1. Antipsychotic medication
Dr C Kotzé

2. Introduction Introduced in 1950’s Decreases relapse significantly
Only treats the Sx
Not a cure
2 Major classes:
Dopamine receptor antagonists (typical)
Serotonin-dopamine antagonists (atypical)

3. Dopamine hypothesis D2 receptor block improves positive Sx
Mesolimbic & mesocortical tracts
Other transmitters : 5HT, NE, GABA, glutamate

4. Four key Dopamine Pathways

5. Mesolimbic pathway
Hyperactivity of DA → hallucinations, delusions and thought disorders
Role in aggressive Sx
Drugs that ↑ DA → psychotic Sx
Antipsychotics ↓ DA (blocks receptors)
DA cell bodies in the ventral tegmental area of the brainstem.
Axons to limbic areas of brain.

7. Mesocortical pathway Related to mesolimbic pathway
Projects to different brain areas
DA deficit postulated to have role in negative & cognitive Sx in schizophrenia
Causes of ↓ DA
excitotoxic overactivity of glutamate system
2° to inhibition by excess serotonin
D2 block by antipsychotics
Degenerative process here could explain worsening of negative Sx over time
Axons projects to cerebral cortex.
Theraeutic dilemma: Theoretically an increase in DA in the mesocortical pathway might improve negative Sx but the excess of DA in the mesolimbic pathway can be increased and worsen positive symptoms.

8. Nigrostriatal & Tuberoinfundibular
part of extrapyramidal nervous system
Controls motor movements
↓ DA → movement disorders & EPSE
Tuberoinfundibular:
controls prolactin secretion
DA inhibits prolactin

9. Acute management Aggression treated with chemical restraints:
lorazepam 2-4mg imi and
serenace 5 mg imi or
zuclopenthixol-acetate mg imi
Decide if admission is warranted / essential

10. Classes of antipsychotics
Typical (DA)
Block D2 receptors
E.g. Haloperidol, chlorpromazine
Atypical (SDA)
Serotonin-dopamine antagonists
E.g. Clozapine, risperidone, olanzapine

11. Dopamine antagonists (typical)
Butyrophenone (haloperidol)
Phenothiazines (chlorpromazine, trifluperazine, fluphenazine)
Diphenylbutylpiperidine (pimozide)
Benzamide (sulpiride)
Thioxanthenes (flupenthixol, zuclopenthixol)

12. Dopamine antagonists Differ in molecular structure & potency
Equal efficacy for positive symptoms
Side-effect profiles differ
Average dosage:
chlorpromazine mg
haloperidol 2-6mg
trifluoperazine 20mg

13. Dopamine antagonists Peak concentration: ↑ potency associated with
oral within 1-4 hours
parenteral minutes
↑ potency associated with
↑EPSE
↓anti-Ach
↓ epileptogenic effect
DA receptor block is immediate but antipsychotic effect takes weeks

14. Dopamine antagonists D2 block responsible for:
Antipsychotic effect (mesolimbic)
Worsen negative Sx (mesocortical)
Movement disorders & EPSE (nigrostriatal)
Hyperprolactinemia (tuberoinfundibular)
Also muscarinic cholinergic block
Ach & DA → reciprocal relationship in nigrostriatal pathway
Excess Ach when DA inhibited
Cholinergic block mitigate effects of D2 block in nigrostriatal pathway → less EPSE
Also blocks alpha1 & histaminergic receptors
Ideal medication would decrease DA in mesolimbic pathway and simultaneously increase DA in the mesocortical pathway while leaving DA unchanged in the Nigrostriatal and Tuberoinfundibular pathway.

16. DA antagonists: side-effects
Neurological (D2 antagonism):
Lowers seizure threshold
Extrapyramidal reactions
Urinary incontinence
Dysphagia
Cognitive (Histaminergic antagonism):
Sedation
Decreased concentration
Depression

17. DA antagonists: side-effects
Anticholinergic (Muscarinic R antagonism):
Dry mouth
Blurred vision / dry eyes
Constipation / urinary retention
Cognitive dysfunction
Cardiovascular (Alpha1 & muscarinic block):
Dizziness, hypotension, syncope, tachycardia
ECG changes, prolonged QT interval
↑ risk for sudden death (arrhythmias)

18. DA antagonists: side-effects
GI (muscarinic & H1 antagonism):
Weight gain
Constipation, occasionally diarrhea
Vomiting
Difficulty swallowing
Sexual (D2, Alpha1 & muscarinic block):
Decreased libido
Erectile dysfunction, inhibition of ejaculation
Anorgasmia

19. DA antagonists: side-effects
Endocrine effects:
Increased prolactin (sexual dysfx, galactorrhea, ↑weight, ↑/↓ glucose, SIAHD)
Hypersensitivity reactions:
Photosensitivity, skin reactions
Agranulocytosis
Anaphylactic reactions
Ocular effects:
Retinitis pigmentosa
Lenticular pigmentation

20. DA antagonists: EPSE Acute dystonia Parkinsonism Akathisia
Neuroleptic malignant syndrome
Tardive dyskinesia

21. Acute Dystonia First 4-7 days ↑ risk: young males; high potency
Painful contraction of muscles that result in abnormal movements or posture:
Torticollis
Trismus
Protrusion of tongue
Dysphagia
Laringo-pharyngeal spasm
Oculogyrus crisis
Biperidine 5mg ivi / imi

22. Parkinsonism Tremors, rigidity & bradikinesia DA inhibits ACh
If DA receptors blocked → ↑ACh
↑ ACh associated with ↑ EPS
Rx: Anticholinergics
Orphenadrine 50mg po 1-3x /d or
Biperidine 2mg 1-3x /d
Always try to lower dosage of antipsychotics
If severe, replace with SDA

23. Akathisia Develops within 1st few weeks
Subjective tension & anxiety combined with objective restlessness
Unable to sit still, fidgets, rocks, paces
Lower dosage if possible
B-blockers: Propanolol 10-30mg tds
Benzodiazepine
Change to low potency typical or SDA

24. Neurolept Malignant Syndrome
Mostly in 1st week; 10-30% mortality
Muscle rigidity & fever with 2/ > of following:
Diaphoresis
Autonomic instability (labile BP/ tachycardia)
Tremor
Dysphagia
Mutism
Incontinence
Leukocytosis
Change in level of consciousness
Lab evidence of injured muscle: ↑ CK

25. NMS: Management Emergency (ICU); stop all anti-psychotics
Cool pt off, aggressive hydration
Monitor vitals, nasogastric tube
Diazepam or lorazepam
DVT prophylaxis
Beware renal failure (↑CK / myoglobin)
Dantrolene 3-5mg/kg IV in divided dose
Bromocriptine 5mg qid (? L dopa)
If no response : ECT
Rechalenge: low dose, atypical, ECT

26. Tardive dyskinesia Appears very late (>4 years); irreversible
Risk factors: Female, elderly, ↑dosage,
Up-regulation of D2-R in nigrostriatal pathway
Abnormal involuntary movements:
Oral movements, protrusion of tongue, grimaces
Choreoatesosis of extremities & abN postures
Not alleviated by antichol / antiparkinsons drugs
Reduce dose, stop anticholinergics
Try SDA / clozapine

27. Serotonin – dopamine antagonists (atypical)
Clozapine (Leponex, Cloment)
Risperidone (Risperdal)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Aripiprazole (Abilify)
Ziprasidone (Geodon)
Amisulpride (Solian) (Selective D2/3 antagonist)

28. SDAs 5HT2A-D2 antagonists Serotonin inhibits DA release
Strongest inhibition in nigrostriatal pathway
Blocking 5HT here promotes DA release → ↓ movement disorders
Serotonin fails to reverse D2 antagonism in mesolimbic pathway

29. SDAs
Side-effects depend on relative receptor affinities: DA, NA, H1, Ach
Usual daily dosages:
Olanzepine 5-20 mg /d p.o.
Clozapine : mg / d p.o.
Risperidone : 2-6mg / d p.o
Sulpiride : mg / d p.o

30. SDA: Indications Severe side-effects such as EPSE Tardive dyskinesia
Young person with first episode
Better treatment for negative symptoms (?)
Treatment-resistant : clozapine
Rechallenge after NMS
Unacceptable prolactin levels
Mood symptoms and ↑ suicide risk
Elderly with behavioral symptoms

31. SDA: Side-effects Neurological (D2 antagonism):
Lowered seizure threshold (esp clozapine)
EPS (low risk); Dysphagia
Urinary incontinence
Cognitive (H1 antagonism):
Headache & sedation (esp in 1st 2 weeks)
Anticholinergic (Musc-antagonism):
Dry mucous membranes; Blurred vision
Constipation; Urinary retention

32. SDA: Side-effects Cardiovascular (Alpha1 & Ach block):
Hypotension, tachicardia
T-wave inversion, ST segment depression
Prolonged QT interval, sudden death
Cardiomyopathy (Clozapine)
GI (5HT2c & H1 block):
Weight gain & metabolic syndrome
(worst: clozapine & olanzapine)
Constipation (severe with clozapine)
Sialorrhea (esp clozapine)

33. SDA: Side-effects Endocrine Changes in temperature regulation
↑ Prolactin (esp risperidone)
Hyperglycemia
Changes in temperature regulation
Sexual (D2, Ach, Alpha1, 5HT block)
Ocular: Lens changes with Quetiapine
Hypersensitivity reactions:
Transaminase↑ & Hepatic dysfx (rare)
Pancreatitis
Agranulocytosis (esp clozapine in first 6 months)

34. Clozapine Only for treatment resistant cases
Highest risk for agranulocytosis, weight gain and metabolic syndrome
Sialhorrhea, constipation, sedation & convulsions

35. Risperidone ↑ risk for EPSE with high dosages
↑ prolactin with galactorrhea

36. Olanzapine High risk for weight gain, metabolic syndrome and sedation
Increases AST

37. Metabolic Syndrome (Syndrome X)
Abdominal circumference >102 cm in men >88cm in women (BMI ≥ 30kg/m²)
Triglycerides > 150mg/dl (1.7mmol/l)
HDL cholesterol < 40mg/dl (0.9 mmol/l) in men and 50 mg/dl (1.0 mmol/l) in females
Blood pressure ≥ 130/85 mmHg
Fasting glucose >110 mg/dl (6.5 mmol/l)
Micro-albuminuria

39. Metabolic syndrome Co-occurrence of interrelated risks including:
Obesity
Insulin resistance
Dyslipidemia
Hypertension
Pro-inflammatory &, pro-thrombotic state
To continue SDA or not
Life style changes (exercise, stop smoking, diet)
Benefits vs risks

40. Depot preparations
Should not be used until response to oral medication demonstrated
Lowest possible dose (IMI)
Flupentixol decanoate 20-80mg 2-4 weekly
Fluphenazine decanoate mg 2-4 weekly
Zuclopenthixol decanoate mg 2-4weekly
Risperidone 25-50mg 2 weekly

41. General principles Start treatment early Gradual increase of dose
Use lowest effective dose
Sufficient time (4-6 w)
Prolonged use of prophylactic treatment (1st episode = 2 yrs; 2nd episode = 5 / > yrs)
Non-compliance: long acting depot injections

42. Thank you