexual behaviour, and to determine if someone is happy or sad. The amygdala receives tactile, auditory, visual and olfactory stimuli and overstimulation of the amygdala and the limbic system is thought to be the source of sensory based hallucinations in the person with schizophrenia, who hears things, sees things, can smell and taste things and feel tactile sensations which are not present.

True or False? There are several areas of cognitive function which may be impaired in schizophrenia and this dysfunction can occur even if the positive symptoms are in remission.

TRUE! These areas of dysfunction include: short and long term memory; vigilance or sustained attention; verbal fluency or the ability to generate new words; executive functioning including volition, planning, purposive action and self monitoring behaviours.

The biogenic amine hypothesis suggests what?

That changes in levels of neurotransmitters in the synaptic cleft, due to either increased or decreased presynaptic release or increased or decreased postsynaptic sensitivity is the underlying pathologic process in mental illness.

Why would there be trouble with verbal and visual memory?

The temporal lobe also stores auditory and verbal and visual information or memories, the amygdala being involved in emotional memory and the hippocampus taking short term memories and storing them as long term memories in the temporal lobe. The hippocampus interacts with the amygdala and stores the emotional attributes of the memories. These stored memories are then the basis for dreams and hallucinations. These verbal and visual memories which are stored in the temporal lobe can become stimulated in schizophrenia, without an external stimulus, and this is believed to be the basis of verbal and visual hallucinations and delusions, which can become quite bizarre and complex. When you dream, these areas and memories are also stimulated and this is what makes up the verbal and visual content of our dreams. Most of the time when we dream it is as if it is really happening to us. When we wake up, we realize it was only a dream. For the person with schizophrenia, it is as if the dream occurs upon wakefulness and there is no convincing that person that what is happening is not real.

How do antipsychotic drugs work?

They have the general effect of blocking dopamine transmission in the brain by blocking D2 receptors on the postsynaptic neuron, preventing dopamine from stimulating the receptors. Symptoms seem to be mostly associated with the D2 receptor, although some of the drugs block other dopamine receptors and travel to all dopamine receptor sights in the brain resulting in unpleasant and undesirable side effects. The basal nuclei or ganglia are particularly rich in D2 receptors. Schizophrenia is thought to involve dysfunction of the behavioural neuron circuits between the basal ganglia and the limbic system.

What does the hypofrontality perhaps relate to? (hint: think of the types of symptoms)

This hypofrontality of the frontal lobe perhaps relates to negative symptoms and neurocognitive impairment in schizophrenia as has been previously described, for example, there is a poverty of thought and speech and the person has trouble functioning and may have unusual movements and postures including when a person becomes locked in a posture in a catatonic state. It has been suggested that this cognitive impairment may be related to a D1 or dopamine 1 receptor deficit in the prefrontal cortex.

DSM-5: The Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association states that Schizophrenia is a mixture of positive and negative symptoms that present for a significant portion of a 1 month period but with continuous signs of disturbance persisting for at least 6 months.

True dat! See next card...

Personal therapy is a psychosocial intervention designed to help persons recognize and respond appropriately to arousing stimuli to improve function and reduce relapse. Cognitive behavioral therapy is seen to be of some value in the short term. Employment programs help people obtain competitive employment. Family therapy and educational therapy are important to assist the patient and family and support persons to cope with the disease and better understand its course, treatment regimens, support systems and life management skills.

WOOHOO

We also know that the atypical antipsychotic medications have been found to be just as effective in controlling psychosis, particularly the negative symptoms despite the fact that they have a lower affinity for dopamine receptors, although recent evidence shows that these drugs also have a tendency to bind and unbind rapidly and repeatedly to the dopamine receptor. This research supports that schizophrenia is not solely caused by an excess of dopamine, but that there are other neurotransmitters involved and there are genetic developmental and brain structural factors that contribute to its etiology.

WOOHOO more gumble to memorize coming to you soon in a theatre nearby!

In neuroplasticity nerve signals may be rerooted, nerve cells may learn new functions, the sensitivity of or number of nerve cells may increase or decrease or nerve tissue may be regenerated. What happens in the brain of a person who develops schizophrenia in late adolescence or early adulthood is that when the person has that first psychotic break, if they do not receive treatment, first and foremost medication to block the D2 receptor and regulate levels of dopamine, they can develop further neuroplastic changes and even neurotoxicological changes that can further and permanently affect the brain anatomically and functionally.

WOW!

Can cannabis use be a risk factor for Schizophrenia?

Yes, increased risk of psychosis and earlier onset of psychosis and there is a dose response. Active ingredient in marijuana delta 9-tetrahydrocannabinol or THC has been shown to quadruple a teen's chance of developing this disorder.

The major action of atypical antipsychotic medications is to act by blocking several different receptor types in the brain including the...

dopamine D2 receptors and alpha-adrenergic receptors These second generation medications act as a serotonin agonist which is a compound that activates serotonin receptors, mimicking the effect of the neurotransmitter serotonin, increasing levels of serotonin and therefore decreasing levels of dopamine. Atypical antipsychotics are used for both positive and negative symptoms and depressive symptoms.

Recent PET scan studies have demonstrated ___________ presynaptic dopamine levels in persons with schizophrenia.

elevated Occupancy of D2 receptors has also been found to be increased. There has been found to be at most a modest elevation in receptor density independent of the effects of antipsychotic drugs. These increases in dopamine have been associated with the positive symptoms. Dopamine transmission in the prefrontal cortex is mainly mediated by D1 receptors and D1 dysfunction in this region of the brain and hypofrontality has been associated with cognitive impairment and negative symptoms.

__________, an excitatory neurotransmitter is also thought to be associated with schizophrenia and when phencyclidine (PCP or angel dust) and ketamine are used to block __________ receptors, this causes a psychosis resembling schizophrenia.

glutamate, glutamate (NMDA) receptors NMDA is a receptor that is implicated in learning and memory. If we have a decrease in the NMDA receptor then we have less glutamate transmission. There is an anatomical and functional interrelationship between the dopamine and glutamate systems such that inhibition of the NMDA receptor enhances the firing rate of dopamine neurons, and in turn there would be more psychosis. In post-mortem studies there has been shown to be a reduction in the brain of glutamate receptors in people with schizophrenia.

Examples of disturbances in thought processes include...

loosening of association where there is a lack of a logical relationship between thoughts and ideas and conversation shifts from one topic to another in a completely unrelated manner. Another example is thought blocking where there is an abrupt pause or interruption in one's train of thought, after which the individual cannot recall what they were saying. *** see charts from notes on common disturbances of thought content and common disturbances of thought processes

The limbic system is a primitive area deep in our brain in the temporal lobe that regulates our emotional behaviour. As previously discussed, this is the area of the brain where the ___________ symptoms of _____________ and ____________ originate.

positive, hallucinations and delusions Limbic system includes: hippocampus, parahippocampal gyrus, cingulate gyrus, amygdala and a bridge like structure called the fornix which connects the hippocampus with the hypothalamus. Higher and lower brain centres communicate with the limbic system to link thoughts and autonomic nervous system responses and emotions. The limbic system is involved with primitive behavioural responses or visceral (instinct rather than conscious reasoning) reactions to emotion, feeding, biological rhythms, sense of smell and affect which are emotional and behaviour states.

The mesolimbic pathway begins in the ventral tegmental area of the midbrain and connects to the limbic system via...

the nucleus accumbens, the amygdala and the hippocampus as well as to the medial prefrontal cortex.