PBL 8 - Schizophrenia- Psychosis Flashcards
What is the prefrontal association cortex?
What are the regions within it?
What is its function?
- The cortical region that receives thalamic input from the dorsomedial nucleus
- Little or no input from other thalamic nuclei
- Granular cortex of frontal lobe
- Region of frontal lobe that does not cause movement when stimulated
Regions:
• Orbitofrontal cortex (approximates limbic prefrontal)
• Medial prefrontal
• Dorsolateral prefrontal
Functions: • Planning for voluntary movements • Emotional regulation • Decision making • Working memory • Problem solving • Inhibition of inappropriate social responses • Verbal reasoning • Mental flexibility • Personality traits
What is the process of feeling fear?
• stimulus is presented
• Information is projected to the thalamus
• Amygdala receives information from
○ Hippocampus - about a conditioned stimulus
○ Thalamus- about current stimulus
• Amygdala integrates information and sends it to the hypothalamus
• Behaviour, autonomic, endocrine and inflammatory response occurs
What test can you perform to examine the pre-frontal cortex?
• Wisconsin card sorting test
○ Patient will show perseveration- persisting with a response that incorrect because they are unable to adapt
Where are the dopaminergic neurons located?
Where do they project to?
Origin:
• substantia nigra
• Ventral tegmental area
Project:
• VTA dopamine neurons project to the prefrontal cortex limbic structures, some basal ganglia components (ventral striatum
What is the target for controlling the psychotic symptoms of schizophrenia?
• Dopamine D2R antagonists located in the midbrain
How does the prefrontal cortex module dopaminergic input?
- VTA dopamine cells project to the prefrontal cortex
- The PFC then inhibits the limbic area (NuAcc) and the VTA dopaminergic cells
- Feedback loop
What type of receptors does dopamine work on?
What effect do antipsychotics have?
• They are ALL GPCR • There are at least 6 of them ○ D1 ○ D2a and D2b ○ D3-5 • Two major groups ○ D1 and D5 ○ D2-5
What is the function of the different Dopamine receptors?
Where are they located?
What is the clinical function ?
D1 = in the striatum
D5 is in the cerebral cortex and hipocampus
Function:
• Coupled to Gs and STIMULATE CAMP
Clinical fx:
• Low affinity for most antipsychotic drugs
D2= In Neurons of the midbrain. Caudate and limbic regions (amygdala, nucleus accumbens, hippocampus and cerebral cortex)
Function:
• D2a = INHIBITS camp
○ Function as inhibitory autoreceptors decreasing firing of AP and dopamine release (feedback loop)
• D2b = stimualtes PKC and increases intracellular CA
Clinical Fx:
• High affinity for typical antipsychotic drugs
• D2 receptors may contribute to extrapyramidal side effects
D3 and D4
Location:
• restricted to the limbic system and cerebral cortex
• Weakly expressed in the basal ganglia
Function:
• atypical antipsychotics bind here and do not give rise to Extrapyramidal side effects
What is the possible link between Dopamine and Schizophrenia?
Overactivity of the meso-corticolimbic dopamine system. Depends on the following:
• Overdose of drugs that enhance dopamine release (L-DOPA) can lead to positive symptoms
• Drugs that are effective in treating positive symtpoms are potent blockers of dopamine receptors particularly D2
• The same drugs used for positive symptoms are used for drug induced psychosis
• Brains of patients at autopsy show increased levels of D2 receptors in caudate and nucleus accumbens especially in patients showing positive symptoms
• Negative symptoms resemble defect seen in patients after prefrontal damage
Explain the reward/pleasure pathway:
• 5HT neurons are located in the raphe neurons in the midbrain:
○ Activate the DA neurons in the Ventral tegmental area
○ Increased the release of Da in the Nucleus Accumbens
○ Auto inhibits the raphe neurons (where it comes from)
• Dopaminergic neurons
○ Originates in the VTA where it is stimulated by 5HT
○ Releases Dopamine which causes pleasure
What is the neurodevelopmental hypothesis of Schizophrenia?
- Schizophrenia involves a primary lesion in the prefrontal cortex
- This normally acts to modulate the stress response by inhibiting the amygdala
- Usually comes online in adolescence and early adulthood
- In Schizophrenia PFC does not come online to modulate stress
- PFC deficit causes negative symptoms of ZA
- PFC deficit reduces feedback inhibition of VTA dopamine neurons
- Excessive mesolimbic dopamine transmission causes positive symptoms
What is the Glutamate Hypothesis in relation to schizophrenia?
- Phencyclidine induces hallucinations and paranoia
- Symptoms of intoxication are similar to those in schizophrenia- both positive and negative
- PC does not affect dopaminergic transmission
- PCP affects glutamatergic transmission by specifically BLOCKING NMDA receptors
- VTA neurons require activity of glutamatergic afferent inputs in order to release dopamine in PFC or limbic system
What is Psychosis?
• it is a generic term that means a break from reality
• It is a symptom not an illness
• Caused by a variety of conditions that affect the functioning of the brain
• Includes:
○ Hallucinations
○ Delusions
○ Thought disorder
What are some differential diagnosis for Psychosis?
• Dementia • Delirium • Medications • Substance induced • Mood disorders ○ Bipolar ○ Major depression with psychotic features • Personality disorders ○ Paranoid ○ Borderline ○ Antisocial • Misc ○ PTSD ○ Dissociative disorders
What are the functional causes of psychosis?
- Schizophrenia
- Biopolar
- Severe depression
- Sleep deprivation
- Epileptic disorders
- Exposure to traumatic event
- Stress
What are some organic causes of psychosis?
• Neurological disorders ○ Brain tumour ○ Dementia with lewy bodies ○ Multiple sclerosis ○ Sarcoidosis ○ Syphilis • Electrolyte disorders ○ Hypocalcaemia ○ Hypernatraemia ○ Hyponatraemia ○ Hypokalaemia • Hypoglycaemia • Lupus • Aids
How does cannabis effect your risk of developing schizophrenia?
• Frequent use doubles the risk of psychosis and schizophrenia
What are important diagnostic questions in Psychosis?
- Have organic cause been ruled out?
- Is there a delirium or dementia (cognitive deficits)?
- Is the illness episodic or continuous?
- Are any negative or positive symptoms present
- Is there a history of substance abuse?
- What is the duration?
What is the workup for someone with new onset psychosis?
• Good clinical history • Physical exam • Labs: ○ Metabolic panel ○ CBC with differential ○ B12, folate ○ RPR, VDRL ○ Serum alcohol ○ Urinalysis ○ Thyroid profile ○ Urine drug screen ○ CSF/LP ○ HIV serology ○ CT-MRI ○ EEG
What Medications cause psychosis?
- Bromocriptine
- Phenylpropanolamine
- Vigabatrin (antiepileptic by increasing GABA)
What is the prevalence of Schizophrenia?
Epidemiology?
- 1% of population worldwide
- Lifetime risk equal for males and females
- Age of onset for males = 18-25 years
- Age of onset for females = 26-45 years
- 20% have a second peak at 40-50 years
- Early aggressive treatment decreases long term problems
What is the diagnostic criteria for Schizophrenia?
Must have at least two of the following symptoms • Delusions • Hallucinations • Disorganised speech • Disorganised or catatonic behaviour • Negative symptoms
At Least 1 of the symptoms must be the presence of delusion. Hallucinations or disorganised speech.
* Impairment in social or occupational functioning * Duration of illness for at least 6 months * Symptoms not due to mood disorder or schizoaffective disorder * Symptoms not due to medical, neurological, or substance induced disorder
What are the clinical features of Schizophrenia?
• Formal thought disorders: ○ Neologisms ○ Tangentiality ○ Derailment ○ Loosening of associations (word salad) ○ Perseveration • Delusions ○ Paranoid/persecutory ○ Ideas of reference ○ External locus of control ○ Thought broadcasting ○ Thought insertion, withdrawal ○ Jealously ○ Guilt ○ Grandiosity ○ Religious delusions ○ Somatic delusions • Hallucinations ○ Auditory ○ Visual ○ Olfactory ○ Somatic/tactile ○ Gustatory • Behaviour ○ Bizarre dress/appearance ○ Catatonia ○ Poor impulse control ○ Anger/agitation ○ Stereotypies • Mood and affect ○ Inappropriate affect ○ Blunting of affect/mood ○ Flat affect ○ Isolation or dissociation affect ○ Incongruent affect
What is the onset and course of Schizophrenia?
- Insiduous onset
- Chronic course
- More than 6 months
What are the anatomical abnormalities found in patients with schizophrenia?
• Enlargement of the lateral ventricles
• Smaller than normal total brain volume
○ Particularly frontal and temporal lobes
• Cortical atrophy
○ Reduction in interneurons that inhibit the pyramidal neurons
○ Less cortical synchronisation
• Widening of third ventricle
• Smaller hippocampus
• Normal global cerebral flow
• Hypofrontality
• Failure to activate dorsolateral prefrontal cortex
What are the differences between the dopamine systems?
Cell bodies, projections, functions and implications in schizophrenia?
Nigro striatal: Cell bodies = substantia Nigra Projections = Caudate and Putament Functions = movement Clinical implications = EPS, dystonias and Tardive dyskinesia
Mesolimbic:
Cell bodies = Ventral tegmental area, substantia Nigra
Projections = accumbens, amygdala, olfactory tubercle
Funcitons = emotions, affect and memory
Implication = Positive symptoms
Mesocortical: Cell bodies = VTA Projections = Prefrontal cortex Function = thought, volition, memory Implications = blockade can worsen negative symptoms
What is the psychosocial treatment options for schizophrenia?
- Education and compliance
- Hospitalise for acute loss of funcitoning
- Outpatient rehabilitation treatment
- Cognitive remediation therapy
- Psychoanalysis - exploratory therapies have limited value
- Families should be involved
What is the role of Genetics in schizophrenia?
- Schizophrenia is estimated to be 80% heritable
- Monozygotic twins 40-50%
- Dizygotic twins = 10-15% (same as first degree relatives)
What is the medication approach to schizophrenia?
- essential starting point of treatment
- Minimum effective dosing
- Avoid large doses if possible
- Use what has been effective in the past
- Avoid medications that have had poor side effects
- First onset start with Atypicals antipsychotics
How common is co-occuring disorders?
What risks are increased?
• Occur in 50% of serious mental health disorder • Increased risk of: ○ Relapse and rehospitalisation ○ Suicide ○ Financial stress ○ Violence ○ Medical illness
What are the positive symptoms of schizophrenia?
- Hallucinations
- Delusions
- Bizarre behaviour
- Positive formal thought disorder
- Disorganised speech
- Catatonic behaviour
What are the Negative symptoms of Schizophrenia?
- Loss of function
- Flat affect
- Alogia (poverty of speech)
- Avolition and apathy
- Social withdrawal
- Lack of grooming and hygiene
What are the cognitive deficits found in Schizophrenia?
• Poor performance on tasks involved in working memory and attention
What are the proposed causes of schizophrenia?
• Genetic predisposition
• Developmental abnormality in utero and other developmental insults
• Structural abnormalities have been found in many brain regions
○ Temporal cortex (superior temporal gyrus, parahippocampal gyrus, hippocampus, amygdala)
○ Frontal cortex
• Several neurotransmitters implicated
What are the neurotransmitters that are proposed to be involved in schizophrenia?
- Dopamine increase
- Lack of Glutamate
- Serotonin increase
What dopaminergic pathways are believed to be involved in schizophrenia?
- Reduced activity at the D1 receptors of the mesocortical pathway leads to negative symptoms
- Hyperactivity at the D2 receptors of the mesolimbic pathway lead to psychosis
- Nigrostriatal pathway
- Ventral tegmental area
- Tuberohypophyseal pathway
What is the first line treatment for the first schizophrenic episode?
what is second line?
First line =
Second Generation Anti-psychotic OTHER than Sertindole and clozapine and including aripiprazole
Second line =
An alternate second generation Anti-psychotic or a irst generation anti-psychotic
How common is co-occuring disorders?
What risks are increased?
• Occur in 50% of serious mental health disorder • Increased risk of: ○ Relapse and rehospitalisation ○ Suicide ○ Financial stress ○ Violence Medical illness
