Antipsychotic Flashcards
PSYCHOTIC DISORDERS - Definition
A group of conditions that involve loss of contact with reality
Types of Psychotic Disorders
Primary psychosis – no other underlying condition causing psychosis (“psychiatric” cause, e.g., schizophrenia, bipolar)
Secondary psychosis – due to “organic” causes such as drug toxicity, dementia, or a non-psychiatric illness
SCHIZOPHRENIA SYMPTOMS - POSITIVE
Positive symptoms - auditory, visual or tactile hallucinations, delusions, disorganized or bizarre behavior
Most dramatic; tend to prompt treatment
SCHIZOPHRENIA SYMPTOMS - NEGATIVE
Negative symptoms - inexpressive face or blank looks, few gestures, monotone or monosyllabic speech, inability to feel pleasure, incapacity to initiate volitional behavior
Seem subtle but greatest contributors to long-term impairment and poor QOL
SCHIZOPHRENIA SYMPTOMS - COGNITIVE
Cognitive symptoms - poor executive functioning, inability to focus or pay attention, impaired working memory
Seem subtle but greatest contributors to long-term impairment and poor QOL
DOPAMINE RECEPTORS
All dopamine receptors are GPCR
D1-like receptors are stimulatory
D2-like receptors are inhibitory (↓ AC, cAMP, PKA)
DOPAMINE PATHWAYS IN BRAIN
Antipsychotics block D2 receptors along all 4 pathways
mesocortical pathway
mesolimbic pathway
nigrostriatal pathway
tuberoinfundibular pathway
Mesocortical Pathway
DA neurons in the VTA release DA onto the…
frontal cortex (involved in planning, judgment, personality and social behavior)
Mesolimbic Pathway
DA neurons in the ventral tegmental area (VTA) release DA onto the…
nucleus accumbens (NAc) and limbic system (involved in reward, motivation & emotion)
Nigrostriatal Pathway
DA neurons in the substantia nigra (SN) release DA onto the…
striatum (regulates motor control, posture)
Tuberoinfundibular Pathway
DA neurons in the hypothalamus release DA onto the…
pituitary gland, involved in secretion of hormones (e.g., prolactin)
TYPICALS DRUGS– LOW & HIGH POTENCY
“First-generation antipsychotics” or “major tranquilizers” or “neuroleptics”
LOW - Chlorpromazine & Thioridazine
HIGH - Perphenazine & Haloperidol
TYPICALS – ADVERSE MOTOR EFFECTS
ADVERSE MOTOR EFFECTS extrapyramidal symptoms (EPS) via D2 block:
- Acute dystonia
- Parkinsonism
- Akathisia
- Tardive dyskinesia
Extrapyramidal tracts - originate in brainstem, carry motor signals to spinal
cord (includes nigrostriatal pathway) - mediates balance, posture, coordination
TYPICALS – ACUTE EXTRAPYRAMIDAL SIDE EFFECTS
Acute EPS appear early in treatment, they are dose-related and reversible
Akathisia - uncontrollable restlessness, urge to move
Parkinsonism – rigidity, tremor, bradykinesia (extreme slowness)
Acute dystonia – sustained muscle contractions → painful twisting, abnormal posture
TYPICALS – DELAYED EXTRAPYRAMIDAL SIDE EFFECTS
Tardive dyskinesia – repetitive, involuntary movements (grimacing, tongue thrusting, lip smacking, rapid blinking)
Tardive dyskinesias can occur after prolonged use of antipsychotics – higher risk with greater D2 blockade
TYPICALS – OTHER ADVERSE EFFECTS
Hyperprolactinemia – due to block of receptors in tuberoinfundibular DA pathway; Causes reproductive organ and endocrine problems in both women and men
Neuroleptic malignant syndrome (NMS) - rare, but life-threatening, idiosyncratic
reaction to dopamine-blocking drugs, characterized by…
- fever
- muscular rigidity
- altered mental status
- autonomic dysfunction
low-potency typicals most potently block these three off-target receptors (histamine, muscarinic and adrenergic)
ATYPICAL ANTIPSYCHOTICS
Atypicals are “atypical” due to lack of neuroleptic effects (once thought essential)
MOA: Block 5-HT more strongly than D2; Lower risk of dopamine-related adverse
effects (EPS, NMS, hyperprolactinemia)
Atypical antipsychotics are now more commonly prescribed than typicals
CLOZAPINE
THE FIRST ATYPICAL (produces negligible EPS)
USE: treatment-resistant patients only; schizophrenia (more effective)
BLACK BOX WARNINGS…
- Agranulocytosis → REMS program
- Orthostatic hypotension / bradycardia
- Seizures
- Myocarditis / cardiomyopathy
- Dementia-related psychosis
ATYPICAL ANTIPSYCHOTICS – RECEPTOR BLOCKING
Like high potency typicals, atypicals have fewer off-target side effects
MOA: Atypicals block serotonin receptors more strongly than dopamine receptors;
serotonin blockade may contribute to therapeutic and adverse effects
ATYPICAL ANTIPSYCHOTICS – ADVERSE EFFECTS
clozapine & olanzapine cause metabolic problems, including weight gain (drug discontinuation), dyslipidemia, and type 2 diabetes, requiring monitoring
Samidorphan, an opioid receptor antagonist is given with olanzapine to reduce weight gain
Prolonged QTc interval - caused by inhibition of the delayed potassium rectifier current IKr (rapid) by specific drugs
Retinal deposits:
- Thioridazine only**
- Associated with browning of vision
Treatments
Drugs reduce symptoms
Atypicals are slightly better for treating negative symptoms
High rates of discontinuation for all antipsychotics
What factors make treatment adherence difficult in schizophrenia?
- Severe, unpleasant, disabling drug side effects / incomplete efficacy
- Lack of insight about being ill
- Increased rates of unemployment, homelessness, substance use
What approaches can increase compliance?
- Counseling and support
- Behavioral strategies
- Long-acting injections (depot)
Which pathways likely mediate the therapeutic effects of antipsychotic agents?
MC & ML
Which pathways likely contribute to the adverse effects of antipsychotic agents?
NS and TI
(a) Name 4 antipsychotic adverse effects (extrapyramidal effects) that result from D2R blockage along the nigrostriatal pathway
(b) Which 3 occur immediately after starting an antipsychotic, or increasing the dose, and are dose-related and reversible?
(c) Which 1 occurs only after prolonged antipsychotic drug use, and can be irreversible after a certain point?
Acute EPS appear early in treatment; they are dose-related and reversible
- Akathisia: uncontrollable restlessness, urge to move
- Parkinsonism: rigidity, tremor, bradykinesia (extreme slowness)
- Acute Dystonia: sustained muscle → painful twisting, abnormal posture
- Tardive Dyskinesia: repetitive, involuntary movements (grimacing, tongue thrusting, lip smacking, rapid blinking)
(b)
- Akathisia: uncontrollable restlessness, urge to move
- Parkinsonism: rigidity, tremor, bradykinesia (extreme slowness)
- Acute Dystonia: sustained muscle → painful twisting, abnormal posture
(c)
- Tardive Dyskinesia: repetitive, involuntary movements (grimacing, tongue thrusting, lip smacking, rapid blinking
- Can occur after prolonged use of antipsychotics - higher risk with greater D2 blockade
- Irreversible if not caught early
- Patient pay not notice symptoms
Name 1 antipsychotic adverse effect that results from D2R blockage along the tuberoinfundibular pathway – what general kinds of problems does this cause?
Hyperprolactinemia: due to block of receptors in tuberoinfundibular DA pathway: causes reproductive organ and endocrine problems in both women and men
Name 1 rare but life-threatening idiosyncratic reaction to dopamine-blocking drug
Neuroleptic malignant syndrome (NMS) - rare, but life-threatening, idiosyncratic reaction to dopamine-blocking drugs, characterized by fever, muscular rigidity, altered mental status, and autonomic dysfunction
Rank the classes of antipsychotic agents from most to least likely to produce dopamine-blockage related adverse effects.
- Low-potency typicals most potently block off target receptors
- Atypicals have weaker dopamine blockage affinity, but stronger serotonin receptor affinity
What type of receptors are D2 dopamine receptors?
D2-like receptors are inhibitory; decrease AC, cAMP, PKA
Are antipsychotics agonist or antagonist at D2 receptors?
antagonists
rank the classes of antipsychotic agents from strongest to weakest binding at D2 receptors
- Atypicals- weakest binding at D2 receptor
- Typical antipsychotics side chains affect “tightness” of binding to D2 and other receptors
Are binding affinity and potency related – how? And is this the same as efficacy?
Yes, binding affinity and potency are similar in that they decide dose and side effects
Efficacy is equivalent to intrinsic affinity
Which class of antipsychotics binds serotonin receptors with the highest affinity, and more strongly than they block D2 receptors?
Atypicals
What types of side effects arise from antipsychotics’ antagonist effects at dopamine (see objective A), serotonin, histamine, and adrenergic receptors?
Dopamine: extrapyramidal symptoms, weight gain, endocrine effects
Seortonin: weight gain, diabetes, increased appetite
Histamine: weight gain, diabetes, sedation
Adrenergic: postrural hypotension, dizziness, syncope
Which antipsychotic class most potently blocks off-target receptors?
Low potency typicals (histamine, muscarinic and adrenergic)
Blockage of which two types of neurotransmitter receptors contributes to the therapeutic effects of antipsychotics?
Blockage of serotonin and dopamine receptors
Which class is most likely to produce weight gain, dyslipidemia and type 2 diabetes?
Atypicals; requires monitoring
Weight gain is major cause of drug discontinuation
Do antipsychotic drugs cure or prevent schizophrenia?
No, antipsychotic drugs just treat the symptoms of schizoprenia
How long does it take for antipsychotics to produce clinical improvements, and why?
Clinical improvements are delayed; usually become maximal over weeks to months
Are the 3 classes similarly effective for positive symptoms? What about negative symptoms?
All antipsychotics have similar efficacy against positive symptoms
Atypicals are more effective at treating negative symptoms
What was the first atypical antipsychotic, and what is its major use today?
Clozapine: The First Atypical antipsychotic - produce negligible EPS
- Despite safety concerns, is approved for use (with monitoring) for treatment-resistant patients only
What are the 5 black box warnings for clozapine?
Clozapine/s 5 FDA Black Box Warnings:
- Agranulocytosis → REMS program
- Orthostatic hypotension / bradycardia
- Seizures
- Myocarditis / cardiomyopathy
- Dementia-related psychosis
Are antipsychotics generally well-tolerated?
Antipsychotics show a high rate of discontinuation, with percentage of patients with first-episode schizophrenia discontinuing treatment within one year
What is the major cause of discontinuation of atypical antipsychotics?
Severe, unpleasant, disabling drug side effects / incomplete efficacy
Lack of insight about being ill
Increased rates of unemployment, homelessness, substance use
