How can understanding drug treatments for a disease help us understand the disease itself?

Schizophrenia is?
A chronic and severe neurological brain disorder
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It is estimated what?
as in 2014 to affect 1.1% of the population or 2.6 million adults in the UK aged 18 or older Rethink 201
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What factors cause schizophrenia?
Genetic, environmental and social factors have been implicated
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Although there is no cure for schizophrenia, what has been introduced?
A myriad of drugs which are available for inital and maintenance therapy with the goal of controlling symptoms. two types of drugs; typical and atypical
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Emsley, 2005
Overall outcome of treating the acute symptoms of psychosis; there remains a subset of patients who are refractory to treatment
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What will this essay look at?
What schizophrenia is, what drugs have been developed to treat it and how understanding these drugs have enabled us to understand some of the mechanisms of schizophrenia
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What will this essay conclude?
Understanding anti-psychotic drugs has enabled us to start to understand the mechanism involved in schizophrenia, however not all the mechanisms
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Kraeplin (1898)
First described schizophrenia using the term Dementia Praecox, Dementia described the glo
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Coined the term schizophrenia 'schizo' meaning split and 'phrene' meaning mind
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What is schizophrenia?
A mental illness characterised by positive symptoms, negative symptoms and cognitive symptoms
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What happens following the first episode of psychosis
reasonable control of psychotic symptoms can be achieved in over 80% of patients with effective treatment
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What happens without maintenance antipsychotic medication?
90% of patients relapse, highlighting the critial importance of long term treatment in improving outcome
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What is schizophrenia associated with?
15 year average reduction in life expectancy. Suicide accounts for 40% of the excess mortality, with 5-10% of patients committing suicide
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How was Chlorpromazine discovered?
It was found accidently when scientists were looking for a new anaethetic. Due to observations of chlorpromazine on the CNS
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What did Laborit and Hugenard do?
Tested chlorpromazine on 2 different psychiatry hospitals
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Hamon et al 1950
French surgeon Henri Laborit pioneered the use of chlorpromazine in a cocktail to sedate surgical patients and reduce shock without sending them to sleep and persuaded psychiatrist colleagues to experiment with it
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What happened at first tests?
Promising results were described with chlorpromazine in a series of 38 psychotic patients (Delay et al, 1952) and before long reports were accumulating from Canada (Lehmann et al) and the UK (Elkes and Elkes, 1954) and the US (Winkleman, 195)
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Of what?
Recovery and significant improvement in large numbers of institutionalised patients with schizophrenia or mania
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What happened to the first reported patients with chlorpromazine?
Noted to be a lot calmer after taking chlorpromazine and after 3 weeks appeared to be completely normal (Shen, 2008)
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What happened as a result of introduction of chlorpromazine?
Large decreases in psychiatric impatient populations were witnessed around the world because of the widespread use of chlorpromazine or its related drugs
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Dolley 1991
Chlorpromazine and later agents has shown that their primary anti-psychotic activity is through the blockade of dopamine receptors in the mesolimbic pathway of the brain
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What does overactivity lead to?
positive symptoms of schizophrenia
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There is little or no what?
Effect on the negative symptoms of schizophrenia. THe dopamine blocking effects of antipsychotic agents on other neurological pathways such as the nigrostriatal pathway and their effects on other neurotransmitter systems such as serotonin and AC
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Creese, Burt and snyder (1976)
The effect that is common to all FGAs is a high affinity for D2 receptors, an there is a strong correlation between the therapeutic doses of the rugs and their binding affinity for D2 receptors
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What does Invitro data show
The FGAs such as haloperido and chlorpromazine bind tightly to the D2 receptors and dissociate slowly
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Remington and Kapur
PET and SPECT studies have further demonstrated the importance of dopamine receptor occupancy as a predictor of antipsychotic respons and adverse effects
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What are antipsychotic effects associated with?
Striatal D2 receptor occupancy of 65%-70%, D2 occupancy greater than 80% significance increases the risk of EPS
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What are the side effects of Chlorpromazine?
2 years after chlorpromazine was introuced to clinical use of schizophrenia acute extrapyrimidal symptoms including parkinson, dystonias and akathisia began to be described
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Ayd, 1961
Prevalence of EPS in patients treated with antipsychotic drugs was estimated 38.9%
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What happened to the majority of clinicians and pharmacologists?
Became convinced of an absolute connection between EPS and clinical effectiveness of antipsychotic drugs
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Merill, Lyon and mataico (2013)
A less common side effect was dyskinesia
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How does Dyskensia manifest itself?
Presence as abnormal involuntary, repetitive, persistent, stereotypic movements of the facial muscles but can also involved other muscle groups including extremities and the torso
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When does this condition occur?
Sometime after initiation of antipsychotic drugs that damage GABAergic medium spiny neurons, it is referred to as Tardive Dyskinesia
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What is the incidence rate of TD?
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Crossley, Mcguire and Power, 2010
54.7% relapse rate, if people with schizophrenia are relapsing at a rate of 50% there must be other mechanisms involved in schizophrenia rather than D2 receptors
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Miyamoto (2005)
30% of patients with acutely psychotic symtoms have little or no response to typical drugs
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60% of patients have what?
A partial response to medication
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Typical drugs are less what?
Effective against negative than positive symptoms
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Typical drugs enable us to?
understand that positive symptoms are likely to be caused by Dopamine receptors such as D2 receptors, however negative symptoms are likely to be caused by another system in the brain, such as Serotonin Systems
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Such as?
this led to the development of Atypical drugs such as Clozapine. These aim to reduce negative as well as positive symptoms.
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By understanding the mechanism of what?
action for chlorpromazine enables us to understand why TD develops as a side effect of these drugs, further enabling scientists to create other drugs which could reduce the chances of TD developing.
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How was Clozapine discovered?
German Psychatrists in the early 1960s worked to refute the concept that EPS and antipsychotic efficacy were linked.
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What did their work lead to?
Introduction of Clozapine, an antipsychotic with no EPS minimally associated with EPS
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What is the clinical confirmation of this profile?
Clozapine was provided in open studies by Austrian, German and Swedish investigators in a double blind trial in 1971
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Why is Clozapine called atypical?
became the prototype for other agents that produced antipsychotic effects at doses with minimal or at least significantly fewer EPS
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Petit (1996)
Atypical drug: he atypical antipsychotic zotepine was compared to haloperidol in 126 patients suffering from acute exacerbation of schizophrenia (DSM-III-R) in a randomized, double-blind study
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- Seven haloperidol patients reported akathisia but no zotepine patients did (p < .05). Uric acid reductions (which appear to have no clinical consequence) and transient raised liver enzymes were recorded with zotepine
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Weight increased on zotepine (2.32 kg; P < .001) and a small increase in pulse rate occurred (P < .05). Both drugs were effective in reducing positive symptoms of schizophrenia; zotepine was significantly more effective against negative symptoms and
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Reduced EPMS
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Clozapine administration to schizophrenic patients was found to produce what?
dopamine (D2) and Serotonin (5-HT2) blockade
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What evidence?
evidenced by the ability to block the increases in growth homron and cortisol secretion produced by apomorphine and MK-212, respectively, direct acting dopamine (DA) and 5HT2 agonists.
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What has been hypothesised?
antagonism of D2 receptors and 5HT2 receptors and enhancement of Da and 5HT release are critical elements in the action of clozapine to minimise both positive and negative symptoms without producing significant EPS
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What has been proposed?
schizophrenia may also involve a dysregulation of 5HT2 and D2 mediated neurotransmission, normal balance in serotnergic and dopaminergic neurotransmission is at least partially restored by Clozapine
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What is seronergic modulation is associated with a beneficial increase in what?
Striatal dopamine release
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What are the effects?
Effects on the negative and cognitive symptoms of schizophrenia relate to dopamine release in the prefrontal cortex; this can be modulated by combined D2 and serotonin 5-HT2A receptor antagonism
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by olanzapine and risperidone), partial D2 receptor antagonism or the preferential blockade of inhibitory dopamine autoreceptors.
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Greater antagonistic action on what?
D4 receptors
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Metzler, 2004
- Clozapine remains the most atypical of the ‘atypicals’ in so far as it is the most effective agent to treat the psychosis of patients with schizophrenia who fail to respond to other typical or atypical agents.
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although one metaanalysis of the effect of clozapine versus other atypicals showed its superiority another did not
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Clozapine has recently been shown what?
particularly effective at reducing the risk of suicide in patients with schizophrenia, whereas typical agents have little or no effect on this dimension of the illness, suggesting that Clozapine reduces negative symptoms
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Mukku and Reddy (2018)
Clozapine use is limited by its frequent and serious adverse effects. Adverse reactions are classified into common and serious fatal reactions.
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What are the common adverse effects?
Central nervous system reactions (sedation, dizziness/vertigo, headache, and tremor), cardiovascular reactions (tachycardia, hypotension, and syncope), autonomic nervous system reactions (hypersalivation, weight gain, drooling, sweating, dry mouth, a
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Garder et al, 2005
The serious and fatal adverse effects are seizures (1–3%) (Varma et al., 2011), myocarditis (0.015%–1.3%) (Kamphuis et al., 2010) and agranulocytosis (0.8%) (Claas, 1989)
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Evaluation for Clozapine
Around 30% of patients fail to respond significantly to two or more antipsychotics, and are therefore considered to have ‘treatment-resistant’ illness.
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Approximately what?
30–50% of treatment-resistant patients respond to clozapine, making it an important and unique second-line treatment. (Meyer and MacCabe, 2016)
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It is estimated what?


as in 2014 to affect 1.1% of the population or 2.6 million adults in the UK aged 18 or older Rethink 201

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What factors cause schizophrenia?


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Although there is no cure for schizophrenia, what has been introduced?


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Emsley, 2005


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