Lecture psychiatric disorders 13: schizophrenia Flashcards
Symptoms of schizophrenia can be termed as positive, negative or as cognitive symptoms. What are positive symptoms? Also name a few positive symptoms.
With positive symptoms, it’s meant that there is an excess of normal function. Examples of positive symptoms are:
- psychosis (delusions + hallucinations)
- disorganized speech
- distortions/exaggerations in language and communication
- disorganized behavior
- agitation
What are delusions?
A misinterpretation of perception or experience
Name examples of specific types of delusions.
- Paranoid or persecutory delusions (persectution, espionage, conspiracy)
- Referential delusions → erroneously thinking that something refer to oneself (secret messages)
- Grandiase delusions (megalomania) → erroneously thinking that one is a powerful person
- Scientific delusions
- Religious delusion (thinking you are Jezus or another divine being)
- Delusions that you are poisoned
- Sexual delusion (one is convinced to be irrestible)
- Leaky mind delusion → thought are leaking out of the brain and can be read by others or are broadcasted
- Delusion that your thoughts are not yourself, but are transplanted into the brain (e.g. by aliens).
In what way can hallucinations present themselves?
- Most common → auditory hallucinations (harsh voices giving negative comments/orders)
- May occur in any sensory modality (visual, tactile, gustatory, olfactory (smell of gas, rotting meat)
Symptoms of schizophrenia can be termed as positive, negative or as cognitive symptoms. What are negative symptoms? Also name a few negative symptoms.
With negative symptoms, there’s a reduction in normal function.
- Blunted affect → restrictions in range and intensity of emotional expression (feeling empty, recalls few emotional experiences, little facial expression)
- Dysfunction of motivation → reduced motivation persistence, passivity, reduced ability to undertake and complete everyday tasks
- Anhedonia → dysfunction of capacity for pleasure, reduced ability to experience pleasure, decreased interest in previous hobbies.
- Asociality → reduced social drive and interaction, little sexual interest, few friend, little interest in spending time with friends.
Symptoms of schizophrenia can be termed as positive, negative or as cognitive symptoms. What are cognitive symptoms and how do these symptoms display themselves?
Cognitive symptoms are problems in attention. Schizophrenia patients with cognitive symptoms have executive dysfunction → problems with planning, with maintaining goals or with problem solving or prioritizing.
How do symptoms of schizophrenia arise and what do these different symptoms tell us?
Symptoms arise due to malfunctioning brain circuits. This tells us that these different symptoms arise due to problems in different brain circuits.
The following brain areas are important for the arise of the different symptoms. Match the brain area with the following symptoms.
Brain areas: mesolimbic, ventromedial PFC, orbito/frontal cortex and amygdala, dorsolateral PFC, nucleus accumbens/reward circuits and mesocortical/PFC
Symptoms: positive, negative, affective, aggresive, cognitive.
- Mesolimbic → positive symptoms
- Ventromedial PFC → affective symptoms
- Orbito/frontal cortex and amygdala → aggressive symptoms
- Dorsolateral PFC → cognitive symptoms
- Nucleus accumbens/reward circuit and mesocortical/PFC → negative symptoms
Dopamine has long played a prominent role in hypotheses of schizophrenia. Name drugs that could elicit psychosis and what function these drugs have on the brain.
Cocaine and amphetamine.
- Cocaine is a DAT reuptake inhibitor
- Amphetamine is a DAT reuptake inhibitor and DA releaser
Both drugs cause more dopamine (DA) to accumulate in the synapse, which results in psychosis.
What effect do antipsychotics have on the brain?
Antipsychotics are DA receptor blockers (DA antagonist) and prevent that too much dopamine can interact with their receptors.
Name the four brain areas that are important in dopaminergic pathways.
Nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular.
Describe what projections there are for the four pathways that are important in dopaminergic pathways.
- Nigrostriatal → cell body in substantia nigra, which projects to the striatum
- Mesolimbic → cell body in midbrain/mesencephalon, which projects to the limbic system/nucleus accumbens
- Mesocortical → cell body in midbrain/mesencephalon, which projects to the cortex
- Tuberoinfundibular → cell body in hypothalamys, which projects to the pituitary.
So what do these brain areas with their projections tell us about symptoms of schizophrenia (don’t answer this question)?
What brain area is associated with positive symptoms of schizophrenia and how do these symptoms occur?
The brain area that is associated with positive symptoms, is the mesolimbic dopamine pathway. These symptoms are caused by a hyperactive mesolimbic system, causing a release of too much dopamine that ends up in the ventral striatum (VTA).
So what do these brain areas with their projections tell us about symptoms of schizophrenia (don’t answer this question)?
What brain area is associated with negative, cognitive and affective symptoms of schizophrenia and how do these symptoms occur?
The brain area that is associated with these symptoms, is the mesocortical dopamine pathway. These symptoms are caused by a hypoactive mesocortical system. This results in too little dopamine release in the prefrontal cortex.
Do the other dopaminergic pathways (nigrostriatal and tuberoinfundibular) play a role in symptoms of schizophrenia?
No, these pathways are normal in schizophrenia patients.
Already discussed a few questions back, is that D2 antagonists can be used to treat symptoms of schizophrenia. What is the advantage and disadvantage of using D2 antagonist to treat symptoms?
- Advantage → the mesolimbic pathway is known to be hyperactive in schizophrenic patients. By blocking the receptor (D2) of dopamine, it is prevented that there’s too much DA stimulation. It can reduce the positive symptoms.
- Disadvantage → the nigrostriatal pathway is normal in schizophrenic patients. D2 antagonists will also bind to D2 receptors in the nigrostriatal pathways, therefore affecting a pathway that is still normal and resulting in hypoactivation of this pathway. This results in extrapyrimidal symptoms (EPS), or Parkinson-like symptoms.
Describe what projections there are for these pathways that are important in glutamate pathways.
- Cortical brainstem glutamate projection
- Corticostriatal glutamate pathway
- Thalamocortical glutamate pathway
- Corticothalamic glutamate pathway
- Corticocortical glutamate pathway
- Cortical brainstem glutamate projection → cell bodies in the cortex, projections to the brainstem
- Corticostriatal glutamate pathway → cell bodies in the cortex, projections to the striatum
- Thalamocortical glutamate pathway → cell bodies in the thalamus, projections to the cortex
- Corticothalamic glutamate pathway → cell bodies in the cortex, projections to the thalamus
- Corticocortical glutamate pathway → cell bodies and projections in cortex
What is crucial for the corticobrainstem projection in healthy people?
That the corticobrainstem projections communicates directly with dopaminergic neurons of the mesocortical DA pathway. This is called tonic excitation. Here, glutamate stimulates the mesocortical DA neurons via AMPA-R and NMDA-R, this activates the mesocortical pathway to release DA in the PFC.
What happens to this corticobrainstem projection in schizophrenia?
The NMDA-R is hypoactive, this means that glutamate can no longer stimulate the mesocortical DA pathway as effective as normal. This causes less dopamine release in the PFC, which causes negative and cognitive symptoms of schizophrenia.
So in short: NMDA-R hypofunction causes hypoactivation of the mesocortical DA pathway.
Besides that the corticobrainstem projection of glutamate activates the mesocortical DA pathway in healthy people, the corticobrainstem projection also has another important function. What function is this?
The corticobrainstem projection also acts as a brake on mesolimbic DA pathways via GABA interneurons. Here, glutamate coming from the corticobrainstem projection stimulates GABA-neurons. GABA is released and inhibits DA neurons, causing less DA to be released in the VTA/nucleus accumbens.
This is called tonic inhibition.
What happens to the process of tonic inhibition in schizophrenia?
Since the NMDA-R is hypoactive, less glutamate can be used to stimulate GABA neurons. GABA neurons therefore release less GABA and less GABA is available to inhibit DA neurons. So this means that there’s release of more DA in the VTA/nucleus accumbens. This causes the positive symptoms of schizophrenia.
So in short: NMDA-R hypofunction causes hyperactivation of the mesolimbic DA pathway.
Describe the thalamic filter (what projections and neurotransmitters are used).
- The thalamus is connected to the prefrontal cortex through thalamalcortical projection of the glutamate pathway.
- The prefrontal cortex is indirectly connected to the thalamus via the nucleus accumbens/striatum (corticalstriatal glutamate pathway), where the nucleus accumbens/striatum has connections with the thalamus via a GABA neuron.
How does the thalamic filter function in healthy people?
- Sensory information is ‘caught’ by glutamatergic neurons that project to the thalamus. In the thalamus, released glutamate is able to stimulate the thalamalcortical projection of the glutamate pathway, which released glutamate in the prefrontal cortex.
- At the same time, glutamatergic neurons of the corticalstriatal projection activate GABA neurons in the nucleus accumbens. GABA neurons then release GABA in the thalamus. GABA binds to neurons of the thalamalcortical projection, which prevents that all sensory information can be passed down to the cortex.
How does the sensory filter in schizophrenia dysfunction?
The answer to this lies actually on two things that are already discussed and are based on the fact that there’s less GABA in the thalamus → dopaminergic and glutamatergic pathway.
- Mesolimbic dopaminergic pathway is hyperactive, which causes too much DA released in the striatum. The DA released in the striatum has inhibitory receptors on the cell body of the GABA neuron and due to the high concentration of DA, DA outcompetes glutamate (that is able to activate GABA neurons). This results in a hypoactive GABA neuron, which causes less GABA to be released in the thalamus.
- NMDA-R is hypoactive, therefore the glutamatergic neurons of the corticalstriatal projections are also hypoactive. Therefore, less glutamate is released in the striatum and less glutamate is able to stimulate the relase of GABA in the thalamus.
So hopefully it’s clear by now that problems that cause schizophrenia arise during neurodevelopment. Why does the disease then manifest only during adolescence or adult life?
The risk genes (DISC-1, neuregulin, dysbindin) are necessary for good synaptic strengthening by long-term potentiation (if genes are normal). The variants of these genes that cause schizophrenia, create proteins that do not allow strengthening of synapses. So during neurodevelopment there’s no long-term potentiation and synapses stay weak. But during adolescence there’s pruning → aberrant elimination of weakened synapses (use it or lose it). So, only after pruning, symptoms of schizophrenia develop.
How can personality be a risk factor for schizophrenia?
When a certain life event occur, it’s dependent on the type of personality whether you are able to cope/adapt with this life event or not. Certain risk genes can be affected by this life event. If you have a personality that is not good at coping with certain life events, this can result in a unsuccesful compensation of certain (risk) genes. This can lead to the breakdown into psychiatric symptoms.
