35. Schizophrenia Flashcards
Define
Schizophrenia
a chronic and severe mental disorder affecting 20 million people worldwide characterized by distortions in thinking, perception, emotions, language, sense of self and behaviour
Define
Positive symptoms
highly exaggerated ideas, perceptions, or actions that show the person can’t tell what’s real from what isn’t.
Define
Negative symptoms
refer to an absence or lack of normal mental function involving thinking, behavior, and perception
Define
Two-hit hypothesis
suggests that a prenatal genetic or environmental “first hit” disrupts some aspect of brain development, and establishes increased vulnerability to a second hit that may occur later in life. Neither insult by itself is sufficient to induce schizophrenia.
Define
Copy number variation (CNV)
a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals
Define
DISC 1
shown to participate in the regulation of cell proliferation, differentiation, migration, neuronal axon and dendrite outgrowth, mitochondrial transport, fission and/or fusion, and cell-to-cell adhesion. Several studies have shown that unregulated expression or altered protein structure of this protein may predispose individuals to the development of schizophrenia
Define
Neuroleptic
tending to reduce nervous tension by depressing nerve functions
Define
Atypical anti-psychotic
thought to be better in treating the negative symptoms of schizophrenia although differences may also be due to fewer adverse effects and/or better patient compliance. Members of this class include amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone
Definition
a chronic and severe mental disorder affecting 20 million people worldwide characterized by distortions in thinking, perception, emotions, language, sense of self and behaviour
Schizophrenia
Definition
highly exaggerated ideas, perceptions, or actions that show the person can’t tell what’s real from what isn’t.
Positive symptoms
Definition
refer to an absence or lack of normal mental function involving thinking, behavior, and perception
Negative symptoms
Definition
suggests that a prenatal genetic or environmental “first hit” disrupts some aspect of brain development, and establishes increased vulnerability to a second hit that may occur later in life. Neither insult by itself is sufficient to induce schizophrenia.
Two-hit hypothesis
Definition
a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals
Copy number variation (CNV)
Definition
shown to participate in the regulation of cell proliferation, differentiation, migration, neuronal axon and dendrite outgrowth, mitochondrial transport, fission and/or fusion, and cell-to-cell adhesion. Several studies have shown that unregulated expression or altered protein structure of this protein may predispose individuals to the development of schizophrenia
DISC 1
Definition
tending to reduce nervous tension by depressing nerve functions
Neuroleptic
Definition
thought to be better in treating the negative symptoms of schizophrenia although differences may also be due to fewer adverse effects and/or better patient compliance. Members of this class include amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone
Atypical anti-psychotic
Why is schozophrenia considered a syndrome?
No single defining symptom or sign, no known diagnostic laboratory test
What are the positive symptoms of schizophrenia?
Positive symptoms include paranoid delusions, hallucinations, thought disorder
What are the negative symptoms of schizophrenia?
Negative symptoms include diminished emotional expression and reaction, diminished participation in interpersonal relationships, loss of energy, drive and interests
Which neurotransmitter was initially believed to cause schizophrenia?
Dopamine
What is the estimated prevalence of schizophrenia?
0.5-1%
When is schizophrenia usually diagnosed?
Disorder usually diagnosed in young adults, peaking around 18-25 years of age
What is seen in children with early-onset schizophrenia?
In children with early onset schizophrenia, there is excessive loss of gray matter and cortical thinning detected by neuroimaging
Why do people with schizophrenia typically have a shorter lifespan?
Suicide is the major contributor early in the course of the disorder and cardiovascular disease in later years
What is the gender difference in schizophrenia?
Slightly more frequent in males than in females (1.4:1 ratio) but the disorder is more severe in men
What are the symptoms of schizophrenia?
- Positive symptoms (fluctuates) – hallucinations, delusions, disorganised speech and behaviour
- Negative symptoms (fluctuates) – decreased emotional range, loss of interest and motivation, inertia and apathy, poverty of speech, diminished participation in interpersonal relationships
- Cognitive symptoms (stable) – deficits in working memory/attention/executive function, difficulty in understanding subtle interpersonal cues
- Mood symptoms – depression is common, often cheerful/sad without reason
How does the DSM diagnose schizophrenia?
- Diagnostic & Statistical Manual of the American Psychiatry Association (DSM) (at least 2 of the following symptoms)
- Delusions
- Hallucinations
- Disorganized speech
- Catatonic behaviour
- Negative symptoms
- And at least 1 of the symptoms must be delusions/hallucinations/disorganized speech
- Signs of disturbance must persist for at least 6 months and active symptoms must be experienced for at least 1 month and the problems must not be caused by other conditions
Which protein networks are dysregulated in schizophrenia?
DISC1
Neureglin 1
SHANK3
Reelin
Kalirin 7
Neurexin 1
What is the cause of the PFC and/or hippocampal asymchony seen in schizophrenia?
Disrupted E-I balance
Glutamate (NMDA)
GABA
What is the nauropathology of schizophrenia?
Reductions in total grey and white matter and overall whole brain volume
Abnormalities in striatal connectivity to the prefrontal cortex linked to positive and negative symptoms
Executive dysfunction associated with abnormalities in dorsolateral prefrontal cortex, anterior cingulate cortex and inferior parietal lobe.
What brain abnormalities have been linked to the positive and negative symptoms of schizophrenia?
Abnormalities in striatal connectivity to the PFC
What brain abnormalities have been linked to the executive dysfunction in schizophrenia?
Abnormalities in dorsolateral prefrontal cortex, anterior cingulate cortex and inferior parietal lobe.
Which prenatal/perinatal events are risk factors for schizophrenia?
Maternal malnutrition – increase incidence following famine
Maternal infections – increase incidence following influenza epidemic
Maternal adverse life events
Labour-delivery complications
Which premorbid events are risk factors for schizophrenia?
social adversities - physical and sexual abuse, neglect, bullying
drug abuse - amphetamine, cocaine use
urban environment,
migrant status
What is the heritability of schizophrenia?
64-81%
Which candidate genes have been linked to schizophrenia?
DISC1
Neurexin
Dopamine D2R, Glutamate R components
What is the best supported candidate gene of schizophrenia?
DISC1
What is the role of DISC1?
neurodevelopmental roles in regulating neuronal migration, neurite outgrowth and neuronal maturation, adult roles in modulation of cytoskeletal function, synaptic transmission and plasticity
What neuroleptic drugs are used to treat schizophrenia?
- Chlorpromazine and haloperidol
- DA2R antagonistic activity but not very selective
- Can cause extrapyramidal motor disabilities such as rigidity and involuntary tremors
What atypical antipsychotic drugs are used to treat schizophrenia?
- Second generation antipsychotics
- E.g. clozapine, risperidone, paliperidone
- Exact mechanisms of action - unknown
- Generally thought to also antagonise the DA2 receptors
- Equally potent in blocking 5HT2A receptors
- Decreased incidence of extrapyramidal side effects
Which classes of drugs are used to treat schizophrenia?
Neuroleptics
Atypical antipsychotics
What type of behavioural therapies are used in schizophrenia?
CBT
Supportive psychotherapy
How is CBT used to treat schizophrenia?
- Aim is to reduce the impact of positive symptoms
- Generally comprising of 10 planned session with specially trained therapist over 6 month period
- Explores patient’s own understanding of his/her symptoms
- Should not be seen as a replacement for anti-psychotic medication but an addition
- Not effective for all patients
How is supportive psychotherapy used to treat schizophrenia?
Aim is to help patients deal with loss, disability and stigma of living with schizophrenia
What types of animal models are used to study schizophrenia?
Pharmacological
Lesion
Genetic
What do we look at in pharmacological models of schizophrenia?
NMDA R antagonist – PCP/ketamine, produce range of schizophrenic symptoms including hyperlocomotion, enhanced stereotype behaviour, cognitive and sensorimotor gating deficits, impaired social interactions
What do we look at in lesion models of schizophrenia?
Neonatal lesion of the ventral hippocampus – hyperlocomotion, social and working memory deficits
What do we look at in genetic models of schizophrenia?
- DISC 1 mutant mice (N/C terminal truncation) – some but not all symptoms including increased aggression, social deficits, contextual associative learning and short term memory deficits
- Neuregulin KO/knockdown – some but not all symptoms including hyperactivity, impairment of contextual associative learning, increased aggression, social deficits
- NMDAR (NR1) knockdown
- a7-Nicotinic R knockdown
- Fisher344 rat
- N-CAM-180 depletion
