Lecture 2-3 Antipsychotics - Pete

Front 1

Describe the dopamine hypothesis of schizophrenia.

Back 1

Overactivity of one of the three dopamine transmitter systems in brain – antipsychotics work by inhibiting dopamine neurotransmission – over simplistic.

Front 2

Describe recent modifications to the dopamine hypothesis of schizophrenia.

Back 2

Positive symptoms are due to increased activity in the mesolimbic dopamine pathway.
Negative symptoms are due to decreased activity in the mesocortical pathyway.

Front 3

Describe the negative symptoms that support the dopamine hypothesis of schizophrenia (3).

Back 3

Patients with schizophrenia show impairments consistent with impairment in reward system function;

1. anhedonia

2. decreased motivation

3. failure to use feedback to enhance goal directed behaviour

Front 4

Describe the hypothesised role of glutamate in schizophrenia.

Back 4

Glutamate may be involved in both negative and positive symptoms and cognitive impairments.

Front 5

In schizophrenia, changes in which neurotransmitters are consdered important in cognitive changes seen?

Back 5

Cholinergic and GABA-ergic changes are considered important in the cognitive changes.

Front 6

What are the five key dopamine pathways in the brain?

Exam tip - must know these!

Back 6

Mesolimbic Dopamine Pathway
Mesocortical Dopamine Pathway
Nigrostriatal Dopamine Pathway
Tuberohypophyseal Dopamine Pathway
Thalamic Dopamine Pathway

Front 7

Mesolimbic Dopamine Pathway:
- Where does it arise from and project to?

- Dopamine levels in untreated schizophrenia?
- What is its main role?
- What does hyperactivity cause?
- What does hypoactivity cause?

Back 7

VTA - nucleus accumbens

High

Positive symptoms, reward, pleasure (? agg)
Deficient functioning - lack of motivation, interest, anhedonia and lack of pleasure.

Front 8

What are the accepted criteria that a biomarker must fulfil to be called an endophenotype?

Back 8

- Associated with illness in the population
- Heritable
- Primarily state-independent (manifests in an individual whether or not illness is active)
- Within families, endophenotype and illness co-segregate
- The endophenotype found in affected family members is found in nonaffected family members at a higher rate than in the general population

Front 9

Define pathonomic. How is it relevant to schizophrenia?

Back 9

Pathonomic = occurs in one disease only
*There is nothing pathonomic in schizophrenia – i.e. nothing in schizophrenia that occurs only in schizophrenia

Front 10

Describe three key negative symptoms that can be identified solely on observation.

Back 10

1. Reduced speech – restricted speech quantity, uses few words and nonverbal responses; impoverished content of speech – words convey little meaning.
2. Poor grooming / hygiene, clothes dirty or stained, has odor.
3. Limited eye contact

Front 11

Describe three key negative symptoms that can be identified with some questioning.

Exam tip:know how to differentiate the different positive and negative symptom pathways.

Back 11

1. Reduced emotional responsiveness
2. Reduced interest
3. Reduced social drive

Front 12

Anti-psychotic drugs: 1st Generation: Typical Antipsychotics:
Which receptor are they antagonists for?
What affects tx outcome of a typical anti-psychotic?
What type of symptoms do they target?
What are typical side effects?

Back 12

All anti-psychotics are dopamine D2 receptor antagonists

The affinity of a typical anti-psychotic for the D2 receptor is positively associated with tx outcome (higher affinity – better outcome)

Only effective at treating positive symptoms

Side effects – Parkinson-like syndromes (because blocking dopamine in basal ganglia too)
Tardive dyskinesia – abnormal facial and limb movements due to sensitisation of D2 receptors

Front 13

When anti-psychotic drugs/neuroleptics are used to treat acute schizophrenia...
What % of patients go into remission without meds?
What % go into remission with meds?
What symptoms are meds most effective in treating?
What conclusion can be drawn about the effectiveness of anti-psychotic medication?

Back 13

25% patients go into remission without medication
80%+ go into remission with medication
Medications most effective in treating positive symptoms
Much more effective than placebo

Front 14

When using anti-psychotic drugs / neuroleptics for maintenance tx of schizophrenia, what is the annual relapse rate:
1. On treatment?
2. Off treatment?

Back 14

Annual relapse rates

On tx = 10-20%

Off tx = 60%+

Front 15

How long should anti-psychotics be taken in treatment of first episode of psychosis?

Back 15

Length of tx for first episode – 9 months

Front 16

How long should anti-psychotics be taken for after 2+ episodes of psychosis?

Back 16

Continue tx to prevent further relapse for minimum of 5 years without further episodes (unless episodes brief, minimal functional impact and interspersed with lengthy periods when the person is well).

Front 17

Apart from maintenance tx of schizophrenia, what else can anti-psychotic drugs/neuroleptics be indicated for?

Back 17

1. Other acute psychoses – e.g. mania, psychotic depression (esp with delusions and/or agitation), puerperal psychosis

2. Behavioural disturbance – e.g. dementia (but caution necessary)

Front 18

Why do anti-psychotic medications have side effects that are additional to those associated with lowered dopamine?

Back 18

Most anti-psychotics also affect other neurotransmitter systems – e.g. histamine, acetylcholine, adrenaline and serotonin
Explains additional side effects
E.g. anticholinergic effect – memory deficits

Front 19

Why were atypical antipsychotics developed?

Back 19

Atypical antipsychotics have been developed because of their more selective action on the dopamine system and/or action on other neurotransmitter systems (most notably serotonin)

Front 20

What are three main types of side-effects caused by anti-psychotic medication?

Back 20

1. Dopaminergic effects on the striatum (EPSE)
oDystonia (held postures)/oculogyric crisis (eyes rolling back)
oParkinsonism
oAkathesia (motor restlessness)
oTardive dyskinesia and BLMs (buccolinguomasticatory symptoms)
2. Anti-cholinergic
oDry mouth
oBlurred vision
oConstipation
oDifficulty in passing urine
3. Anti-adrenergic
oDrop in blood pressure on standing
oSedation
oFailure of ejaculation (esp Thioridazine)
oSkin rashes (e.g. photosensitivity)
oWeight gain

Front 21

Apart from dopamine, what else do new gen antipsychotics affect?

Back 21

New generation (atypical) antipsychotics affect serotonin as well (SDAs)

Front 22

What can help with negative symptoms?

Back 22

Glutamate antagonists can help with negative symptoms

Front 23

Why does schizophrenia consist of a wide range of symptoms?

Back 23

Schizophrenia likely effects a host of symptoms perhaps by disturbing a fundamental balance among neurotransmitters

Front 24

What are the three “generations” of drugs which are used to treat schizophrenia and related psychotic disorders (anti-psychotics)

Back 24

1st gen: neuroleptics or typical antipsychotics
2nd gen: atypical anti-psychotics (SDAs = serotonin dopamine agonist)
3rd gen: Aripiprazole (Abilify)

Front 25

How do each of the generations of anti-psychotics differ (3)?

Back 25

1. Different neurotransmitter systems
2. Different effects on symptoms
3. Different side-effects

Front 26

Which receptors do atypical anti-psychotics affect?

Back 26

Atypical anti-psychotics are both D2 receptor and serotonin 2A (5HT2A) antagonisis

Front 27

Is the affinity of an atypical anti-psychotic greater for 5-HT2A or D2 receptors?

Back 27

The affinity of an atypical anti-psychotic is greater for 5-HT2A receptors than for D2 receptors

Influences more symptom slower affinity for D2

Front 28

What are the advantages of atypical antipsychotics over typical anti-psychotics?

Back 28

Less risk of Parkinsoniam and tardive dyskinesia
Effective at treating both positive and negative symptoms

Front 29

What is one negative of atypical anti-psychotics and one common side effect?

Back 29

They don't have any effect on cognitive dysfunction
Side effects – weight gain (Type II diabetes) - through influence on hypothalamus

Front 30

What was the first atypical anti-psychotic to become commonly used?

Back 30

Clozapine

(no new movement disorders from clozapine onwards)

Front 31

What is the potential risk arising from clozapine use, and what must be done about it?

Back 31

Causes agranular cytosis – need blood monitoring (of white blood cell count)

Front 32

If tx failure with any anti-psychotic, what is the second tx of choice?

Back 32

Clozapine

Front 33

Atypical anti-psychotics: what are the results of clinical trials?

Back 33

Cloazpine less likely to cause EPSE such as parkinsonism and akathesia

Dystonia and TD are rare

No reports of new cases of TD arising in patients receiving clozapine

Sig imp in both positive and negative symptoms in 30% of people with ‘treatment-resistent schizophrenia’ at 6 weeks

Sig imp in up to 60% at 6 months

Better outcomes in terms of people obtaining training or work

Have not had great effects on cognitive symptoms – seem to be tx resistant (is the onset of schizophrenia in fact a dementia??)

Front 34

In an emergency situation of acute psychosis, what medications would be used?

Back 34

In an emergency situation of psychosis, would commence D2 antagonist (which will take 2-4 weeks before effect) and also immediately benzodiazepine (fast acting, causes significant sedation, makes patient more comfortable until hall/del settles down)

Front 35

What is a partial agonist?

Back 35

Partial agonists – have affinity for a receptor but only partial efficacy (partially activate the receptor; modulator)

Front 36

What is the third generation anti-psychotic?

Back 36

Aripiprazole (abilify) is considered an atypical anti-psychotic, but is a partial agonist at D2 receptors

Partial agonists: have affinity for a receptor but only partial efficacy
oWhen dopamine is low, it acts like an agonist
oWhen dopamine is high, it is sitting there only partially activating the receptor, so acting more like an antagonist
- Effective at treating both positive and negative symptoms
-Still not very effective at treating cog dysfunction
-Side effects – no typical side-effects or weight gain
-Considered a ‘golden bullet’
-Been around since mid 2000s

Front 37

What are SDAs? Give the two types and examples.

Back 37

SDAs = Serotonin 2A/D2 antagonists
‘pines’ – clozapine, olanzapine, quetiapine, low dose loxapine.
'dones’ – respiridone, ziprasidone, paliperidone.

Front 38

What are DPAs? Give the two types and examples.

Back 38

DPA = D2 receptor partial agonists
‘oles’ – aripiprazole
‘ides’ – sulpride, amisulpiride

Front 39

What are the 5 stages of treatment for positive symptoms?

(E, 1, 2, 3, N)

Back 39

Stages of treatment for positive symptoms:
Emergency – SDA, BZ, D2
First line tx – SDA, DPA
Noncompliant – depot (SDA or D2)
Second line tx – D2, clozapine
Third line tx – Polypharmacy, combos

Front 40

What are the three stages of treatment for aggressive symptoms?

(E, 1, 2)

Back 40

Stages of treatment for aggressive symptoms:
Emergency - SDA, BZ, D2
First line tx – SDA, DPA
Second line tx – D2, clozapine, BZ, mood stabiliser

Front 41

What are the 2 stages of treatment for negative symptoms?

Back 41

Stages of treatment for negative symptoms:
1st line tx: SDA, DPA
2nd line tx: ADM, NRI, modafinil, amisulpride, clozapine.

Front 42

What are the 2 stages of tx for cognitive symptoms?

Back 42

Stages of treatment for cognitive symptoms:
1st line tx: SDA, DPA
2nd line tx: alpha 2 agonist, 5HT1A, NRI, modafinil, AChEl, ACh decreasing med.

Front 43

What are the main adverse effects of clozapine (7)? no need to know this?

Back 43

1. Agranulocytosis
2. Sedation
3. Seizures
4. Salivation
5. Weight gain
6. Hyperlipidemias
7. Diabetes mellitus

Front 44

What is the effectiveness of clozapine in treating positive symptoms?
What is it a major risk factor for?

Back 44

The only 2nd gen antipsychotic effective for refractory positive symptoms – clinical improvement in 30-60%.
Major risk factor for metabolic abnormalities

Front 45

What are the main adverse effects of Risperidone (3)?

Back 45

1. Insomnia, agitation
2. EPS at higher doses
3. Prolactin elevation

Front 46

What are two advantages of risperidone?

Back 46

1. Enhanced relapse prevention
2. Available in long-acting intramuscular preparation (depo)

Front 47

What are the main adverse effects of olanzepine (6)?

Back 47

1. Headache
2. Sedation
3. Weight gain
4. Hyperlipidemias
5. Diabetes mellitus
6. Major risk factor for metabolic abnormalities

Front 48

What are two advantages of olanzepine (SDA)?

Back 48

Few EPS

Front 49

What are the main adverse effects of quetiapine (5)?

Back 49

1. Sedation
2. Postural hypotension
3. Dizziness
4. Constipation
5. Moderate risk factor for metabolic abnormalities

Front 50

What is an advantage of quetiapine (SDA)?

Back 50

Few or no EPS

Front 51

What are the main adverse effects of Amisulpride (DPA)?

Back 51

Prolactin elevation
EPS at higher doses

Front 52

Which receptor sites is the action of Amisulpride (DPA) specific to?

Back 52

D2 and D3 specific

Front 53

What are the main adverse effects of Ziprasidone (SDA) (2)?

Back 53

1. Insomnia
2. EPS at higher dose

Front 54

What are two advantages of ziprasidone?

Back 54

1. Weight neutral
2. Low risk factor for metabolic abnormalities

Front 55

What is 1 adverse effect of Aripiprazole?

Back 55

Mild dose-related EPS

Front 56

What are advantages of aripiprazole?

Back 56

1. Partial D2 agonist
2. Long half-life
3. Low risk factor for metabolic abnormalities

Front 57

Which SDA is weight neutral?

Back 57

ziprasidone

Front 58

Which atypical antipsychotic can cause agranulocytosis?

Back 58

Clozapine

Front 59

Which atypical antipsychotics cause few or no EPS (3)?

Back 59

Olanzepine and Quetiapine - few or no EPS

Aripiprazole - mild dose-related EPS

Front 60

Which atypical antipsychotic has a cholinergic action, causing anticholinergic SEs?

Back 60

Quetiapine

- sedation

- postural hypotension

- dizziness

- constipation

Front 61

Which atypical antipsychotic can cause insomnia?

Back 61

Risperidone, Ziprasidone