Antipsychotic medicationAntipsychotic medication

Dr C Kotzé

IntroductionIntroduction

• 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 hypothesisDopamine hypothesis

• D2 receptor block improves positive Sx

• Mesolimbic & mesocortical tracts

• Other transmitters : 5HT, NE, GABA, glutamate

Four key Dopamine PathwaysFour key Dopamine Pathways

Mesolimbic pathwayMesolimbic pathway

• Hyperactivity of DA → hallucinations, delusions and thought disorders

• Role in aggressive Sx

• Drugs that ↑ DA → psychotic Sx

• Antipsychotics ↓ DA (blocks receptors)

Mesocortical pathwayMesocortical 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

Nigrostriatal & TuberoinfundibularNigrostriatal & Tuberoinfundibular

• Nigrostriatal: – part of extrapyramidal nervous system– Controls motor movements– ↓ DA → movement disorders & EPSE

• Tuberoinfundibular: – controls prolactin secretion– DA inhibits prolactin

Acute managementAcute 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 antipsychoticsClasses of antipsychotics

• Typical (DA)– Block D2 receptors

– E.g. Haloperidol, chlorpromazine

• Atypical (SDA)– Serotonin-dopamine

antagonists – E.g. Clozapine,

risperidone, olanzapine

Dopamine antagonists (typical)Dopamine antagonists (typical)

• Butyrophenone (haloperidol)

• Phenothiazines (chlorpromazine,

trifluperazine, fluphenazine)

• Diphenylbutylpiperidine (pimozide)

• Benzamide (sulpiride)

• Thioxanthenes (flupenthixol, zuclopenthixol)

Dopamine antagonistsDopamine 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 antagonistsDopamine antagonists

• Peak concentration:– 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 antagonistsDopamine 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

DA antagonists: side-effectsDA antagonists: side-effects

• Neurological (D2 antagonism):

– Lowers seizure threshold– Extrapyramidal reactions– Urinary incontinence – Dysphagia

• Cognitive (Histaminergic antagonism):– Sedation– Decreased concentration– Depression

DA antagonists: side-effectsDA 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-effectsDA 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-effectsDA 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: EPSEDA antagonists: EPSE

• Acute dystonia

• Parkinsonism

• Akathisia

• Neuroleptic malignant syndrome

• Tardive dyskinesia

Acute DystoniaAcute 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

ParkinsonismParkinsonism

• 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

AkathisiaAkathisia

• 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 SyndromeNeurolept 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: ManagementNMS: 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 dyskinesiaTardive 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 Serotonin – dopamine antagonists (atypical)antagonists (atypical)

• Clozapine (Leponex, Cloment)

• Risperidone (Risperdal)

• Olanzapine (Zyprexa)

• Quetiapine (Seroquel)

• Aripiprazole (Abilify)

• Ziprasidone (Geodon) • Amisulpride (Solian) (Selective D2/3

antagonist)

SDAsSDAs

• 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

SDAsSDAs

• 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: IndicationsSDA: 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-effectsSDA: 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-effectsSDA: 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-effectsSDA: Side-effects

• Endocrine – ↑ 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)

ClozapineClozapine

• Only for treatment resistant cases

• Highest risk for agranulocytosis, weight gain and metabolic syndrome

• Sialhorrhea, constipation, sedation & convulsions

RisperidoneRisperidone

• ↑ risk for EPSE with high dosages

• ↑ prolactin with galactorrhea

OlanzapineOlanzapine

• High risk for weight gain, metabolic syndrome and sedation

• Increases AST

Metabolic Syndrome Metabolic Syndrome (Syndrome X)(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 syndromeMetabolic 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 preparationsDepot 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 principlesGeneral 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

Thank youThank you