1. Actions, uses and side effects
Antipsychotics
Actions, uses and side effects

2. Aims Overview of dopamine physiology Antipsychotic classifications
Movement disorders +neuroleptic malignant syndrome
Stroke and mortality risk
PCF/NICE guidelines delirium + challenging behaviour in dementia
Conclusions
Not going to cover some specifics or doses and side effects etc of each drug

3. Dopamine Physiology
Neurophysiology of dopamine underpins an understanding of the therapeutic uses and side effects of dopamine antagonists
Mesolimbic
mesocortical pathway
Nigrostriatal pathway
tubero-infundibular pathway
(chemoreceptor trigger zone)

4. Mesolimbic + mesocortical pathways
Mesolimbic (midbrain – limbic cortex)
Pleasure, motivation and reward
Increase in dopamine leads to ‘positive’ symptoms of psychosis
Mesocortical (midbrain to prefrontal cortex)
Mood, cognitive function, concentration
Decrease in dopamine leads to ‘negative’ symptoms of psychosis’
‘positive’ symptoms of psychosis(hallucinations, delusions
Decrease in dopamine leads to ‘negative’ symptoms of psychosis’ (apathy, anhedonia, cognitive blunting

5. Thalamic Sensory Gating
Arousal, motivation and attention regulated by a two way loop between mesolimbic/cortical systems and thalamus
Thalamus acts as a filter to allow relevant information through to cerebral cortex
gate formed by GABAergic neurones which are switched off by dopamine to allow salient information through
Dopamine excess leads to excessive throughput resulting in hallucinations and delusions

6. Nigrostriatal Pathway
Nigrostriatal (Substantia nigra – corpus striatum)
as part of the extrapyramidal nervous system, controls movements
degenerates in Parkinson’s disease
Blockade of D2 receptors in this pathway causes the drug-induced movement disorders

7. Tubero-infundibular pathway
Tubero-infundibular pathway (hypothalamus – pituitary)
Dopamine acts on the pituitary as an inhibitor of prolactin secretion
Blockade of D2 receptors by typical antipsychotics and risperidone can cause hyperprolactinaemia
Other atypical antipsychotics do not cause sustained hyperprolactinaemia because of their lower affinity for D2 receptors.
Symptoms of hyperprolactinaemia include amenorrhoea, galactorrhoea, infertility, loss of libido and erectile dysfunction, gynaecomastia. Resulting hypogonadism may cause osteoporosis.

8. Effect of D2 receptor antagonism
Meto and domperidone! Domperidone does not cross blood brain barrier therefore less movement disorders but still works on CTZ (outside blood brain barrier). METO?????
Cholinergic system in wall GI tract – dopamine acts as a break on GI transit so blocking can act as prokinetic

9. Classification of antipsychotics
‘Typical’
Phenothiazines – Levomepromazine, chlorpromazine, prochlorperazine
Butyrophenones – Haloperidol
‘atypical’
Aripripazole, clozapine, olanzapine, quetiapine, risperidone

10. Typical Vs. Atypical Variation within and overlap between classes
ALL D2 antagonists to varying degrees
Variable effects on other receptors:
Muscarinic (dry mouth, constipation etc)
Adrenergic (postural hypotension)
Histamine (drowsiness)
Serotoninergic (weight gain)
16 different receptors!

11. Typical Vs. Atypical
Atypical generally have lower affinity and shorter duration of D2 antagonism
Atypicals generally have greater seretonin receptor antagonism (5HT2) than D2 antagonism
Atypicals have greater seretonin receptor antagonism than typicals

12. 5HT2 Antagonism
Serotonin regulates dopamine release in dopamine pathways apart from mesolimbic
serotonin inhibits the release of dopamine in those pathways
When serotonin receptors are blocked dopamine levels increase.
naturally occurring dopamine then fills D2 receptors preventing blockade by the antipsychotic agent.
Less D2 blockade therefore no worsening of negative symptoms, less movement disorders and less hyperprolactanaemia (apart from risperidone)
Mirtazapine increases dopamine release by 5ht2 antagonism and is one its antidepressant actions
Olanzapine + respiridone ? Improve negative symptoms

13. Antipsychotic Receptor Affinities
* Decreasing levels of movement disorders as you get lower down the list D2
5HT2a
5HT2c
5HT3 H1 α1 α2
AChm
Haloperidol
+++ + ++
Levomeprozine
risperidone
olanzapine
quetiapine

14. Antipsychotic Tolerability
Movement disorders/ extrapyramidal; side effects. Worst haloperidol, best quetiapine.
Acute extrapyrimadal side effects would be avoided in one patient for every 3-6 patients treated with atypical vs. typical
5 times lower risk of longer term extrapyramidal side effects with atypicals vs. haloperidol
Overall discontinuation for undesirable side effects are comparable

15. Movement Disorders Acute Dystonia (spasms)
10% of patients treated with antipsychotics (commoner in young adults)
Starts abruptly within days accompanied by anxiety
Retrocolis, torticolis, trismus, grimacing, tongue dysfunction, oculogyric crisis, abnormal positioning limbs or trunk
Diazepam 5mg IV (benzo) or Procyclidine 5-10mg IV/IM (repeat after 30 min if needed)
Continue oral antimuscarinic for 1 week (procyclidine or orophenadrine)

16. Movement Disorders Acute Akathisia (motor restlessness)
20% when using typical antipsychotics
Within days and resolves within week of stopping
Restless, pacing, rocking from foot to foot, fidgety movements, inability to sit or stand for a few minutes
Propranolol 10mg tds +/- benzodiazepine

17. Movement Disorders Parkinsonism 30-60% on long term antipsychotics
Any point other than first week but more usually weeks to months
Coarse resting tremor, muscular rigidity, shuffling gait, sialorrhoea, bradkinesia (face)
procyclidine 2.5mg-5mg tds
Metoclopramide and all antipsychotics typical>atypical
Lowest dose for shortest period time
Dementia. Elderly, pre-existing extrapyramidal signs, genetics play factor
Meto and antidep

18. Movement Disorders Tardive Dyskinesia
20% when using typical antipsychotics long term (> 3 months or > 1month in elderly)
Involuntary stereotyped chewing movements tongue and orofascial muscles reduced by sleep, torticollis, lordosis, akathesia (25%)
Early sign inability to hold tongue out for more than a few seconds and worm like movements
Resolution 30% 3 months, further 40% 5 years, sometimes irreversible especially elderly
Specialist advice on treatments (tetrabenazine, levodopa, clonidine, baclofen, diazepam,valproate, pyridoxine)
Tetrabenazine depletes presynaptic dopamine stores and blocks post synaptic dopamine receptors

19. Neuroleptic Malignant Syndrome
Caused by acute dopamine depletion
Usually within two weeks of starting or dose increase of antipsychotic
Occurs less than 1% of patients on antipsychotics
Death occurs in 20% and bromocriptine halves mortality
Self limiting and resolves in 1-2 weeks if causal drug stopped
Subsequent antipsychotic use has a 30-50% chance of causing a reoccurance
Similar syndrome if parkinsons and stop levodopa or bromocriptine (dopamine agonsists)

20. Neuroleptic Malignant Syndrome
Bradykinesia – immobilisation – akinsesia – stupor accompanied by lead pipe rigidity, fever and autonomic instability
Essential features – severe muscle rigidity, pyrexia +/- sweating
Additional – muteness/stupor, tachycardia, labile BP
Management – stop causal drug, benzo +/- bromocriptine, may need IVI
If acidosis, hypoxia, renal failure may need acute management/ICU

21. Other considerations Stroke/All cause mortality risk
In dementia - Risk of stroke with olanzapine and risperidone 2-3 times higher than placebo + doubling of all cause mortality with olanzapine (meta-analysis)
Increase risk in all elderly patients for both typicals and atypicals, greatest in those with dementia and within first month of starting treatment and with higher doses (metanalysis). (? Worse with typical)
Relative risk with individual drugs has yet to be determined
Risperidone 1200 patients, 4 trials, 764/29 cerebrovascular events/4 deaths vs 466/7/1 = 4%vs 2 % (5-6 deaths vs 2-3) (40 vs 20) NNH =25 (1-3months)
Olanzapine 1600 patients, 5 trials, 1178/15 (1.3%) vs 478/2 (0.4%) = (4 vs 13 out of 1000) absolute increased risk was 0.9 % RR 3 (CI )
Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration, contrasts of atypical antipsychotic drugs with placebo met criteria patients drug and 1757 placebo. Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%]
retrospective cohort study involving 22,890 0ver 65
Conventional antipsychotic medications were associated with a significantly higher adjusted
risk of death than were atypical antipsychotic medications at all intervals studied
(≤180 days: relative risk, 1.37; <40 days:relative risk, 1.56; 40 to 79 days: relative risk,
1.37; 80 to 180 days: relative risk, 1.27;
The greatest increases in risk occurred soon after therapy was initiated and with higher dosages of conventional antipsychotic medications.

22. Other considerations Parkinsons
Try and avoid antipsychotics but if needed use queitiapine (could try trazadone or benzo)
Epilepsy
All antipsychotics cause dose dependent reduction in seizure threshold. Lowest risk with Haloperidol

23. NICE Guidelines Delirium
Find and treat reversible causes
Use environmental factors to help keep patient from distress
If a person with delirium is distressed or considered a risk to themselves or others and verbal and non-verbal de-escalation techniques are ineffective or inappropriate, consider giving short-term (usually for 1 week or less) haloperidol or olanzapine.
Start at the lowest clinically appropriate dose and titrate cautiously according to symptoms.
antipsychotic drugs such as haloperidol and olanzapine should be used with caution or not at all for people with conditions such as Parkinson‟s disease and/or Lewy-body dementia.

24. PCF4 – Delirium
Delirium is distressing and associated with higher mortality, reduced performance status and increased admissions to nursing homes
Antipsychotics should be considered in ALL forms of delirium alongside environmental measures (including hypoactive)
Reduce distressing symptoms, shortened the duration of delirium and improved outcomes in ALL forms delirium (RCTs)
When antipsychotics alone insufficient or sedation needed for hyperactive/frightened patients benzos or trazadone can be added.
175 patients, olanzapine (74) haloperidol (72) and a control group (29).They were prospectively observed and treated for a week, CGI SI scores of olanzapine, haloperidol and control group were reduced significantly 82.4%,87.5% and 31% respectively. The effective rate of treatment groups and control group had significant difference ( P 0.01) olanzapine was the earliest on response time,haloperidol was the second,and the control was the last The incidence rates of dry mouth and extrapyramidal symptoms in haloperidol group were higher than that in olanzapine,which had significant difference( P 0.01).Conclusion Olanzapine and haloperidol had similar effects on senile delirium.However,olanzapine effected more rapidly and had fewer side effects
A total of 42 patients were randomized to quetiapine or a placebo group. The primary outcome measure was the Delirium Rating Scale Revised 98. The quetiapine group improved more rapidly than the placebo group. Specifically, the quetiapine group recovered 82.7% faster (S.E. 37.1%, P=.026) than the placebo group in terms of DRS-R-98 severity score: Quetiapine has the potential to more quickly reduce the severity of noncognitive aspects of delirium. This study was underpowered for treatment comparisons at specific points in time but nonetheless detected significant differences when analyzing the whole study period. While it is not possible to draw definitive conclusions, further larger studies exploring the use of quetiapine in other delirium populations seem justified. Larger increments in the dose of quetiapine may yield even stronger results.
36 adult intensive care unit patients with delirium. Patients were randomized to receive quetiapine 50 mg every 12 hrs or placebo. Quetiapine was increased every 24 hrs (50 to 100 to 150 to 200 mg every 12 hrs) if more than one dose of haloperidol was given in the previous 24 hrs.
Quetiapine was associated with a shorter time to first resolution of delirium 1.0 vs. 4.5 days a reduced duration of delirium [36 vs.120 hrs), and less agitation 6 vs. 36 hrs. Whereas mortality (11% quetiapine vs. 17%) and intensive care unit length of stay (16 quetiapine vs. 16 days) were similar, subjects treated with quetiapine were more likely to be discharged home or to rehabilitation (89% quetiapine vs. 56%). Subjects treated with quetiapine required fewer days of as-needed haloperidol 3 vs.4

25. Nice Guidelines Dementia
Do not use for mild-to-moderate symptoms
Consider for severe symptoms (psychosis and/or agitated behaviour causing significant distress) only if:
risks and benefits have been fully discussed
changes in cognition are regularly assessed and recorded
target symptoms identified and changes regularly assessed and recorded
comorbid conditions, such as depression, have been considered
drug is chosen after an individual risk–benefit analysis
start low and titrated upward
treatment is time limited and regularly reviewed

26. PCF4 – Agitation in Dementia
Treat causes (inc infection/pain)
Environmental factors first
Drugs as a last resort, evidence of benefit modest at best and risks are significant
If drugs needed lowest dose for shortest period
Haloperidol, olanzapine, queitapine, risperidone

27. Individual Drug Properties
bio-availability
Onset
Time to peak plasma concentration
Half life (Hr)
Duration
(Hr)
Haloperidol
45-75%
1hr (PO)
10-15 (SC)
2-6hr (PO)
10-20min (SC)
13-35
24+
Levomepromazine
20-40%
30min
1-3hr (PO)
30-90min (SC)
15-30
12-24
risperidone
99% *
1-2hr (PO) 24
12-48
olanzapine
60%
5-8hr (PO)
34-52
quetiapine
100%
1.5hr (PO)
7-14
12h
*hours to days in delirium, days to weeks in psychosis
N.B all metabolised by various CP450 enzymes (liver)
Reduce doses in elderly, renal and liver impairment (generally half of usual dose)

28. Interesting facts! Haloperidol
Bioavailability 45-75% orally and 60-70% SC
? Should reduce dose by injection
Liquid is odourless, colourless and tasteless
Prolongs QT interval
Plasma concentration halved by carbamazepine
Evidence for N+V in post op and gastroenterology not palliative care

29. Interesting facts! Levomepromazine Licensed for pain! Olanzapine
Evidence in phase 1 and phase 2 trial of efficacy for vomiting with moderately and highly emetogenic chemotherapy
Adversely affects diabetic control
Drowsiness and wt. gain most common side effects
Smoking can decrease plasma levels (as can omeprazole, carbamazepine, rifampicin)

30. Conclusions
Be aware of side effects and risks but keep them in perspective and review need to continue drugs regularly(be cautious but not to cautious)
Look out for movement disorders and don’t miss NMS!
Be aware of different profiles of typicals vs atypicals
Use antipsychotics in agitated delirium, jury still out about hypoactive delirium (? Use atypicals)
Be cautious in dementia but not to cautious and if using anything use low doses and review regularly