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M202 > W21 Schizophrenia (RT and AG) > Flashcards

W21 Schizophrenia (RT and AG) Flashcards

- 2 lectures

1
Q

What is the definition of schizophrenia?

A

Schizophrenia is a serious mental disorder in which people interpret reality abnormally.
Schizophrenia may result in some combination of hallucinations, delusions, and extremely disordered thinking and behavior that impairs daily functioning, and can be disabling.
* People with schizophrenia require lifelong treatment. Early treatment may help get symptoms under control before serious complications develop and may help improve the long-term
outlook.
* Schizophrenia involves a range of problems with thinking (cognition), behavior and emotions. Signs and symptoms may vary, but usually involve delusions, hallucinations or disorganized speech, and reflect an impaired ability to function.

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2
Q

Schizophrenia - Epidemiology

A
  • Prevalence ~1%
  • 10% suicide risk – 40% single attempt
  • Onset
    -♂: median 26 yrs
  • ♀: median 29 yrs
    -♂:♀ ~1.3:1
  • Increased prevalence in lower economic strata
  • Course
    -Relapsing and remitting: episodic
    -Chronic and progressive
  • Prognosis
    ~10% continuous hospitalisation
    ~30% 5 year symptom free
    ~60% continued episodic problems
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3
Q

What are the symptoms of schizophrenia?
Positive?
Negative?
Cognitive?

A

Positive:
Increase in abnormal active behaviours
including positive hallucinations
delusions disordered thoughts
language abnormality motor disorders

Negative:
Absence of normal active behaviours, occur prior to positive symptoms affective blunting avolition anhedonia poverty of speech social withdrawal neglect of hygiene

Cognitive: disturbance of of normal
thought processes, poor executive function and decision making, recognition deficits
memory problems, attention deficit

Diagnosis: Clinical – 2 or more over 1 month
(No current diagnostic biomarkers)

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4
Q

Interactions leading to structural and functional deficit

A

Genetic predisposition
- 50% in monozygotic twins
- No specific gene- many of mall effect
Environmental insult
- No specific factors
- Prenatal and childhood virus
- Urban birth/residence
- Psychosocial factors- early childhood (dysfunctional family env)
Neurodevelopment defect
** Structural abnormalities**
** Functional abnormalities**
** Cognitive impairment positive and negative symptoms**
* developmental disruption of neuronal migration
* enlarged ventricles
* reduced regional cerebral volumes
* loss of neurones
* reduced network and functional activity

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5
Q

Structural changes - biomarkers in MRI scans:
What are the changes to the brain in schizophrenia? (2)

A
  • Enlarged ventricles
  • Loss of neuronal tissue (thinner cortex)
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6
Q

Altered function- biomarkers in EEG

A
  • Following an auditory stimuli
  • Characteristic pattern in a subject without Schizophrenia
  • Changed in individual with early schizophrenia
  • More marked in individual with late schizophrenia
  • Demonstrating marked measurable functional changes
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7
Q

What are the Dopamine pathways in the CNS?

A

Dopamine: midbrain origin - SN and VTA
* SN to striatum: Nigro-striatal –basal ganglia and movement
* VTA to hippocampus: mesolimbic pathway
* VTA to cortex: mesocortical pathway
* Also :Tubero-infidibula system from hypothalamus to pituitary

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8
Q

Excess dopamine and schizophrenia

A
  • Cocaine and amphetamine release DA
  • Chronic abuse can elicit toxic psychosis
    -paranoid delusions
    -hallucinations
    -compulsive behaviour
  • Exacerbates positive symptoms
  • L-DOPA increases DA levels
    -delusions and hallucinations
  • Antipsychotic/neuroleptic drug action correlates with D2 DA receptor block
  • D2 DA gene - risk factor in schizophrenia
  • DA receptors may be increased in schizophrenics
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9
Q

Treating schizophrenia - Typical (first generation) antipsychotics

A

High affinity D2-receptor antagonists
* phenothiazines - chlorpromazine, thioridazine, fluphenazine
* butyrophenones - haloperidol
* thioxanthenes – chlroprothixene
* dibenzodiazepines – clozapine
* Effective ONLY against positive symptoms
* Serious side effects - EPS

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10
Q

Treating schizophrenia - Typical (first generation) antipsychotics:
What are the DA related hormonal and EPS?(4)

A

DA related include hormonal and extrapyramidal motor (on target side effects):
* pseudoparkinsonism (early Parkinson’s like) eg bradykinesia, tremor
* tardive dyskinesia (late Huntington’s like)
* other motor effects (akathisia, dystonia)
* increased prolactin release – sexual dysfunction

Non-DA (off target side effects)
* sedation - antihistamine, anticholinergic (H1 mACh)
* hypotension – central adrenergic (alpha 1)
* peripheral autonomic – blurred vision, dry mouth, constipation (MACh)

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11
Q

Treating schizophrenia - Atypical (second generation) antipsychotics (antagonists)
What are examples that have a low affinity for D2?

A
  • Relatively low affinity for D2
    • Benzamides:
      -Olanzapine, Quetiapine, Risperidone, Ziprasidone, Quitiapine, Aripiprazole
      -Also Clozapine
  • Effective against both positive and negative
  • High affinity at 5HT2
  • High ratio 5HT2:DA may be desirable
  • Less side effects than Typical antipsychotics, especially motor effects.
  • but other side effects
    -weight gain
    -diabetes
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12
Q

Role for 5HT

A
  • Problems with DA
  • Serious dopaminergic side effects
  • many neuroleptics only control positive symptoms
  • DA block immediate – clinical onset 6-8 weeks – adapative changes
  • drugs block many other receptors
  • muscarinic, histaminergic, alpha-noradrenergic
  • Role of 5HT
  • Increased levels in schizophrenics
  • LSD - 5HT agonist induces hallucinations, cognitive impairment, aggression
  • 5HT metabolites (Dimethyltryptamine) hallucinogenic
  • many neuroleptics are potent 5HT2 receptor blockers
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13
Q

Role of glutamate

A
  • Neurodevelopmental change – glutamate neurones affected
  • Disordered migration - abnormal circuits
  • Neuronal and synaptic loss
  • NMDA antagonists e.g. ketamine, phencyclidine are psychotomimetic
  • NMDA receptor knockout - social withdrawal in mice
  • Reduced glutamate in CSF of patients with active schizophrenia
  • Loss of cortical glutamate receptors in post mortem schizophrenics
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14
Q

Disordered neuronal organisation

A
  • Fewer neurones
  • More disordered
  • Individual cells also look different
  • Probably fewer synaptic connections
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15
Q

Schizophrenia clinical definition?

A

Schizophrenia is the most common psychotic disorder. The symptoms of psychosis
and schizophrenia are usually divided into ‘positive symptoms’ such as
hallucinations and delusions, and ‘negative symptoms’ such as emotional apathy

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16
Q

Schizophrenia treatment:

A
  • Antipsychotic drugs are effective in the treatment of acute schizophrenic episodes; they are more effective at alleviating positive symptoms than negative symptoms
  • Offer ONE oral antipsychotic drug + psychological therapy
  • Start low and slowly titrate up to the minimum effective dose
  • The drug should be given at an optimum dose for 4-6 weeks before it is deemed ineffective
  • Prescribing > one anti-psychotic at a time should be avoided except in exceptional circumstances because of the increased risk of ADRs
  • Long-acting depot injectable antipsychotic drugs can be considered to promote adherence.
17
Q

What are the positive and negative symptoms of schizophrenia?

A

Postive:
* Hallucinations
* Delusions
* Disorganised thinking
* Abnormal motor behaviour

Negative:
* Emotional apathy
* Social withdrawal

18
Q

First-generation Antipsychotic drugs:

A
  • Act predominantly by blocking dopamine D2 receptors in the brain.
  • They are more likely to cause a range of side
    effects

Phenothiazine derivates:
* Chlorpromazine
* fluphenazine
* Levomepromazine
* Pericyazine
* Prochlorperazine
* Trifluoperazine

Butyrophenones
* Benperidol
* haloperidol

Thioxanthenes
* Flupentixol
* zuclopenthixol

Others:
* Pimozide
* Sulpiride

19
Q

Second-generation antipsychotics

A
  • Act on a range of receptors in comparison
    to 1o generation and are generally
    associated with a lower risk of acute
    extrapyramidal symptoms and tardive
    dyskinesia;
  • However, they are associated with other
    adverse effects such as weight gain and
    glucose intolerance
  • Amisulpride
  • Aripiprazole
  • Asenapine
     Cariprazine
     Clozapine
     Lurasidone
     Olanzapine
     Paliperidone
     Quetiapine
     Risperidone
20
Q

Prescribing high-dose antipsychotic drugs:
Define a ‘high-dose antipsychotic’?

A

A high-dose antipsychotic is defined as a total daily dose of a single antipsychotic drug which
exceeds the maximum licensed dose with respect to the age of the patient and the indication being treated, and a total daily dose of two or more antipsychotic drugs which exceeds the maximum licensed dose using the percentage method.

21
Q

Prescribing high-dose antipsychotic drugs
What are the steps?

A

When prescribing an antipsychotic drug for administration in an emergency situation (e.g. for rapid tranquillisation), the aim of treatment is to calm and sedate the patient without inducing sleep.

  • The initial prescription should be written as a single dose, and not repeated until the
    effects of the initial dose has been reviewed.
  • Oral and intramuscular drugs should be prescribed separately.
  • The patient must be monitored for side-effects and vital signs at least every hour
    until there are no further concerns about their physical health status.
  • Monitor the patient every 15 minutes if a high-dose antipsychotic drug has been given.
22
Q

Antipsychotic drugs
Prescribing for the elderly:
What are the considerations?

A
  • The balance of risk and benefit should be considered and discussed with the patient or carers before prescribing antipsychotic drugs for elderly patients.
  • In elderly patients with dementia, the use of antipsychotic drugs are associated with a small increased risk of mortality and an increased risk of stroke or transient ischaemic attack (TIA).
  • Elderly patients are particularly susceptible to postural hypotension

It is recommended that:
* Antipsychotic drugs should NOT be used in elderly patients with dementia, unless they are at risk of harming themselves or others, or experiencing agitation, hallucinations or delusions that are causing them severe distress.
*The lowest effective dose should be used for the shortest period of time.
* Treatment should be reviewed regularly; at least every 6 weeks (earlier for in-patients).

23
Q

Prescribing of antipsychotic drugs in patients with learning disabilities

A

In patients with learning disabilities who are taking antipsychotic drugs and not experiencing psychotic symptoms, the following considerations should be taken into account:
 A reduction in dose or the discontinuation of long-term antipsychotic treatment;
 Review of the patient’s condition after dose reduction or discontinuation of an antipsychotic drug;
 Referral to a psychiatrist experienced in working with patients who have learning disabilities and mental health problems;
 Annual documentation of the reasons for continuing a prescription if the antipsychotic drug is not reduced in dose or discontinued

24
Q

Antipsychotic drugs – Side Effects
Extrapyramidal symptoms
Which drugs cause them?

A

Dose related, most likely to occur with:
* The piperazine phenothiazines
(fluphenazine decanoate and trifluoperazine)
* The butyrophenones (benperidol and haloperidol)
* 1° generation depot preparations
* Less common with some 2° generation antipsychotics e.g. clozapine, olanzapine, quetiapine, and aripiprazole

When parkinsonian symptoms are identified:
* Treatment should be reviewed with the aim of reducing exposure to high-dose and high-potency antipsychotic drugs.
* Antimuscarinics can relieve symptom burden but should NOT be routinely prescribed

25
Q

Antipsychotic drugs – Side Effects
What are the Extrapyramidal symptoms?

A
  • Parkinsonian symptoms (including bradykinesia, tremor)
  • Dystonia (uncontrolled muscle spasm in any part of the body)
  • Akathisia (restlessness) - may be mistaken for psychotic agitation
  • Tardive dyskinesia (abnormal involuntary movements of lips, tongue, face,
    and jaw)- in some patients it can be irreversible
26
Q

Antipsychotic drugs – Side Effects
Hyperprolactinaemia

A

Both 1° and 2° generation, increase prolactin
concentration to some extent because DA
inhibits prolactin release.
 Aripiprazole reduces prolactin
concentration in a dose-dependent
manner because it is a DA-receptor
partial agonist.
 Risperidone, amisulpride, sulpiride,
and 1o generation antipsychotic drugs
are most likely to cause symptomatic
hyperprolactinaemia.

Clinical symptoms
Sexual dysfunction, reduced mineral density, menstrual disturbances , breast enlargement,
galactorrhoea , increased risk of breast cancer

27
Q

Antipsychotic drugs – Side Effects
Sexual dysfunction

A

Reduced DA transmission and hyper-
prolactinaemia decrease libido; antimuscarinic
effects can cause disorders of arousal; and α-
1-adrenoceptor antagonists are associated
with erection and ejaculation problems in men.
 Risperidone, haloperidol, and
olanzapine have a higher prevalence to
cause sexual dysfunction.
 lowest risk of sexual dysfunction are
aripiprazole and quetiapine.

Consider dose reduction or discontinuation

28
Q

Antipsychotic drugs – Side Effects
Cardiovascular side-effects:
Hypotension
Which drugs cause this?

A

These include: tachycardia, arrhythmias,
and hypotension.
* QT-interval prolongation is a particular concern with pimozide.
* Aripiprazole less like to cause CV side effects

Can lead to syncope and dangerous falls
related injuries, especially in the elderly
* Most likely to cause postural hypotension are clozapine and quetiapine
* Slow dose titration is commonly used to minimise postural hypotension

29
Q

Antipsychotic drugs – SE
Hyperglycaemia and Diabetes & Weight gain
Which drugs are less likely to cause diabetes?
Which drugs cause weight gain?

A

Schizophrenia is associated with insulin resistance and diabetes
* 1° generation antipsychotic drugs are less likely to cause diabetes: fluphenazine decanoate and haloperidol have the lowest risk
* Amisulpride and aripiprazole have the lowest risk of diabetes of the 2° generation antipsychotic drugs.

  • Clozapine and olanzapine commonly cause weight gain
30
Q

Antipsychotic drugs – Side Effects

A

Neuroleptic malignant syndrome (NMS)

Antipsychotic drugs – Side Effects
NMS - all antipsychotics:
 Hyperthermia, fluctuating level of
consciousness, muscle rigidity, and
autonomic dysfunction with fever,
tachycardia, labile BP, and sweating
 Discontinuation of the
antipsychotic drug is essential for at
least 5 days or longer

Bromocriptine and dantrolene have
been used for treatment

Monitoring
* Weight
* Fasting blood glucose, HbA1c
* Blood lipid concentrations
* ECG - cardiovascular risk factors
* Blood pressure monitoring
* Full blood count, urea and electrolytes
* Liver function tests

Monitoring should be done at the start of
therapy, then weekly for the first 6
weeks, then at 12 weeks, at 1 year and
then yearly

31
Q

Clozapine - High risk drug
Side effects?

A
  • Second gen
  • Used for treatment resistant schizophrenia apathy and social withdrawal.
  • Clozapine is a dopamine D1, dopamine D2, 5 HT2A, alpha1-adrenoceptor, and muscarinic-receptor antagonist.

Clozapine should be offered if schizophrenia is not controlled despite the sequential use of at least 2 different antipsychotic drugs

MHRA/CHM advice: potentially fatal risk of intestinal obstruction, faecal impaction, and paralytic ileus

MHRA/CHM advice: monitoring blood concentrations for toxicity (blood tests to manage the risk of agranulocytosis), such as when:
* a patient stops smoking or switches to an e-cigarette;
* concomitant medicines may interact to increase blood clozapine levels;
* a patient has pneumonia or other serious infection;
* reduced clozapine metabolism is suspected;
* toxicity is suspected.

32
Q

Clozapine
What are the cautions? (3)

A

Agranulocytosis
* Neutropenia and potentially fatal agranulocytosis reported.
* Leucocyte and differential blood counts must be normal before starting; monitor counts every week for 18 weeks then at least every 2 weeks and if clozapine continued and blood count stable after 1 year at least every 4 weeks (and 4 weeks after discontinuation);
* If leucocyte count below 3000 /mm3 or if absolute neutrophil count below 1500/mm3 discontinue permanently and refer to haematologist

Myocarditis and cardiomyopathy
* Fatal myocarditis (most commonly in first 2 months) and cardiomyopathy reported.
* Perform physical examination and take full medical history before starting

Intestinal obstruction
Impairment of intestinal peristalsis, including constipation, intestinal obstruction, faecal impaction, and paralytic ileus, (including fatal cases) reported.

  • Ensure patient is signed up with Patient monitoring service
33
Q

Quiz
1. Give examples of positive and negative symptoms
2. Define a high dose anti-psychotic
3. Discuss the safety nets that should be in place when a high dose antipsychotic is prescribed
4. What is the drug of choice that is least likely to cause hyperprolactineamia?
5. What is the drug of choice that is least likely to cause sexual dysfunction?
6. What is the drug of choice that is least likely to cause diabetes?
7. What is the drug of choice that is most likely to cause hyperprolactineamia?
8. What is the drug of choice that is most likely to cause hypotension?
9. What is the drug of choice that is most likely to cause weight gain?
10.List the monitoring required for anti-psychotics? And the frequency of these tests?
11.List three main side effects that can be caused by clozapine

A
  1. Agranulocytosis, myocarditis and myopathy, intestinal obstruction

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