W21 Schizophrenia (RT and AG)

Question 1

What is the definition of schizophrenia?

Answer 1

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.

Question 2

Schizophrenia - Epidemiology

Answer 2

• 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

Question 3

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

Answer 3

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)

Question 4

Interactions leading to structural and functional deficit

Answer 4

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

Question 5

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

Answer 5

• Enlarged ventricles
• Loss of neuronal tissue (thinner cortex)

Question 6

Altered function- biomarkers in EEG

Answer 6

• 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

Question 7

What are the Dopamine pathways in the CNS?

Answer 7

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

Question 8

Excess dopamine and schizophrenia

Answer 8

• 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

Question 9

Treating schizophrenia - Typical (first generation) antipsychotics

Answer 9

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

Question 10

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

Answer 10

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)

Question 11

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

Answer 11

• 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

Question 12

Role for 5HT

Answer 12

• 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

Question 13

Role of glutamate

Answer 13

• 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

Question 14

Disordered neuronal organisation

Answer 14

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

Question 15

Schizophrenia clinical definition?

Answer 15

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

Question 16

Schizophrenia treatment:

Answer 16

• 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.

Question 17

What are the positive and negative symptoms of schizophrenia?

Answer 17

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

Negative:
* Emotional apathy
* Social withdrawal

Question 18

First-generation Antipsychotic drugs:

Answer 18

• 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

Question 19

Second-generation antipsychotics

Answer 19

• 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

Question 20

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

Answer 20

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.

Question 21

Prescribing high-dose antipsychotic drugs
What are the steps?

Answer 21

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.

Question 22

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

Answer 22

• 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).

Question 23

Prescribing of antipsychotic drugs in patients with learning disabilities

Answer 23

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

Question 24

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

Answer 24

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

Question 25

Antipsychotic drugs – Side Effects What are the Extrapyramidal symptoms?

Answer 25

* 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

Question 26

Antipsychotic drugs – Side Effects Hyperprolactinaemia

Answer 26

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

Question 27

Antipsychotic drugs – Side Effects Sexual dysfunction

Answer 27

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

Question 28

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

Answer 28

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

Question 29

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

Answer 29

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

Question 30

Antipsychotic drugs – Side Effects

Answer 30

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

Question 31

Clozapine - High risk drug Side effects?

Answer 31

* 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.

Question 32

Clozapine What are the cautions? (3)

Answer 32

**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

Question 33

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

Answer 33

11. Agranulocytosis, myocarditis and myopathy, intestinal obstruction