Schizophrenia 2

Question 1

What was the original idea about schizophrenia?

Answer 1

For a long time schizophrenia considered as a ‘functional’ disorder rather than an ‘organic’ one. Nothing wrong in the brain, problems related to environmental factors (in particular schizophrenogenic mothers). In 1948, Frieda Fromm-Reichmann coined the poisonous term schizophrenogenic mother.

Question 2

What did Freud say about delusions?

Answer 2

Sigmund Freud attributed paranoid delusions to “unconscious impulses”, created by dominant mothers and weak fathers.

Question 3

What was the common idea about schizophrenia and the brain?

Answer 3

Until the 70s, most psychiatrists wouldn’t say there is anything that could be said about schizo in terms of brain analysis. This was so popular that even in 1974 the psychiatrist Silvano Arieti attributed the illness to a “domineering, nagging, and hostile mother who gives the child no chance to assert himself”. In 1972, the eminent neurologist Frederick Plum famously said “Schizophrenia is the graveyard of neuropathologists,” meaning that no one had understood or would understand its neurobiology.

Question 4

What was found by Jacobi and Winkler (1927)?

Answer 4

Enlargement of brain ventricles first shown by Jacobi and Winkler, and then confined by CT studies in 70s and recently by MRI studies. Especially in people with chronic schizophrenia. Enlargement of ventricles is coupled with reduced brain size.

Question 5

What changes in the brain can be seen in schizophrenia? (1)

Answer 5

Reduced brain volume (decrease 2-3%) is shown by post-mortem neuropathological studies and structural MRI studies. Can see enlargement of ventricles, changes become bigger as time goes on. Have grey matter loss - prominent changes in frontal cortex, hence why problems in memory. Also changes in the cerebellum.

Question 6

What are problems with connectivity?

Answer 6

Abnormal connectivity? Special MRI methods have shown abnormalities in connectivity (especially in the left frontal and temporal lobes), cortical thickness, surface area, and sulcogyral patterns.

Question 7

What changes in the brain can be seen in schizophrenia? (2)

Answer 7

No evidence of neurodegenerative processes, suggesting pathology of schizo is due to neurodevelopment abnormalities. Alterations in markers of synapses and dendrites in cortex, hippocampus, and thalamus, confirming the notion of abnormal connectivity. Abnormal position and clustering of neurons in the cortex,

Question 8

What have MRI studies found?

Answer 8

Can see enlargement of ventricles and thinning of the cortex. This change becomes larger as the time goes by - first episode to 5 years later show this pattern. Average annual loss in brain mass - most lost in frontal cortex, temporal cortex (Thompson). Much cognitive function depends on the activity in these areas. Also see changes in the cerebellum - not previously thought of as important. This is involved in many functions.

Question 9

What have fMRI studies found?

Answer 9

The frontal cortex is less active in people with schizophrenia (hypofrontality) than in healthy controls.

Question 10

What have MEGI studies found?

Answer 10

Resting MEGI Functional Connectivity in Schizophrenia predicts symptoms. Can see deficit in conductivity. Conducted by people engaging in different kinds of cognitive activities.

Question 11

What have EEG studies found?

Answer 11

Abnormal cortical connectivity in schizophrenia. Show connected areas that exhibit greater fronts-temporal EEG coherence during talking than listening - the thicker the line, the latter the difference between the two coherences.

Question 12

What is involved in the genetics of schizophrenia?

Answer 12

Contribution of genetic factors (and role of shared environmental factors), heritability, types of genetic variation, models of inheritance, and genetic association studies.

Question 13

What is the contribution of genetic factors to schizophrenia?

Answer 13

MZ twins, concordance rate is 48% - 17% for DZ twins, 13% for children, 9% for siblings, 6% for parents, 1% for general population.

Question 14

What is the interesting thing about the contribution of genetic factors to schizophrenia?

Answer 14

Children, siblings, and parents share 50% of DNA - so concordance rate should be the same, but it’s different. Research has shown importance of environmental factors - shared environment of MZ twins have an effect. Even shared environment before birth has an impact - e.g. exposed to same infectious influences on development, effect of malnutrition, etc. Includes epigenetic modification, which takes place after the genome has been defined. Important contribution of both genes and environment.

Question 15

What is the heritability of schizophrenia?

Answer 15

81% of variability is due to genetic factors. Schizophrenia comes in 2 forms: familial and sporadic. Familial - possible to trace the disorder through multiple generations. Sporadic (or de novo) - person from family with no prior history may suddenly experience a cognitive collapse.

Question 16

What are the types of genetic variation in schizophrenia?

Answer 16

There are 2 main types of genetic variations relevant to the aetiology of schizophrenia - polymorphisms and mutations, and copy number variation.

Question 17

What are copy number variations?

Answer 17

They are duplications or deletions of stretches of DNA ranging in size from hundreds to thousands of nucleotides and they may be thought of as miniature chromosomal abnormalities.

Question 18

What are polymorphisms and mutations?

Answer 18

DNA sequence variants. The two alleles of every autosomal gene may be identical (homozygosity) or differ (heterozygosity). Most polymorphisms involve change in a single nucleotide (Single Nucleotide Polymorphism, SNP). Most polymorphisms do not lead to changes in protein encoding (conservative or non-coding substitutions) and have no known consequences. Some polymorphisms may be beneficial or harmful in a probabilistic sense. Variation that has high prevalence in the general population (polymorphisms).

Question 19

What is a non-mendelian model of inheritance?

Answer 19

Transmission is non-mendelian. Complex genetic disorders. No gene is either necessary or sufficient to cause the disorder.

Question 20

What are genetic association studies in schizophrenia?

Answer 20

Candidate gene studies have failed even though they’ve given evidence of an involvement of D2 and D3 receptors. Genome-Wide Association Studies and linkage analysis succeeded.

Question 21

What are GWAS?

Answer 21

Don’t need to make assumption about what genes are implicated, just take entire genome of people with schizophrenia and compare them to a control. Scan large populations to identify common genetic variants associated with common diseases. However, they are expensive, time consuming, and require collaboration among different groups.

Question 22

What are risk alleles in schizophrenia?

Answer 22

What proportion of our genome have been associated with schizo, and what variation? Can be copy number variation, of single nuclide variation (most people will have at least one of this kind of polymorphisms, slightly increases the risk of schizophrenia). There are also ones that you inherit from your parents, but this is rare (impart high risk of schizophrenia). 
♣	De novo CNVs
♣	De novo SNVs/indels
♣	Rare CNVs
♣	Rare SNVs
♣	Common SNPs

Question 23

What did Nature (2014) find?

Answer 23

623 schizo young people with unaffected parents and siblings (sporadic schizo). In 617 cases a culprit variant was found in the child that was not present in either parent. In nearly 80% of cases, variation was in chromosome derived from the father, suggesting it occured during spermiogenesis. Many of variations involved genes that affect synapses (e.g. ARC and NMDAR complex). Many genes implicated in sporadic autism and intellectual disabilities.

Question 24

What did Owen (2016) find?

Answer 24

Most of the CNVs associated with schizophrenia impact on multiple genes, with the exception of deletions of NRXN1, the gene encodes the presynaptic cell adhesion protein neurexin1. Few rare CNVS, each conferring high risk of schizo. Thousands more/less common SNPs, each conferring low risk of schizo. Different genes interact together.

Question 25

What is the molecular pathway for schizophrenia?

Answer 25

All types of variation of schizophrenia seem to involve the glutamatergic synapse, in particular the postsynaptic portion of this synapse, where there are glutamate receptors and the ARC complex. Also sites where there are potential genetic abnormalities, to do with glutamatergic transmission.

Question 26

What did Sekar et al. (2016) propose?

Answer 26

Previous studies have shown that strong associations between genetic variations and schizo occur in the major histocompotbility complex (MHC) - region of genome containing 3 classes of gene with differing roles in immunity. Help mark pathogens and damaged cell debris and may promote their clearance by phagocytic cells of the immune system. In the nervous system, components of the complement system are also known to be involved in synaptic pruning.

Question 27

What did Sekar et al. (2016) find? (1)

Answer 27

Genetic loci that are associated with risk are found along the entire region. However, genetic variants in C4A and C4B are most strongly associated with increased risk. Involvement of C4 supports increase vulnerability in people with CSMD1.

Question 28

What did Sekar et al. (2016) find? (2)

Answer 28

Another genome-wide significant association on chromosome 8 lies near CSMD1, which encodes a protein that regulates C4.

Question 29

What did Sekar et al. (2016) find? (3)

Answer 29

The number of copies of C4A and C4B varies from person to person. There are long and short versions of each gene, which are determined by the presence or absence of a human endogenous retroviral (HERV) insertion in a non-coding region of the gene.

Question 30

What did Sekar et al. (2016) find? (4)

Answer 30

Expression of C4A and C4B increases with copy number, and the presence of the HERV insertion increases the ratio of C4A to C4B expression. The higher the levels of C4A expression, the greater the risk of schizo independent of other genetic variations in the MHC region. C4A = greater risk of schizo, found in the cerebellum.

Question 31

What did Sekar et al. (2016) find? (5)

Answer 31

C4 known to promote activation of complement component 3 (C3). In mice C3 can target specific synapses and is required for synapse elimination by microglia (synaptic pruning). Excessive dosage of C4 (successive pruning on dendrites) might lead to increased postnatal synaptic pruning, which in turn might explain loss of grey matter and reduced numbers of synaptic structures in the neurons of patients with schizo.

Question 32

What did Sekar et al. (2016) find? (6)

Answer 32

Small-effect-size alleles such as C4A must act in combo with other genetic and/or environmental risk factors to cause schizo. Need other abnormalities to get schizo. Possibility of multiple factors acting on the same pathway.

Question 33

What is involved in C4 structures, C4A expression, and schizophrenia risk?

Answer 33

From control (C4B short form) to C4A expression can see an increase in the risk of schizophrenia (20-30% increased vulnerability). C4A seems to be important in increasing the risk of schizophrenia.

Question 34

What did Sellgren et al. 2019 find? (1)

Answer 34

Combine with findings from Sekar that C4 is involved in vulnerability of schizophrenia.

Question 35

What did Sellgren et al. 2019 find? (2)

Answer 35

Excessive synaptic pruning occurs in patient-derived cellular models, depending on both neural and microglial factors.

Question 36

What did Sellgren et al. 2019 find? (3)

Answer 36

Consistent with findings by Sekar, C3 complement deposition was positively correlated with C4AL copy number. Results show an association between increased synapse engulfment and the schizophrenia risk variant. C4AL helps glia target the cell. One of the possible mechanisms that leads to schizophrenia. If have many C4AL copies you can increase the risk of schizo, therefore may be possible to prevent schizo by blocking this process.

Question 37

What did Sellgren et al. 2019 find? (4)

Answer 37

Minocycline, an antibiotic with anti-inflammatory effects, decreased synaptic pruning.

Question 38

What is the neurodevelopment hypothesis of schizophrenia?

Answer 38

Schzio typically manifests in late adolescence/early adulthood. Time course of schizo is mirrored by the time course of neurodevelopment. During the preceding phase, you have this abnormality in synaptic pruning, especially in the prefrontal cortex, so you have deficit in inhibitory and exhibitory inputs, which regulates activity. Can also have abnormality in myelinisation of neurons. After symptoms starts to appear, you have development of this abnormality.

Question 39

What did Feinberg (1983) propose? (neurodevelopment hypothesis of schizophrenia)

Answer 39

Feinberg proposed that the excessive/abnormal synaptic pruning could be involved in schizo. Feinberg suggested that abnormal synapse elimination during this period (too much / too little) could lead to the profound behavioural changes and cognitive impairments that categorise schizophrenia.

Question 40

Interaction between glutamatergic and dopaminergic systems in schizophrenia - where is abnormality important?

Answer 40

Important in the cortex, in glutamatergic neurons, in MNDA receptors, and in the ARC complex.

Question 41

What happens in the key glutamatergic pathways?

Answer 41

Projections from the prefrontal cortex back to the mid-brain - midbrain is cell body region for dopaminergic neurons. This projection regulates activity of dopaminergic neurons. When something is wrong with the glutamatergic synaptic connection – neurons less active, have less inhibitory control of other glutamatergic neurons that project back to the midbrain. Leads to positive symptoms (one explanation).

Question 42

What is involved in NMDAR hypo functionality and negative symptoms?

Answer 42

Excessive glutamatergic input to the brain stem neurons that control dopaminergic transmission - inhibitory control of dopaminergic neurons. Reduced dopaminergic transmission in the cortex = hypothesis for negative symptoms.

Question 43

What is the history of antipsychotic medications (1931)?

Answer 43

Indian physicians G. Sen and K.C. Bose describe the antihypertensive effects of Rauwolfia serpentine – for the treatment of mental insanity, hypertension, and other ailments.

Question 44

What is the history of antipsychotic medications (1953)?

Answer 44

Dr. Hakim of Ahmedabad received a gold medal for having successfully treated schizo patients with meds containing R. serpentina. Effects of this were tested, and found that the treatment proved to be effective in patients with schizophrenia.

Question 45

What is reserpine, and did it continue to be used?

Answer 45

By the end of the 50s there were 26 prescriptions containing reserpine (active component in R. serpentine). Worked by blocking the transmission of dopamine, meaning D2 receptors not stimulated. Lots of side effects meant it is no longer used.

Question 46

What is the history of antipsychotic medications (1940s)?

Answer 46

Company Rhône-Poulenc develop antihistamines based on a phenothiazine structure (to control allergies, found it produced state of sedation). Thought to be useful during anaesthesia. Surgeon Henry Laborit used promethazine in anaesthesia and reports that it produces a state of “euphoric quietude” or “ataraxia”.

Question 47

What is the history of antipsychotic medications (1952)?

Answer 47

The psychiatrists J. Delay and P. Deniker administer chlorpromazine to hospitalized psychiatric patients and report on its dramatic effectiveness on psychosis. They coined the term ‘neuroleptic’.

Question 48

What is the history of antipsychotic medications (1960)?

Answer 48

Hundreds of antipsychotic drugs have been developed based on the structure of chlorpromazine and its analogues.

Question 49

What was the findings of medication using dopamine?

Answer 49

1958 - Found DA was not just a precursor of adrenaline and non, but a neurotransmitter in its own right.
1963 - Existence of DA receptors with high affinity for chlorpromazine and haloperidol
1967 - Jacques van Rossum hypothesize that the antipsychotic effect was due to the blockade of DA receptors
1975 - • Philip Seeman and Solomon H. Snyder demonstrated the existence of DA receptors. A striking correlation between the potency of antipsychotic drugs and their affinity for D2 receptors was found immediately thereafter.

Question 50

How do antipsychotic drugs work?

Answer 50

Work by binding receptors - prevent dopamine from binding to receptors, reducing dopaminergic transmission. All antipsychotics have affinity to D2 receptor. Exact binding profile differs for each antipsychotic drug. Side effects can include problems with appetite, and disturbance in sexual behaviour/activity.

Question 51

Is there evidence that antipsychotics affect negative as well as positive symptoms?

Answer 51

Yes - Marques et al (2014). • Administered those with chronic schizophrenia with anti-psychotics, who had never received treatment before. Compared 2 models: one in which you have different effects of symptoms (e.g. certain effects on positive symptoms, negative symptoms, and general symptoms), and another which assumed you have a common factor – all symptoms come from a specific action of a receptor, because of a blockage of receptor. Found that a common factor model showed the best results – therefore all symptoms are affected by a blockage of D2 receptors. Single-factor model explained nearly 90% of variance, however this does not appear to be supported by data.

Question 52

What is an explanation for how antipsychotics affect positive and negative symptoms?

Answer 52

One possibility - in addition to normalizing dopamine transmission in the striatum, they also normalize transmission in the prefrontal cortex – acting on presynaptic D2 receptors, reducing their activity. Dopaminergic hyperactivity in the striatum somehow affects activity in the cortex. Not clear what is the exact mechanism for this.

Question 53

What are side effects of antipsychotics?

Answer 53

In addition to the antipsychotic effects, can also have serious side effects -

1) Extrapyramidal side effects (parkinsonism, akathisia, dystonia, tardive diskinesia).
2) Prolactin elevation (amenorrhea, galactorrhea, hyposexuality, gynecomastia in males - growing milk producing breasts).
3) Dysphoria, anhedonia, depressed mood.

Question 54

What is the effect of minocycline and doxycycline? (anti-inflammatories)

Answer 54

Sellgren et al. (2019) hypothesized that chronic exposure minocycline or doxycycline, commonly prescribed for the treatment of acne vulgaris, during adolescence might decrease schizophrenia risk. Electronic health records from two large medical centers showed that administration of minocycline or doxycycline for at least 90 days to individuals aged 10-18 was associated with significantly decreased risk of incident psychosis. Acting on anti-inflammatory processes in the brain, you reduce the risk of schizophrenia. Although, this would take many years, and it is unknown when exactly this treatment should be administered.