L12: Schizophrenia

When is incidence of schizophrenia increased ?

if there is family history (6-17%)

if got affected Twin (50%)

What is schizophrenia ?

Highly disabling psychiatric illness

When does schizophrenia usually emerge?

In adolescence or young adult life

State the pathology of schizophrenia?

- Larger ventricle so indication of loss of cortical grey matter => clear sign of neurodegeneration in cortex

What do the cortical pyramidal cells show in schizophrenia brain at post-mortem ?

reduced dendritic length and spine density in schizophrenia brain at post-mortem

What is a clear marker of schizophrenia ?

Reduced synapses evident in schizophrenia

- Loss of synapses particularly evident in the prefrontal cortical area

What is the cause of schizophrenia?

Causes = unknown

- appear to be multi-factorial

State the risk factors of schizophrenia?

1)Genetic risk

- 1% risk in gen pop rises to 50% risk if one has an affected twin

- single gene association contributes very little so possibility of coming together

2) Environmental risk

- Cannabis exposure

- Urban living, and stress during adolescence

- Maternal factors including prenatal infections and malnutrition(of fetus)

State the two factors that cause schizophrenia to be classed as a neurodevelopment disorder?

1) Gestational?

- Link between reduced number of ridges and schizophrenia

- Fingerprint is developed between 14th - 22nd weeks of gestation

- Idea that maternal insult during that period of development => trigger schizophrenia

- During this period of time a lot of development occurs and many of them will impacted by maternal insult

2) Adolescence

- Timing of fine tuning & synapse stabilisation may be affected by genetic predisposition or environmental disturbances.

State the positive symptoms of schizophrenia ?

(exaggerations of normal behaviour )

- Hallucinations (auditory>visual)

- Illusions (misinterpreting sensory stimuli )

- Though disorder (wild trains of thought; irrational conclusions)

- Delusions (fixed inaccurate belief of self)

- Abnormal behaviour(aggressive, stereotypical)

State the category of schizophrenia symptoms that are similar to the ones we associate with depression ?

Negative (suppression of normal behaviour)

- Social withdrawal

- Flattened emotions

- Lack of drive (avolition)

- Disorganised speech (alogia )

What are the cognitive symptoms of schizophrenia ?

- Impaired learning and memory)

- Attention

- Executive function (making the right decisions

What are the three clinical symptom categories of schizophrenia?

- Positive (exaggerations of normal behaviour)

- Negative (suppression of normal behaviour)

- Cognitive

What is the key evidence that supports the DA hypothesis of schizophrenia

- Drug amphetamine (releases DA) induces stereotyped psychotic-like symptoms in patients (paranoia, audit/visual hallucinations)

- L-DOPA(used to treat Parkinson's) can induce psychosis in patients with Parkinson's disease

- Genetic associations with dopaminergic system (D2/D3 receptors; Brain derived neurotrophic factor [BDNF); catechol-O-methyl transferase (COMT)

- Increased numbers of D2 dopamine receptors in schizophrenic brain at post-mortem (more receptors so more DA transmission)

- Effective antipsychotic drugs block brain dopamine D2 receptors

- Affinity for D2 receptors directly correlates with clinical potency of drugs

State the strongest evidence for the DA hypothesis of schizophrenia ?

Effective antipsychotic drugs block brain dopamine D2 receptors

State arguments against increased numbers of D2 dopamine receptors in schizophrenic brain at post-mortem?

- Patients took D2 receptor antagonists

- Therefore the brain produced more receptors

(might be secondary change)

What is the correlation between affinity to D2 receptor and clinical potency of antipsychotic drugs ?

Drugs with the highest affinity to bind need lowest dose to get clinical potency

Example = chlorpromazine =low affinity to D2 receptor therefore huge dose required so least clinically effective

Excess stimulation of which receptor leads to the positive symptoms of schizophrenia ?

D2 receptor

What was the previous terminology for antipsychotic drugs ?

•Neuroleptics

•Major Tranquillizers

•Anti-schizophrenic drugs

When were the two classes of antipsychotic drugs developed?

1) Typical antipsychotics (pre-1980s)

2) Atypical/ second-generation antipsychotics (1980s onwards)

State the unifying feature of both classes of antipsychotics ?

1) Both block D2 receptors

2) Both have long half life

What are the ways to administer antipsychotics can increase patient compliance?

Oral = 15-30hrs

intra muscular = 1-2 days

i.m depot = last 2-4 weeks

What is the benefit of antipsychotic drugs having a long half life?

Helpful as a longer half-life means the less frequent need for dose

- Difficult for schizophrenic patient to remember to take med

What does rich pharmacology mean ?

Not specific to a particular receptor

State the order of affinity for receptors that typical antipsychotic drugs act as an antagonist ?

1)Dopamine D2

2) a-adrenoceptor

3) dopamine D1

4) 5-HT2

5) mACh

6) Histamine H1

What are the therapeutic effects of typical antipsychotic drugs a primary result of ?

Blockade of dopamine D2 receptors

What symptoms of schizophrenia do typical antipsychotic drugs tackle ?

Only POSITIVE symptoms

In the past how was chlorpromazine the first typical antipsychotic used ?

- Although it had the least affinity to H1 it acted as an antagonist

- Therefore in mental institutes, it was given to sedate schizophrenic patients

- But they saw improvements of +ve symptoms

How long does it take for clinical relief ?

Lag in clinical relief

- approx 3 weeks

- suggesting that act of blocking receptor alone is insufficient

What is the possible explanation for the lag in clinical relief with antipsychotic drugs ?

- At start of haloperidol treatment in rats, DA neurones increase firing rate (compensation?)

- Firing rate declines over next 3 weeks when neurones finally become inhibited.

What are the side-effects of typical antipsychotics as a result of their rich pharmacology?

- Sedation (H1 block)

- Hypotension (alpha-adrenoceptor block) low bp

- Anticholinergic effects (dry mouth, blurred vision, constipation)

Name two typical antipsychotic drugs ?

Chlorpromazine and Haloperidol

What are the pathways and side effects of typical antipsychotic drugs ?

1) Tuberoinfundibular pathway (hypothalamus to pituitary)

Block of D2R increases

prolactin secretion

- trigger for gynaecomastia = breast growth in males

2) Nigrostriatal pathway (motor)

(substantia nigra to caudate)

Block of D2R brings about extra-pyramidal side-effects (motor impairment)

What is the Brain dopamine systems responsible for the efficacy of typical antipsychotic drugs?

Mesolimbic pathway

(ventral tegmental area to nucleus accumbens & amygdala)

= Excess DA activity linked to POSITIVE symptoms of hallucinations, delusions. Block of D2R brings relief

What does block of dopamine transmission within nigrostriatal pathway triggers ?

- Pseudoparkinsonism: Stooped posture, bradykinesia(slowness of movement), rigidity, tremors

•Acute dystonias: Facial grimacing; muscle spasms of face, neck & back

•Akathisia: Restless; feet rock back and forth

•Occur in 20% patients within few weeks treatment; reversible upon drug withdrawal (occurs in 1/5 patients)

what up-regulation of dopamine D2R due to chronic use of medication triggers ?

-Tardive dyskinesia(excessive movement): Protruding tongue, lip smacking, facial dyskinesia and involuntary movements of limbs.

•If not treated early can become irreversible.

Name three atypical or second-generation antipsychotics (SGAs) ?

Clozapine

Olanzapine

Risperidone

State the receptors that atypical or second-generation antipsychotics (SGAs) have affinity for ?

5-HT2

DA-D4

DA-D2 = DA-D1 = a-adrenoceptor = mACh = Histamine H1

What symptoms does block of dopamine D2 -or D4 receptors in mesolimbic pathway combat ?

POSITIVE symptoms

What might explain the reduced incidence of extrapyramidal side-effects ?

D4 - receptor found in mesolimbic pathway, but not nigrostriatal pathway

What other class of symptoms do atypical or second-generation antipsychotics (SGAs) have some efficacy ?

- NEGATIVE symptoms

5-HT2A receptor blockade might explain this but how is unclear.

What are the side effects of atypical antipsychotics ?

•Sedation; hypotension; anticholinergic effects as per typicals

•Leucopenia or agranulocytosis

•Weight gain - food craving (5-HT2 antagonism)

•Impaired glycaemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes (mechanisms still under scrutiny)

What is leucopenia or agranulocytosis ?

- Reversible, potentially fatal loss of neutrophils, basophils, eosinophils (loss of WBCS)

- Only seen with clozapine

- Idiosyncratic, rare events (1-2% patients) seen in first few weeks

- Regular blood tests to monitor for this

State the advantages and disadvantages of atypical antipsychotics ?

+ Reduced Extrapyramidal side-effects

+ Provide some relief of negative symptoms

- Side effects of weight gain and type 2 diabetes are problematic

- Many patients' psychosis remains drug-refractory

- Provide NO cognitive benefit; attention, learning, memory & executive function are still impaired

What is the evidence for glutamate as new target for drug development ?

Evidence for glutamate hypoactivity in schizophrenia

- Genetic associations with glutamatergic system: GRIN1 (NMDAR1 subunit) NRG1 (neuregulin; controls expression of glutamate receptor subunits

- NMDA-R knock down mice show stereotyped behaviour which is reversible with antipsychotic treatment

- NMDA-type glutamate receptor antagonists e.g. phencyclidine (PCP) and ketamine induce hallucinations, thought disorder, flattened emotional responses in humans. Mimics POSITIVE and NEGATIVE symptoms plus cognitive decline

Why is glutamate a better potential target than dopamine ?

NMDA block mimics POSITIVE and NEGATIVE symptoms plus cognitive decline

DA hyperactivity only mimics POSITIVE