Lecture 52 + 53 - Antipsychotics Flashcards
HISTORY AND BACKGROUND OF TREATING SCHIZOPHRENIA
Early 1900’s: Brain disease
Now: Disease of nature/nurture
Before 1950’s: Treatments included sedation, lobotomy, ECT, and Rauwolfia alkaloids used in Hindu Medicine
1950’s: Reserpine
1952: Phenothiazines (chlorpromazine): Out-patient therapy-emptying mental hospitals
GENERAL CONSIDERATIONS OF SCHIZOPHRENIA
Antipsychotic = Neuroleptic = Anti-Schizophrenic
Severe illness, most debilitating of psychotic
disorders
Affects 1% of population
Onset age 15-20 years old
Not Split personality
ETIOLOGY OF SCHIZOPHRENIA
Neurodevelopmental/anatomical In utero/adolescence-increased ventricle size and changes in gray and white matter
Genetics-neuronal growth, migration of neurons (twin studies, families-multiple genes)
Environmental- Birth complications, infections
Gene-Environment Interaction COMT-marijuana
Neurodevelopment-Environment Interaction
SYMPTOMS
postive
negative
cognitive
Postive Symptoms
Respond well to drug therapy – Examples: hallucinations, delusions, bizarre behavior, thought disorders
Negative Symptoms
Little response to drug therapy, newer agents are better
– Examples: blunted emotion, poor self care, social withdrawal, poverty in speech
Cognitive Symptoms
decrease in cognitive function
Involves D1 receptors and glutamate receptors
NEUROTRANMITTER HYPOTHESES
Dopamine: First to be developed, but incomplete
Serotonin: Based on mechanism of LSD and mescaline
Glutamate: Based on phencyclidine and ketamine
SEROTONIN HYPOTHESIS OF SCHIZOPHRENIA
- LSD and mescaline were identified as 5HT agonists, inspired search for ‘endogenous’ hallucinogens
- Pharmacological studies with 5HT receptors identified 5HT2A receptor as mediator of hallucinations
- Antagonism and inverse agonism linked to antipsychotic activity
- 5HT2A receptors modulate dopamine release in cortex, limbic region, and striatum
- 5HT2A receptors modulate glutamate release and NMDA receptors
- 5HT2C agonists may be beneficial in schizophrenia
GLUTAMATE HYPOTHESIS OF SCHIZOPHRENIA
- Glutamate is major excitatory neurotransmitter
- Phencyclidine and ketamine, noncompetitive inhibitors of NMDA receptors exacerbate psychosis and cognition deficits
- LY2140023-mGLuR2/3 agonist effective in schizophrenia
- Ampakine (AMPA receptors)-effective in animal models
- GlyT inhibitors (under development
as adjuncts)
DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA
- D2 receptor antagonists - Binding and therapeutics; strong correlation receptor binding affinity vs. clinical effectiveness
- Dopaminergic agents (e.g. L-DOPA, amphetamine, bromocriptine) exacerbate symptoms of schizophrenia
- Increased D2 receptor density in treated and untreated patients of schizophrenia
- Imaging studies-increased DA release and receptor occupancy in patients
- Dopamine metabolites in CSF - D2 receptor antagonists initially increase metabolites in the CNS and later decrease metabolites in CNS
DETERMINING BINDING AFFINITY
Binding Affinity: Intermolecular force between ligand and receptor
Kd/Ki: Estimated concentration at which 1⁄2 of the receptors are occupied
Saturation binding experiments – Vary concentration of radio-labeled ligands
Competition binding experiments
– Constant radioligand (hot) concentration competing with unlabeled ligand (cold)
RECEPTORS ANTAGONIZED BY ANTIPSYCHOTICS: major
Dopamine (5 dopamine receptors)
D1-like receptors (D1 and D5)
D2-like receptors (D2, D3, and D4)
RECEPTORS ANTAGONIZED BY ANTIPSYCHOTICS: newer agents
Serotonin (5HT):
5HT2A Receptor Antagonists: clozapine, olanzapine, and risperidone
Older Agents: chlorpromazine, haldol, thioridazine
RECEPTORS ANTAGONIZED BY ANTIPSYCHOTICS: minor
Norepinephrine (NE): alpha1 Receptor Blockade: hypotension, sedation; alpha2 Receptor Blockade: may be helpful in therapy
Acetylcholine (ACh): Muscarinic receptors -anticholinergic effects (clozapine, thioridazine)
Histamine: H1 Receptor Antagonists: sedation, weight gain
Which receptor is key for therapeutic effectiveness?
There is no clear pattern: multiple receptors; individualize therapy based on patient response; unable to predict effectiveness of each therapy for individual patient
multiple receptors –> many SE –> poor adherence
BINDING AFFINITY VS. CLINICAL DOSE
Correlation between binding potency and clinical effectiveness for D2 receptors, therefore more effective drug target
Most antipsychotic drugs are receptor antagonists
Dopamine (D1, D2)
Antagonist actions at synapse
D2 receptors: Modulates synthesis and release of dopamine, block D2 receptor antagonist, get an increase in the synthesis and release of DA
DOPAMINE PHYSIOLOGY & FUNCTION
Actions of D2 Antagonists in CNS:
Basal Ganglia (Nigrostriatal Pathway): Motor effects, extrapyramidal symptoms (EPS)
Mesolimbic: Primary therapeutic effects (only ones we really want to block)
Mesocortical: Hypofunction in schizophrenia, antagonists may exacerbate cognitive deficits
Hypothalamus and Endocrine Systems: D2
receptor blockade in endocrine system
Medulla: Chemoreceptor trigger zone; D2 antagonists are anti-emetics
Receptor Occupancy and PET
PET scan using [18F] fallypride in the absence (baseline) or presence of increasing doses of the antipsychotic drug aripiprazole
Receptor Occupancy and Antipsychotic Effects
see antipsychotic effect threshold at 70%; EPS threshold at 80%, start to see extrapyramidal sx
DRUG-INDUCED MOVEMENT DISORDERS (D2 Antagonism) - extrapyramidal symptoms
- Extrapyramidal Symptoms (EPS) 30-50%:
Occur early, days/weeks, reversible
Symptoms:
– Dystonia – Increased muscle tone
– Pseudoparkinsonism – Muscle rigidity
– Tremor
– Akathisia – Restlessness
Unfortunately most patients will experience EPS as a result of long term antipsychotic drug therapy; important monitoring parameter
Drug Therapy for EPS:
– Benztropine (Cogentin), trihexyphenidyl (Artane), or akineton (Biperiden) – Anticholinergic agents
– Diphenhydramine (Benadryl) – Antihistamine
– Amantadine (Symmetrel) – Dopamine releasing agent
– Propranolol – used for akathisia
NEURONS INVOLVED IN EPS:
dopamine: inhibitory
acetylcholine: excitatory
DRUG-INDUCED MOVEMENT DISORDERS (D2 Antagonism) - tradive dyskinesia
- Tardive Dyskinesia (20-40%):
Occur late, months to a year, IRREVERSIBLE!!!
Symptoms:
– Mouth – Rhythmic involuntary movements
– Choreiform – Irregular purposelessness
– Athetoid – Worm-like
– Axial hyperkinesias – “To-and-fro” movements
Unknown MOA: Neuroadaptive response- Antagonist- induced supersensitivity of receptors to dopamine?
Monitoring: AIMS (Abnormal Involuntary Movement Scale) rating scale; check every 6 months
Treatment: Prevention! Use the least risky agent at the lowest dose possible and monitor - Reduce dose of current agent
- Change to a different drug; possibly a newer agent
- Eliminate anticholinergic drugs
- VMAT inhibitors
Newer Drug Therapies for TD: VMAT2 Inhibitors
– Tetrabenazine (Xenazine) for Huntington’s chorea
– Valbenazine (Ingrezza) for TD
– Deutetrabenazine (Austedo) for TD and Huntington’s chorea
prevent dopamine from being packaged into synaptic vesicles
DRUG-INDUCED MOVEMENT DISORDERS (D2 Antagonism) - neuroleptic malignant syndrome
- Neuroleptic Malignant Syndrome (NMS):
SeriousandRAPID;10%Fatality
Symptoms:
– EPS symptoms with fever
– Impaired cognition – Agitation, delirium, coma
– Muscle rigidity
Treatment: Restore dopamine balance
– Discontinue drug
– DA agonists, diazepam, or dantrolene (skeletal muscle relaxant
THERAPEUTIC USES OF ANTIPSYCHOTIC DRUGS
Treatment of psychosis:
– 2-3 weeks for effectiveness
– 6 weeks to 6 months maximal efficacy
Other Mental Disorders
– Anxiety = Overkill!
– Mood Disorders: Mania = Secondary to lithium, used in combination; Depression = When accompanied by agitation and delusions
– Tourette’s syndrome-tics, vocalizations: Treat with Pimozide (Orap)
MISCELLANEOUS USES: huntington’s chorea
tetrabenazine, deutetrabenazine
MISCELLANEOUS USES: intractable hiccups
chlorpromazine
MISCELLANEOUS USES: alcohol withdrawal (hallucinations)
haloperidol
MISCELLANEOUS USES: nausea and vomiting
metoclopramide, promethazine
MISCELLANEOUS USES: potentiation of opiates and sedatives
droperidol
PHARMACOLOGICAL EFFECTS OF THE ANTIPSYCHOTIC DRUGS
Behavioral Effects: Unpleasant in normal subjects or reversal of signs and symptoms of psychosis in affected individuals
“Neuroleptic” Syndrome: Suppress emotions, reduce initiative and interest, affect; may resemble negative symptoms
Block conditioned avoidance responses in animal studies
Decreased spontaneous activity, aggressive, and impulsive behavior
Adverse Pharmacological Effects types
autonomic
CNS
endocrine system
other
Autonomic mechanism and manifestations
Muscarinic cholinoceptor blockade: Loss of accomodation, dry mouth, difficulty urinating, constipation
Alpha adrenoceptor blockade: Orthostatic hypotension, impotence, failure to ejaculate
CNS mechanism and manifestations
Dopamine receptor blockade: parkinson’s syndrome, akathasia, dystonias
Supersensitivity of dopamine receptors: tardive dyskinesia
Muscarinic blockade: toxic-confusional state
Histamine (H1) receptor blockade: sedation
Endocrine system mechanism and manifestations
Dopamine receptor blockade resutling in hyperprolactinemia: amenorrhea-galactorrhea, infertility, impotence
Other mechanism and manifestations
Possibly combined H1 and 5HT2c blockade: weight gain
PRECAUTIONS AND CONTRAINDICATIONS
Cardiovascular
Parkinson’s Disease
Epilepsy (e.g. Clozapine will lower seizure threshold)
Diabetes (for newer agents)
Typical First Generation Antipsychotics
More movement problems
Increased EPS and tardive dyskinesia due to strong D2 block
PHENOTHIAZINE NUCLEUS
1st antipsychotic: chlorpromazine
R10: requires 3 atom chain (allows nitrogen to bind receptor)
2 atom chain = antihistamine
R2: important for potency
PHENOTHIAZINE NUCLEUS examples
Aliphatic Phenothiazines
Piperidine Phenothiazines
Piperazine Phenothiazines
Aliphatic phenothiazines
Aliphatic Phenothiazines:
– *Chlorpromazine (Thorazine) - No longer 1st line therapy
Aliphatic Phenothiazines: Used for H1 antagonist properties
– *Promethazine (Phenergan) - Also other indications, N/V
Piperidine Phenothiazines
Piperidine Phenothiazines:
– *Thioridazine (Mellaril) - Sedation, hypotension; anticholinergic, many SE
Piperazine Phenothiazines
Piperazine Phenothiazines:
– *Fluphenazine (Permitil, Prolixin) - EPS
– *Prochlorperazine (Compazine) - Antiemetic
– *Perphenazine (Trilafon) -
CATIE studies: Perphenazine and anticholinergic vs. several newer agents
ANTIPSYCHOTICS
thioxanthines
butyrophenones
Thioxanthines
*Thiothixene (Navane) - Modest EPS
Butyrophenones
*Haloperidol (Haldol) - EPS
Miscellaneous Antipsychotics
*Molindone (Moban)
– ModerateEPS
– Zyprexa or Risperidal vs. Moban + Benztropine: Found weight gain/metabolic problems in newer agents; adherence issues
*Pimozide (Orap)
– Tourette’sdisease-tics,vocalizations
Key points of chlorpromazine
1st Antipsychotic, antihistamine side effects
Key points of promethazine
Antihistamine, antiemetic
Key points of thioridazine
Many SE: anticholinergic, sedation, sexual dysfunction, cardiovascular
Key points of fluephenazine
EPS
Key points of proclorperazine
antiemetic
Key points of perphenazine
CATIE studies: combo with anticholinergic
Key points of thiothixene
modest EPS
Key points of haloperidol
EPS
Key points of molindone
moderate EPS
Key points of pimozide
tourette’s disease, suppress motor and vocal tics
Atypical/Second Generation Antipsychotics
Reduced EPS
Efficacy for Negative symptoms?
Similar or enhanced 5HT2A receptor antagonism vs D2 (see “Serotonin Hypothesis of Schizophrenia”)
More metabolic problems
Linked to diabetes (greater risk in patients < 50)
Olanzapine, Clozapine,
Less evidence in Quetiapine and Risperidone
ATYPICAL/2nd GENERATION ANTIPSYCHOTICS
clozapine
olanzapine
loxapine
quetiapine
ziprasidone
asenapine
lurasidone
pimavanserin
aripiprazole
Clozapine
*Clozapine (Clozaril)
-1st atypical antipsychotic
-Very effective
Agranulocytosis
– Occurs in 1-2% within 6 months (weekly blood monitoring) – 2nd or 3rd line therapy
Side Effects: Anticholinergic, Antihistamine
– Reduced D2 potency = decreased movement disorders
– Risk of diabetes
Olanzapine
-Weight gain
-Less likely to causes N&V
-Less likely to cause movement disorders
-Risk of diabetes
Loxapine
-Older agent
-Metabolite = Amoxipine (Ascendin) Inhibits NET –> Antidepressant
Quetiapine
-Metabolite w/ antidepressant activity
-5HT2A and D2 (low antimuscarinic)
-Low EPS
-Hypotension (α1)
-Sedation (H1)
-Risk of diabetes
Ziprasidone
-5HT2A , D2, α1 affinity
-Prolongs QT interval
-Long acting formulation under study
Asenapine
-5HT2A and D2
(nM affinity at most 5HT, α, DA, and histamine receptors)
Lurasidone
5HT2A and D2
Less weight gain and metabolic effects (vs olanzapine)
Fast onset (days without titration)
Low doses similar effectiveness to high doses
Pimavanserin
Inverse agonist 5HT2A (40x vs 5HT2C)
Used for Parkinson disease psychosis
Aripiprazole
-High affinity for 5HT2 and D2 (D2 actions are dopaminergic-state dependent and/or it is functionally selective)
-Partial agonist at 5HT1A receptors (being used in depression)
-Moderate affinity for D4, α, and histamine receptors
-Side Effects: Weight gain, low risk for D2 effects
-Prodrug: aripiprazole lauroxil, given q 4-8 weeks
ATYPICAL ANTIPSYCHOTICS examples
risperidone
paliperidone
iloperidone
Risperidone
-Specifically and structurally designed to be both a 5HT2A and D2 receptor antagonist! (Rational drug design)
-Relatively low EPS at <8 mg/day
-Weight gain; some sedation
Paliperidone
9-hydroxyrisperidone
Iloperidone
- structurally related to risperidone
- very potent at alpha1 receptors (0.5 nM vs 5 nM at 5HT2A and D2)
D2/D3 receptor partial agonists
brexiprazole
cariprazine
lumateperone
Brexpiprazole
a D2/D3 partial agonist with supposedly less akathisia vs. aripiprazole.
Schizophrenia and as an adjunct to antidepressants for major depression
Partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors
Cariprazine
also a D2/D3 partial agonist with greater affinity for D3. Weak partial agonist activity at 5-HT1A. Akathisia is high
Schizophrenia, mania, bipolar disorder
Lumateperone
partial D2 agonist presynaptic receptors/antagonist at postsynaptic receptors (5HT2A antagonist)
Clozapine key points
1st Atypical antipsychotic, agranulocytosis, risk of diabetes, superior efficacy
Olanzapine key points
Weight gain, risk of diabetes
Quetiapine key points
Metabolite w/ antidepressant activity; hypotension, sedation
Risperidone key points
5HT2A/D2 receptor antagonist
Ziprasidone key points
5HT2A/D2, α1 affinity; prolongs QT interval
Lurasidone key points
5HT2A/D2, reduced metabolic effects, rapid titration
Aripiprazole key points
High 5HT2A/D2 affinity, partial agonist activity
