Psychosis and schizophrenia

Question 1

what is psychosis?
what are the symptoms?

Answer 1

set of symptoms of disorders like schizophrenia :
It Includes:
Delusions
Hallucinations
Disorganized speech
Disorganized behaviour
Gross distortion of reality

can be related to depression, Alzheimers disease, mania and congnitive disorders

Question 2

genetics and schizophrenia?

Answer 2

Genetics
Schizophrenia tends to run in families, but nosingle gene is thought to be responsible.
It’s more likelythat different combinations of genes make people more vulnerable to the condition. However, having these genes does not necessarily mean you’ll develop schizophrenia.
Evidence that the disorder is partly inherited comes from studies of twins. Identical twins share the same genes.
Inidentical twins, if a twin develops schizophrenia, the other twin has a 1 in 2 chance of developing it, too. This is true even if they’re raised separately.
In non-identical twins, who have different genetic make-ups, when a twin develops schizophrenia, the other only has a 1 in 8 chance of developing the condition.
While this is higher than in the general population, where the chance is about 1 in 100, it suggests genes are not the only factor influencing the development of schizophrenia.

Question 3

Schizophrenia:neuropathology

Answer 3

1978 – modern imaging techniques (PET, fMRI, EEG, ECoG)
- Enlarged ventricles

Post mortem – reduced temporal lobe volume

Cerebral blood flow – reduced frontal function

Not progressive

Question 4

what is the symptoms of Schizophrenia

Answer 4

Symptoms can be divided in positive and negative types:
Positive: disinhibited behaviours/thoughts
Negative: inhibited/withdrawn behaviours/thoughts.

Some can be either positive or negative or have aspects of both.

Diagnosis and classification of symptoms is solely psychiatric
There are no objective biochemical, metabolic or clinical signs.

Symptom types:
Thought disorder (+/-)
Abnormal beliefs/delusions (+)
Abnormal experiences (+)
Mood disorder (+/-)
Motor alterations (+/-)
Changes in social function (-)

Question 5

Schizophrenia: aetiology

Answer 5

Inherited genetic factors
Increased risk in families if one family member affected
In twins: Dizygotic(fraternal) 17%; Monozygotic (identical) 48%
Identification of susceptibility genes e.g. Neuregulin 1

Environmental factors
Birth complications, viral infection, inner cities, immigration, drug misuse

Neurodevelopmental model:
Early environmental insult and/or genetic factors lead to changes in brain development with later environmental factors contributing to risk

Question 6

what are positive symptoms

Answer 6

delution
hallucination
disorganised speech
disorganised behavoir
catonic behaviour
agitation

Question 7

what are the Changes of symptoms with time

Answer 7

Acute psychotic episode typically alerts HCPs and allows patient to enter healthcare system for treatment.

Symptoms tend to be initially mild but negative before showing increased positive dominance that steadily trails off into largely negative symptoms in the chronic phase.

Question 8

what are the outcomes

Answer 8

~25% of patients will suffer a single episode, recover and lead a normal life.

Prognostic signs for isolated episodes include:
No family history
Stable premorbid personality
Acute onset
Emotional responses preserved
Early diagnosis and treatment

Prognostic signs for persistent (chronic) schizophrenia include:
Family history
Disturbed premorbid personality
Difficulty forming relationships early in life
Poor social adjustment/disrupted domestic life
Insidious onset
Loss of initiative and drive
Delayed diagnosis and treatment

Question 9

what are the treatment options

Answer 9

Control acute attacks (prevent harm to self and others)

Resolve contributory social and domestic factors

Rehabilitate the patient
attacks of psychosis have consequential effects on mood, emotion etc.

Begin long-term maintenance therapy if necessary.

Question 10

what is Aetiology:
glutamate HYPOTHESIS

Answer 10

Novel hypothesis

First novel psychopharmacological agents are based on this hypothesis

Question 11

Effects of ketamine and phencyclidine (PCP) on the nmda receptor

Answer 11

Blockade of NMDA-R may prevent Glu-mediated excitation
NMDA-R hypofunction has been hypothesized as a mechanism for schizophrenia pathogenesis

Question 12

Aetiology: serotonin hypothesis

Answer 12

Increased cortical serotoninergic tone, can lead to reduced dopamine secretion, downstream

Question 13

what are negative symptoms

Answer 13

On observation:
-reduced speech
-poor grooming
-limited eye contact

on questioning
-reduced emotional responseness
-reduced interest
-reduced social drive

Question 14

Schizophrenia: D2 antAgonists

Answer 14

Psychotherapy does not help in early stages since patients lack insight.

Antipsychotic (neuroleptic) drugs
e.g. haloperidol, chlorpromazine (1st Generation)

Generally only treat positive symptoms
Onset slow
~ 30 % of patients do not respond
Depot formulation for secondary care – concordance/compliance

Question 15

Treating Schizophrenia: dopamine hypothesis AND conventional antipsychotics

Answer 15

Reducing mesolimbic dopamine hyperactivity reduces positive symptoms

But leads to exacerbated negative symptoms because it also reduces mesocortical dopaminergic tone

Question 16

Extrapyramidal symptoms

Answer 16

Most common category of side-effect associated with anti-psychotic use.
Manifest as movement disorders

acute dystonia: neck/spine spasm, neck/jaw/larynx rigidity, oculogyric crisis

psuedo-parkinsonism: dyskinesia and dystonia, rigidity, tremor, bradykinesia

akathisia: psychomotor restlessness and agitation, inability to sit still

tardive dyskinesia: abnormal face, mouth, jaw movement

Question 17

Treating Schizophrenia: serotonin hypothesis AND atypical antipsychotics

Answer 17

Reducing mesolimbic dopamine hyperactivity reduces positive symptoms

The 5HT2A antagonism leads to increased DA tone in Nigro-striatal pathways, reducing EPS side-effects

Question 18

what does Blocking 5HT2a in schizophrenia cause

Answer 18

Blocking Serotonin receptors in the cortex, leads to increased dopamine secretion downstream also reducing EPS and prolactinaemia

Question 19

Binding properties of atypicalantipsychotic

Answer 19

(A) Clozapine, olanzapine, and asenapine all bind relatively weakly to the 5HT1B receptor, while quetiapine and asenapine bind to the 5HT1D receptor.
(B) Risperidone, paliperidone, ziprasidone, and iloperidone all have some affinity for the 5HT1B and 5HT1D receptors. In particular, ziprasidone binds more potently to the 5HT1B receptor than to the D2 receptor. Lurasidone does not
bind to 5HT1B/D.
(C) Aripiprazole and brexpiprazole each bind weakly to the 5HT1B receptor; aripiprazole also binds to the 5HT1D receptor; cariprazine does not bind to 5HT1B/D.

better therapeutic profile

Question 20

Atypical antipsychotic side effects

Answer 20

People with schizophrenia smoke more.

D2 Antagonists lead to weight gain, diabetes, increased smoking (lowered dopamine neurotransmission in NAc) etc.

People with schizophrenia develop metabolic syndrome, especially with atypical new medication (Serotonin antagonism). In the old times people treated with haloperidol were skinny and stiff (parkinsonism).

Try reducing smoking, diet.

Question 21

Treating Schizophrenia: D2 antagonists/partial agonistsatypical antipsychotics

Answer 21

Reducing mesolimbic dopamine hyperactivity reduces positive symptoms: es Aripiprazol

The partial agonism towards D2 in the mesocortical pathway, also reduces the negative symptoms

Question 22

what are Schizophrenia drugs

Answer 22

Anti-psychotics
Typical (1st generation)
Atypical (2nd generation)

Typical
Developed in the 1950s and classified by chemical structure chlorpromazine
Butyrophenones, phenothiazines or thioxanthenes (see BNF)

Atypical
Selective (e.g. D2) dopamine antagonists
Some with 5HT antagonist effects (subtype specific - 5HT2A, C and 5HT1A)
Dopamine partial agonists

Treatment tailored to individual patient’s response and tolerance

Summary table of drug classes, target symptoms and side effects etc. provided as revision slide at end of lecture.

Question 23

Schizophrenia: treatment side-effects

Answer 23

Side effects related to dopamine blockade:
Motor (extrapyramidal side effects (EPS))
Acute dystonia (involuntary motor movement)
Akathisia (innner perception of an inability to ‘sit still’)
Parkinsonian
Tardive dyskinesia (writhing movements of tongue and facial muscles)

Hyperprolactinaemia (high blood prolactin levels)
>580 mIU/L women; >450 mIU/L men

Neuroleptic malignant syndrome
Skeletal muscle spasticity
Dysfunctional hypothalamic thermal regulation

Side effects typically related to side-effects arising from drug interactions with other (non-dopaminergic) systems

Anti-cholinergic
Anti-histaminic
Anti-adrenergic
Weight gain
Diabetic symptoms in African-Carribean populations

Question 24

How to manage side effects

Answer 24

Your role as pharmacist is to understand the pharmacology, predict and address side effects.

Example quetiapine, take it at night because it makes you sleepy + postural hypotension.

Question 25

Treatment strategy

Answer 25

Treatments maintained for 12-24 months after acute attack

~75% of patients will relapse

Poor side effect profiles mean sustained treatment has disadvantages (see also revision table at end of slides for more info)

No single best method to deal with relapse:
maintain treatment
or aggressively treat each acute attack?

Question 26

cannabis psychosis

Answer 26

Psychosis is a symptom in schizophrenia but schizophrenia is not psychosis

Acute use (‘one joint’) may be enough to induce a short-term psychotic episode (linked to high THC containing cannabis).
anxiety, depression, paranoid ideas, illusions, hallucinations, delusional beliefs (c.f. ‘wanted’ and ‘unwanted’ effects).

This may be ameliorated by CBD and is NOT the same as cannabis being linked to disorders such as schizophrenia which is where most media confusion lies.

Question 27

Cannabis and schizophrenia

Answer 27

In the same way as cannabis psychosis has been confused/misrepresented, links between cannabis use and schizophrenia are not clear cut.

Facts:
Cannabis use and psychosis are associated in general and clinical populations.
However, studies are not consistent with cannabis increasing the incidence of schizophrenia.
Cannabis may precipitate psychosis in vulnerable individuals or exacerbate symptoms.
Psychotics are more likely to become regular users.

Question 28

check revision slides - week 21 slide 65 +62 - drug classes