Ch 19: Schizophrenia And The Antipsychotics Flashcards
Schizophrenia
- is a neurodevelopemental disorder
- gene x environment interaction
- abnormal development of PFC and hippocampus
First-line treatments
Largely target the dopamine system
Positive Symptoms of Schizophrenia
*behavioral excesses
- incoherent speech, loose associations
- delusions
- hallucinations
- tactile hallucination are often electrical, inkling, or burning sensations
- predominantly positive: tend to be older when experience sudden onset of symptoms
- respond to antipsychotic medications that block dopamine receptors (D2)
Negative Symptoms of Schizophrenia
*behavioral deficits
- inappropriate or flat affect
- inattention to self-care
- social withdrawal
Cognitive Symptoms of Schizophrenia
- resemble PFC dysfunction
- working memory deficits
- poorer functioning in community and greater isolation
Schizophrenia is a neurodevelopment disorder : gene x environment interactions
- genetic predisposition
- synapse structure, function, plasticity
- environmental stressors
- perinatal/ immunological factors confer risk
*Two- hit model
Two-hit model
- Genetic brain development
2. Environment at adolescence
Schizophrenia is a neurodevelopment disorder: alter the developmental trajectory of PFC
- anatomical and functional deficits
- symptoms that resemble abnormal PFC function (reduced function)
- less activation in left DLPFC. ACC, and thalamus
- greater control in VLPFC, amygdala, and insula
Neurodevelopmental Model
- Negative symptoms
2. Positive symptoms
Reduced brain regions occur because:
- small soma
- reduced dendritic trees
- reduced dendritic spine density
- increased cell packing
[…] cells are more disorganized and selected […] layers are atrophied
Hippocampal cells are more disorganized and selected cotical layers are atrophied
DISC1 gene mutations
Increase probability of developing schizophrenia
2 times are much cortical gray matter loss than normal patients
Starts in parietal lobes —> temporal lobes —> DLPFC —> frontal eye field
Amphetamine-induced stereotypy
Animal model for schizophrenia
Hypoglutamate Model
Acute reduction fo Glu NT
Prepulse Inhibition of Startle (PPI)
Used to study sensory-filtering deficits
Two main families of antipsychotic medications
- typical antipsychotics (neuroleptic; FGA)
- atypical antipsychotics (SGA)
- fewer abnormal movement side effects
Primary targets of antipsychotics are
- Dopamine (DA) receptors
- Serotonin (5-HT) receptors
Neuroleptic Drugs
Phenothiazine
- chlorpromazine (aliphatic) (Thorazine) - thioridazine (piperidine) - fluphenzine (piperazine)
Butyrophenone
- haloperidol (Haldol)
Neuroleptics
- are potent D2 receptor antagonists
- pre-synaptic, post-synaptic, and autoreceptors
- can reduce symptoms at low doses because of high affinity
- are effective anitopsychotics
- have significant side-effects
Neuroleptic are potent D2 receptor antagonists
Left: binding to D2 receptors is correlated with clinical efficacy
Right: antipsychotics displace [11C]raclopride from D2 receptors
Clinical Efficacy of Neuroleptics
Of neuroleptics has been shown in 100’s of double-blind RCTs
Symptoms of Neuroleptics
- more effective in treating the positive symptoms
- negative and cognitive symptoms are difficult
Maintenance of Neuroleptics
- after treating acute psychosis, antipsychotic drugs are prescribed for maintenance
- discontinuation is often not attempted
Neuroleptics are effect antipsychotics
- 1/3 respond well, have a meaningful and productive life
- 1/3 show improvement but will relapse, often requiring hospitalization
- 1/3 fail to respond, chronically ill, highest rate of suicide
Neuroleptics are potent […]
Neuroleptics are potent D2 receptor antagonists
*best predictor of antopsychotic efficacy is potency of D2-R antagonism
Parkinsonism symptoms
Side effects that include tremors, akinesia (slowing/ loss of voluntary movement), muscle rigidity, akathisia (constant walking), and loss of facial expression
DA cell groups and pathway: Nigrostriatal (A9)
- activation, motivation, and cognition
- motor side effects
- EPS side effects
DA cell groups and pathway: Mesolimbic (A10)
- behavioral arousal and reward learning
- delusions and hallucinations
- antipsychotic efficacy
DA cell groups and pathway: Mesocortical (A10)
- attention and working memory
* cognitive effects and negative symptoms
DA cell groups and pathway: Tuberohypophyseal (A12)
- prolactin release
- neuroendocrine side effects
- endocrine side effects
EPS side effects
Blocking D2 receptors in the nigro-striatal pathway can cause
- dystopia, parkinsonism - tardive dyskinesia
Endocrine side effects
D2 blockade increases the release of prolactin
- males: gynecomastia, delayed ejaculation - females: galactorrhea, amenorrhea, decreased libido
Additional Side Effects of Neuroleptics
Histamine H1 antagonist
- sedation - weight gain
Alpha1 NE antagonist
- postural hypotension
MACh antagonist
- dry mouth, pupil dilation/ blurred vision, cognitive impairment, constipation, tachycardia
Schizophrenia: Serotonin
- the hallucinogenic drug LSD exerts it’s effects by activating 5-HT2A receptors
- atypical antipsychotics have less affinity for D2, and greater affinity for 5-HT2 receptors
“Atypical “ Antipsychotics (SGA)
Clozaril (clozapine) Zyprexa (olanzapine) Seroquel (quetiapine) Risperdal (risperidone) Geodon (ziprasidone) Latuda (lurasidone) Abilify (aripiprazole) Rexulti (brexpiprazole) Vraylar (cariprazine)
SGA and bipolar disorder
Zyprexa (olanzapine) Seroquel (quetiapine) Risperdal (risperidone) Geodon (ziprasidone) Latuda (lurasidone) Abilify (aripiprazole) Vraylar (cariprazine)
SGA and MDD add-on therapy
Zyprexa (olanzapine)
Rexulti (brexpiprazole)
Severe side effects limit the clinical use of clozapine
Agranulocytosis
- loss of white blood cells in 1-2% of users - reversible, but potentially fatal - requires frequent blood monitoring (increased expense)
Substantial weight gain is also problematic
- increased risk for metabolic syndrome (pre-diabetes) and ensuing cardiovascular disease
Reduction in seizure threshold
Clozapine has some advantages over neuroleptics
Effective in about 1/3 of neuroleptics non-responders
EPS (Parkinsonism) side-effects less severe
Reduces suicide risk in schizophrenia and schizoaffective disorder
Atypical Antipsychotic: Receptor Affinity
- Low affinity D2 antagonist
- High affinity 5-HT2A antagonist (or 5-HT1A partial agonist or D2 partial agonist)
Atypical Antipsychotic: DA-Eric side effect profile
- EPS (Parkinsonism) less severe
- endocrine side-effects (hyperprolactemia) less severe
Atypical antipsychotics are low-affinity dopamine D2 antagonists
- 5-HT2A antagonism increases DA output
- 60% D2 receptor accupancy
Selective D2 Receptor Antagonists
Sulpiride and amisulpride
Dopamine System Stabilizers
Aripiprazole (Abilify)
- DA partial agonist
Broad- Spectrum Antipsychotics
Clozapine
- weak affinities for D1 and D2
Pharmacological Action of Atypical Antipsychotics
Nigrostriatal pathway
2A antagonists decrease cortical excitation
Decrease GABA inhibition
Increased DA release
Increase motor output
Mitigate EPS
5-HT2A regulation of dopamine release is not the same everywhere
No effect on mesolimbic or mesocortical areas (don’t have 5-HT2A receptors)
- Nigrostriatal: decreased EPS side effects
- Tuberohypophyseal: decreased endocrine side effects
5- HT1A and D2 partial agonist contributes to antipsychotics and AD efficacy
“Peens” and “dones”: high affinity 5-HT2A antagonists
“2 pips and a rip”:
- lower affinity for 5-HT2A receptors - 5-HT1A partial agonist - D2 partial agonist
Similar to 5-HT2A antagonism, […] also increase DA release selectively in […] pathway and […]
Similar to 5-HT2A antagonism, 5-HT1A partial agonism also increase DA release selectively in nigrostriatal pathway and pituitary
[…] “stabilizes” DA
D2 partial agonist “stabilizes” DA
“Peens” and “dones”
5-HT1A partial agonist
Depressive episodes in BD
- Seroquel (quetiapine) - Latuda (lurasidone)
“2 pips and a rip”
D2 partial agonist
5-HT1A partial agonist
Adjunct in MDD
- Abilify (apiprazole ) - Rexulti (brexipiprazole)
General side effects of atypical antipsychotics: Sedation
- H1, ACh, a1 antagonism
- Clozaril
- Zyprexa
- Seroquel
General side effects of atypical antipsychotics: Cardiometabolic
- High
- Clozaril
- Zyprexa- very high weight gain
- Moderate
- Risperdal, Seroquel, Fanapt
The Cardiometabolic Effects of Atypical Antipsychotics
- Increased appetite
- Weight gain
- Elevated triglycerides
- Insulin resistance
- Diabetes
- increased risk of type 2
- Cardiovascular events
Acute psychosis
- Neuroleptics- alone or in combo with BDZ and/ or anticholinergic (eg. Benztropine)
- Zyprexa (short- acting IM/ ODT) or Geodon (short-acting IM)
First episode psychosis
- Atypicals often used used due to more favorable side-effect profile
- start with low dose, titration slowly
Switching for Adverse Effects: EPS
1st Alternative: Clozaril; Zyprexa
Other: Seroquel; Abilify
Worst: Haldol; Thorazine
Switching for Adverse Effects: Sedation
1st Alternative: Invega; Fanapt
Other: Abilify; Latuda
Worst: Clozaril; Thorazine
Switching for Adverse Effects: Weight gain
1st Alternative: Haldol; Geodon
Other: Abilify; Seroquel
Worst: Zyprexa; Clozaril
Switching for Adverse Effects: Hyperprolactinemia
1st Alternative: Abilify; Seroquel
Other: Saphris; Zyprexa
Worst: Invega; Risperdal
Switching for Adverse Effects: Long QTc
1st Alternative: Latuda; Abilify
Other: Invega; Haldol
Worst: Serlect; Geodon
Atypical antipsychotics carry a box warning
Increased mortality in elderly patients with dementia-related psychosis:
- 2x increase in death in patients with dementia- related psychosis - cardiovascular (heart failure, sudden death) or infectious
Equivocal evidence of therapeutic efficacy for behavioral and psychological symptoms of dementia
- agitation, aggression, noncompliance with care, disturbed sleep - CMS requires documentation of medical necessity
Should Clozapine be a first-line medication?
Should not be reserved as a treatment of last-resort
Antipsychotics in Children: Schizophrenia
Abilify
Fanapt
Seroquel
Risperdal
Antipsychotics in Children: Bipolar
Abilify
Fanapt
Seroquel
Risperdal
Antipsychotics in Children: Irritaibility/ Autism
Abilify
Risperdal
Hippocampal activity is pathologically enhanced
Antipsychotics work at D2 receptors
The pathology is at the hippocampus
Neuroscience of Schizophrenia
Negative Symptoms: excessive pruning in PFC
Positive Symptoms: loss of top-down control over brain stem DA neurons
Depot injections: atypical antipsychotics
Olonzapine pamoate (Zyprexa Relprevv) Apiprazole lauroxil (Aristada) Palperidone palmitate (Invega Trinza)
Depot Injection Advantages
- avoids first-pass metabolism
- improved adherence
- reduced relapse and rehospitalization
Depot Injection Disadvantage
- less flexibility of dose adjustment
- tolerance to side-effects are delayed
- frequent travel to outpatient clinics
