Bannon: Antipsychotic Drugs Flashcards
Schizophrenia
Epidemiology:
- Affect 1% of the population worldwide
- 30% of all homeless people
- 30% of all hospitalizations
.
Schizophrenia Psychotic Symptoms (Positive/Cognitive Symptoms): (3)
Psychotic Symptoms (Positive/Cognitive Symptoms): emerge in late teens
o Loss of reality
o Delusions and hallucinations (usually auditory)
o Disordered thinking and memory
.
Schizophrenia Prodromal Signs (Negative Symptoms): (5)
Prodromal Signs (Negative Symptoms): poorer prognosis associated with prominent negative symptoms o Social isolation and withdrawal o Poverty of speech o Odd behavior/ideas o Blunted affect o Lack of motivation
Schizophrenia
Biological Findings: (3)
Biological Findings: especially associated with negative symptoms
- Decreased blood flow in frontal lobe and caudate during working memory tasks
- Reduced hippocampal and medial temporal lobe volume
- Enlarged ventricles
Schizophrenia
Genetic Predisposition:
15% incidence in first degree relatives (compared to 1% incidence in the general population)
17% concordance in DZ twins; ~50% concordance in MZ twins
Complex polygenic disorder (as evidenced by high frequency and partial penetrance)
Schizophrenia
Dopamine Hypothesis
Evidence for the Involvement of DA: (3)
- Dopamine agonists can induce/exacerbate psychosis
- Clinically effective APDs block DA receptors
- DA receptor expression increased in schizophrenia (has since been proven UNTRUE)
Dopamine Receptors:
Dopamine Receptors: G-protein coupled receptors
D1 Family includes:
D1 Family: includes D1 and D5 (less prominent)
D1 Family
Location:
Location:
- D1: striatum and neocortex*
- D5: hippocampus and hypothalamus
D1 Family Second Messengers (Gq):
Second Messengers (Gq):
- Increase cAMP
- Increase PIP2 hydrolysis (PKC activation and Ca++ mobilization)
D2 Family includes:
D2 Family: D2, D3 and D4 (latter 2 less prominent)
D2 Family
Location:
D2: striatum, substantia nigra and pituitary gland*
D3: olfactory tubercle, nucleus accumbens, hypothalamus
D4: frontal cortex, medulla, midbrain
D2 Family Second Messengers (Gi):
Decrease cAMP
Increase K+ currents
Decrease voltage-gated Ca++ currents
Dopamine Pathways: single source divergent systems
Nigrostriatal DA:
Mesolimbic DA:
Nigrostriatal DA: modulates movement and learned habits; 80% of total DA
Mesolimbic DA: modulates motivation, goal-directed thinking, affect and reward
Dopamine Pathways: single source divergent systems
Mesocortical DA:
Hypothalamic DA:
Area postrema:
Mesocortical DA: modulates cognition
Hypothalamic DA: hormone regulation
Area postrema: located outside the BBB; mediates emesis (very sensitive to DA drugs)
Dopamine Pathways and their Relation to Psychotic Symptoms
Mesolimbic/Mesocortical DA:
Mesolimbic/Mesocortical DA: overactive –>possibly related to positive Sx
Dopamine Pathways and their Relation to Psychotic Symptoms
Mesocortical DA:
Mesocortical DA: hypofunction –> possibly related to negative Sx (DA blockade not helpful for these)
Dopamine Pathways and their Relation to Psychotic Symptoms
Nigrostriatal DA:
Nigrostriatal DA: highest DA content and related to extrapyramidal (motor) SEs and tardive dyskinesia
Dopamine Pathways and their Relation to Psychotic Symptoms
Tuberoinfundibular/Hypothalamic DA:
Tuberoinfundibular/Hypothalamic DA: related to endocrine effects
D2R Blockade and Clinical Efficacy:
D2R Blockade and Clinical Efficacy: strong correlation between blockage for these R and efficacy
Original D2 Blocking Agents (ie. Chlorpromazine):
Original D2 Blocking Agents (ie. Chlorpromazine): not a real high affinity for D2 receptors and therefore needed very high doses to achieve desired effects (lots of SE)
Newer D2 Blocking Agents with Higher Affinity (ie. Spiroperidol):
Newer D2 Blocking Agents with Higher Affinity (ie. Spiroperidol): although higher affinity, do not have improved efficacy over earlier agents; however, will have different SE profiles
Commonality in APDs Relevant to Antipsychotic Effects
Possibilities
5HT2A:
D4 in cortex:
5HT2A: typical APDs occupy most striatal D2 receptors while atypical APDs occupy a lower proportion of D2 R and more 5HT2A; however, role for 5HT2A receptors in psychosis not clear
D4 in cortex: but not all block here (ie. quetiapine)
Commonality in APDs Relevant to Antipsychotic Effects
Possibilities
Fast dissociation relative to R binding allows better modulation of function (ie. high Kd at D2):
Fast dissociation relative to R binding allows better modulation of function (ie. high Kd at D2): but then atypical APDs should look like low-affinity typical APDs (not the case)
Commonality in APDs Relevant to Antipsychotic Effects
Another issue:
Another issue: blockade of receptors is immediate but effects are delayed
Commonality in APDs Relevant to Antipsychotic Effects
BOTTOM LINE:
Antipsychotic MOA(s) still not really understood
However, D2 DA receptor blockade is a commonality to all agents
Pharmacokinetics of APDs
Absorption:
Absorption: most are READILY but INCOMPLETELY absorbed
- Highly lipid soluble and protein bound
- Long clinical duration relative to plasma half life
Pharmacokinetics of APDs
Administration:
Administration: parenteral forms (IM depot injections) available (especially older APDs); often used when compliance is an issue
Pharmacokinetics of APDs
Metabolism:
Metabolism: significant FIRST PASS metabolism by P450; conjugation for urinary excretion
Adverse Effects of APDs: (6)
Relatively high therapeutic index: pretty safe in overdose
Autonomic Effects
Cardiovascular Effects:
Endocrine Effects
Metabolic Effects
Extrapyramidal Effects:
Adverse Effects of APDs
Relatively high therapeutic index:
Pretty safe in overdose
Adverse Effects of APDs
Autonomic Effects
Muscarinic Block:
Alpha Adrenergic Blockade (α1):
Muscarinic Block: dry mouth, urinary retention, constipation
Alpha Adrenergic Blockade (α1): orthostatic hypotension, impotence
Adverse Effects of APDs
Cardiovascular Effects
Phenothiazines (chlorpromazine and others):
Atypical APDs (esp. ziprasidone):
Overall:
Phenothiazines (chlorpromazine and others): ↑HR, abnormal ECG
Atypical APDs (esp. ziprasidone): significant risk of QT prolongation
Overall: ~2x increased risk of sudden cardiac death with both typical and atypical (dose-dependent)
Adverse Effects of APDs
Endocrine Effects
Hyperprolactinemia:
Hyperprolactinemia: manifest as amenorrhea, galactorrhea, infertility, impotence
- Due to decreased action of DA (normally suppresses prolactin release from anterior pituitary)
Adverse Effects of APDs
Metabolic Effects
Atypical APDs (esp. clozapine and olanzapine): Possible cause:
Atypical APDs (esp. clozapine and olanzapine): weight gain leading to insulin resistance and diabetes - Possible cause: H1 and 5HT blockade
Adverse Effects of APDs
Extrapyramidal Effects:
Seen in proportion to D2R affinity (drugs with higher affinity for this receptor cause more EP effects)
Some effects are short term and limiting, while others are long-term and irreversible
Adverse Neurological Effects of APDs (Extrapyramidal Effects)
Early Adverse Effects: (4)
Acute Dystonic Reaction
Akathisia
Parkinsonism
Neuroleptic Malignant Syndrome
Adverse Neurological Effects of APDs (Extrapyramidal Effects)
Acute Dystonic Reaction:
Acute Dystonic Reaction: of face or back (1-5 days after starting medication); NOT seizures or hysteria
Adverse Neurological Effects of APDs (Extrapyramidal Effects)
Akathisia:
Akathisia: uncontrollable restlessness (5-60 days after starting medication); NOT agitation
Adverse Neurological Effects of APDs (Extrapyramidal Effects)
Parkinsonism:
Treatment of Acute Dystonic Reaction/Akathisia/Parkinsonism: (2)
Parkinsonism: looks like idiopathic PD (5-30 days after starting medication)
Treatment of Acute Dystonic Reaction/Akathisia/Parkinsonism:
- Reduce dose of APD
- Anti-muscarinics/anti-histaminics (bring system back into balance by reducing ACh)
Adverse Neurological Effects of APDs (Extrapyramidal Effects)
Neuroleptic Malignant Syndrome:
When:
Neuroleptic Malignant Syndrome: very rare sensitivity to DA blockade by all types of APDs
When: first few weeks of taking medication OR after increasing dose
Adverse Neurological Effects of APDs (Extrapyramidal Effects)
Neuroleptic Malignant Syndrome
Manifestations: (3)
Hypothalamic DA block leads to very high dangerous fever
Basal ganglia DA block leads to parkinsonism
Others symptoms include autonomic instability and muscle breakdown
Adverse Neurological Effects of APDs (Extrapyramidal Effects)
Neuroleptic Malignant Syndrome
Treatment:
Bromocriptine (DA agonist) and dantrolene
Late Adverse Effects
Tardive Dyskinesia:
Tardive Dyskinesia: occurs months to years after starting medication
Most important side effect of APDs (20-40% of patients chronically treated with typical will develop TD)
Advanced cases are difficult to reverse (early recognition is important)
Masked by increasing APD dose and worsens upon drug withdrawal
Special Adverse Effects with Clozapine: (2)
Seizures (1-4% of patients)
Agranulocytosis (1-2% of patients)
- Potentially fatal
- Develops between weeks 6-18 and reversible if caught early
- Therefore, need to do weekly blood counts for the first 6 months and every 3 weeks after that
CATIE Study
Basics:
Phase I:
Basics: first generation perphenazine vs. second generation olanzapine, quetiapine, risperidone and ziprasidone
Phase I:
- ¾ of patients switched mediations because of adverse side effects
- Olanzapine showed a modest advantage in terms of duration of treatment and symptom relief (but substantial weight-related SEs)
- Other atypicals (second generation) showed no advantage over perphenazine
CATIE Study
Phase II:
Patients who stopped APDs due to SEs/no response (and who refused to take clozapine) given one of the 4 atypicals mentioned above
- Patients continued on olanzapine and risperidone significantly longer
Patients who stopped APDs because of inadequate symptom relief were given clozapine, olanzapine, risperidone or quetiapine
- Clozapine significantly more effective and patients stayed on it longer
CATIE Study
Issues with the Study:
Subject selection limitation (most patients had no EPS/TD and those that had TD were assigned to second generation APDs only)
Therefore, study deals with side effects and efficacy but does not really address the issue of tardive dyskinesia
CUtLASS Study:
Basics:
Basics:
- Clinicians and patients UNBLINDED and initiated drug changes (better mimicked the clinical situation BUT less control of variables)
- Assessed by a blind rater after 1 year on the medications
CUtLASS Study:
Overall Results:
Overall Results:
- Typicals and atypicals equivalent in quality of life, efficacy and side effects
- Clozapine better in managing symptoms than other second generation drugs in treatment resistance patients (overall quality of life also somewhat better)
TEOSS Study
Basics:
Basics:
- Study of young patients on APDs (8-19 years old)
- Looked at olanzapine, risperidone or molindone PLUS benztropine (anticholinergic)
TEOSS Study
Overall Results:
Side effects differed:
Overall Results:Roughly equivalent efficacy
Side effects differed:
- Weight gain (olanzapine>risperidone>molindone)
- Increase in cholesterol and other metabolic disturbances (olanzapine- this arm of the trial was terminated)
Determining the DOC for your Patient
Cost:
Adverse Side Effects:
Compliance:
Treatment-resistance
Cost: newer atypicals 10-100x more costly than generics
Adverse Side Effects: profile of typical vs. atypical; short term vs. long term use
Compliance: depot injections or drug changes
Treatment-resistance
Chlorpromazine (and other phenothiazines)
Receptor Affinities:
Pros: (1)
Cons: (2)
Receptor Affinities: α1=5HT2A>D2=D4=H1>D1=M
Pros: Generic and inexpensive
Cons:
- Many adverse autonomic effects (dirty drug- action at many different receptors)
- Some risk of EPS and TD (action at D2 receptors)
Haloperidol
Receptor Affinities:
Pros: (3)
Cons: (1)
Receptor Affinities: D2>α1>D4>5HT2A>D1»H1»M
Pros:
- Generic and inexpesive
- Parenteral form available (depot injection)
- Less autonomic effects (does not have a high affinity for these receptors)
Cons:
- Strong D2 block means higher risk of EPS and TD
.
Risperidone
Receptor Affinities:
Pros: (4)
Cons: (1)
Receptor Affinities: 5HT2A>D2=α1>D4>H1>D1»M
Pros:
- Generic and inexpensive
- Depot preparation available
- Borderline atypical and therefore LESS 5HT-related weight gain compared to other atypicals
- More tolerable than most others APDs (maybe)
Cons:
- Borderline atypical and therefore MORE DA-related side effects (hyperprolactinemia, EPS)
Olanzapine
Receptor Affinities:
Pros: (3)
Cons: (2)
Receptor Affinities: 5HT2A=M>H1>D4>D2>α1>D1
Pros:
- More tolerable than other APDs (clozapine-like structure without risk for agranulocytosis or seizures)
- May be somewhat more effective than other APDs (subtle)
- Less risk of EPS and TD (less action at D2)
Cons:
- Expensive (no generic)
- Several metabolic adverse effects including weight gain and diabetes (more action at 5HT2A)
Clozapine
Receptor Affinities:
Pros: (2)
Cons: (3)
Receptor Affinities: 5HT2A>D4=α1=M=H1>D2>D1
Pros:
- Clearly the most efficacious drug available for refractory cases
- Less risk for EPS and TD (less action at D2)
Cons:
- Expensive (no generic)
- Risk for weight gain and diabetes (more action at 5HT2A)
- More serious side effects of agranulocytosis and seizures
.
Traditional Use of APDs
Schizophrenia:
Schizoaffective Disorder:
Schizophrenia: primary indication
Schizoaffective Disorder:
- Characteristics of schizophrenia PLUS affective disorders (depression, BPD)
- Treat with APD plus antidepressants, lithium or valproate
Traditional Use of APDs
Neuroleptoanesthesia:
Pre-Surgical Use:
Neuroleptoanesthesia: Droperidol (short-acting and highly sedating) + fentanyl
Pre-Surgical Use: Older APDs (with H1 blockade) used due to strong anti-emetic effects (via CTZ and GI), sedation and relief of pruritis (itching)
Other Uses of APDs
Depression and Bipolar Disorder:
Atypical APDs:
Depression and Bipolar Disorder: some justification for the use of APDs in treatment
Atypical APDs: FDA-approved for acute mania and mixed episodes of BPD
Other Uses of APDs
Depression and Bipolar Disorder
Risperidone/Lithium Combination:
Atypical APD + Antidepressants:
Risperidone/Lithium Combination: FDA-approved for maintenance in refractory BPD
Atypical APD + Antidepressants: tested for drug-refractory depression (fluoxetine/olanzapine tested first); mixed results depending on the drug combination used
Agitation in Alzheimer’s Disease and Dementias
Rationale:
Black Box Warning:
Rationale: calming, sedative, antipsychotic effects
Black Box Warning: both typical and atypical APDs increase death due to CV accidents and infections in patients with AD/dementia (therefore, really need to be careful/limit use in this population)
Control of Aggressive Behavior in Pediatrics
Risperidone:
Quetiapine and Aripiprazole:
Risperidone: FDA-approved for use in autistic children over the age of 5 with aggression or self-injurious behavior
Quetiapine and Aripiprazole: FDA-approved for children over the age of 10 with BPD
Control of Aggressive Behavior in Pediatrics
General Issues:
Use especially high in Medicaid children (poor)- especially off label use for ADHD (cheaper than the drugs for ADHD)
Off-label use in privately insured children aged 2-5 has also doubled
