Antipsychotic medication Dr C Kotzé

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)

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

Four key Dopamine Pathways

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.

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.

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

Acute management Aggression treated with chemical restraints: lorazepam 2-4mg imi and serenace 5 mg imi or zuclopenthixol-acetate 50-100mg imi Decide if admission is warranted / essential

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

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

Dopamine antagonists Differ in molecular structure & potency Equal efficacy for positive symptoms Side-effect profiles differ Average dosage: chlorpromazine 200-600mg haloperidol 2-6mg trifluoperazine 20mg

Dopamine antagonists Peak concentration: ↑ potency associated with oral within 1-4 hours parenteral 30-60 minutes ↑ potency associated with ↑EPSE ↓anti-Ach ↓ epileptogenic effect DA receptor block is immediate but antipsychotic effect takes weeks

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.

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

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)

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

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

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

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

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

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

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

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

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

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

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

SDAs Side-effects depend on relative receptor affinities: DA, NA, H1, Ach Usual daily dosages: Olanzepine 5-20 mg /d p.o. Clozapine : 75-600mg / d p.o. Risperidone : 2-6mg / d p.o Sulpiride : 600-800mg / d p.o

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

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

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)

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)

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

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

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

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

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

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 6.25-50mg 2-4 weekly Zuclopenthixol decanoate 100-400mg 2-4weekly Risperidone 25-50mg 2 weekly

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

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