10 - Schizophrenia Flashcards
Describe Schizophrenia (SZP)
- Usually chronic, often severe & disabling brain disorder
- Broad spectrum of presentation, and of functional impairment
- Persons with SZP are often fearful, withdrawn, isolated, and have gross impairment of capacity for relationships
SZP is a heterogenous disorder - involving ?
thought, behaviour, affect (mood), perception, cognition, abnormal interpretation of reality, IMPAIRED FUNCTION
Is one gender more prone?
No, M = F
What is the usual onset of SZP ?
1st break at:
M: 19-25
F: 20-32
Although “prodromal” features often apparent at a younger age
*Men come to the attention of HCP earlier bc they do more “crazy” or obvious things
SZP etiology:
Describe genetic component
- 45% if both parents positive
- 5-10% if 1 parent positive
SZP etiology:
Describe biologic component
relative dopamine imbalances
SZP etiology:
Describe developmental component
2nd trimester
SZP etiology:
Describe psychosocial component
stress, socioeconomic
SZP etiology:
Describe pathophys component
- Brain asymmetry ?
- Abnormal neuronal pruning (As we go from babies into early childhood, neuronal pruning occurs bc there are too many neurons. This process can go wrong. Too much pruning in some pathways and not enough in other pathways)
Goals of therapy?
There is no precise biochemical Tx Target, Improving QOL & overall function are the goals, but these are challenging to measure
Describe the clinical course of SZP
- Usually prodromal features - odd, suspicious, peculiar, withdrawn
- 1st break between 15-45 years
- Suicide risk highest in 1st 5 years, may be 15% (lifelong)
- Chronic disorder with few or many exacerbations & recoveries
- Wide range of functional status/capacity
- Symptoms may change over time
Neurotransmitter features:
-Relative dopaminergic ____ in mesolithic & mesocortical areas correlate with psychotic Sx
Excess
Neurotransmitter features:
-Relative dopaminergic ____ in frontal lobes correlates with negative & cognitive Sx
Shortfall
Neurotransmitter features:
Roles of ____, ____, ______ apparent but not yet well defined
Glutamate, GABA, Serotonin
*They play a role but we’re not sure what role yet
More about neuronal ________ rather than chemicals or structural defects
communication
Neurosis
a characteristic or trait, perhaps odd but unlikely “pathologic”
Psychosis
an abnormal mental state/symptom (a NOW descriptor)
Schizophrenia
a complex chronic illness involving a prolonged course
Describe the cluster of symptoms of SZP
- Positive symptoms
- Negative symptoms
- Cognitive symptoms
Leads to:
Functional Impairment
What are positive symptoms? Give examples
Something that is there that shouldn’t be there.
Examples:
- hallucinations
- agitation
- anxiety
- suicidal
- delusions
What are negative symptoms? Give examples
Stuff that should be there but isn’t.
Examples:
- lack of pleasure
- diminished ability to initiate and sustain planned activity
- immobile facial expression
- poverty of speech (minimal & simplistic content, flat monotonous voice)
_______ may occur in 1 or more of the senses (auditory, visual, tacitly, olfactory)
Hallucinations
Describe delusions
- False, often fixed beliefs which persist despite “proof” of falseness or impossibility
- May be paranoid, bizarre, grandiose
- Response to even favourable treatment may be limited or poor
Describe the thought disorder
- disorganized, illogical
- abnormal interpretation of reality
- garbled speech
- thought blocking or removal
- made up words (neologisms)
Describe movement disorders
- clumsy, uncoordinated
- involuntary movements, grimacing
- repetitive, unusual patterns
- rarely catatonic (immobile)
Describe the cognitive symptoms
- Poor insight & judgement
- Cognitive impairment: Often related to prolonged neurotransmission imbalance, and impacted by acute symptoms
- Impaired of executive function, sustained attention, working memory - may significantly alter “functional” capabilities
Describe the functional impairment
- The cornerstone of diagnosis, assessment and of treatment & support
- Dysfunction often related primarily to impact of negative & cognitive Sx
- Degree of impairment correlates with time and severity of poorly-controlled symptoms
*First 5 years after Dx is crticial
What are normal features ?
- The senses
- Range of intelligence
- Neurological assessment - findings are usually normal or only mildly impaired
- Concerns/doubts/fears regarding illness and treatment
- Need for understanding/education regarding medications
*Need to understand that we are trying to put them back into control, not trying to change their personality or take them over, etc.
What are some diagnostic factors?
- Deterioration of function
- 6 month duration of symptoms, features
- Onset before 45 years
What do we need to rule out from SZP ?
-Affective disorders, organic disorders, substances, subtype of developmental delay
What are major lifelong goals of therapy for SZP ?
- Prevent harm (to the individual themselves - harm to others is a really tiny subset)
- Bring thought and behaviour under the patient’s control
- Restore contact with reality
- Maximize functional recovery
- Prevent relapse
List some components of treatment
- Pharmacotherapy
- Psychotherapy
- Vocational therapy
- Social therapy
- Support for housing, substance dependency, stress reduction, realistic goal setting
*For most people, we cannot get anywhere with the other areas if pharmacotherapy isn’t happening
List the phases of treatment
- Initial (acute) phase
- Stabilization
- Maintenance and Recovery
What are the primary goals of initial treatment for acute psychosis ?
- Ensure safety, prevent harm
- Prevent rapid & severe decline
What are the secondary goals of initial treatment for acute psychosis ?
- Reduce agitation, hostility, anxiety, tension, suffering, aggression
- Normalize sleeping + eating pattern
- Convey empathy, caring
What are the early effects of initial psychosis treatment?
Reduce agitation, anxiety, hostility, and distress
Frequently, also see drowsiness and dizziness
*Hallucinations may remain intact, but with lessened intensity, frequency, persistence, and individual distress
What are some initial treatments?
- Non-med strategy is helpful for diagnosis
- Benzo’s - may avoid antipsychotics or allow for reduced dosages
- Antipsychotics SGA or FGA may be preferred
What are the targets of initial or acute management?
positive symptoms such as anxiety or harm reduction
What is a note about FGA’s and SGA’s ?
First and second generation antipsychotics
they are “dirty” drugs with multiple receptor effects
What are 1st line ?
- Benzo’s may be fist line
- FGA + Benzo = “Yellow Standard”
*yellow standard bc it’s lacking evidence, hard to study
FGA’s are _____
typical
SGA’s are ________
atypical
List 2 FGA’s
- Haloperidol
- Zuclopenthixol Acetate
FGA’s:
Describe Haloperidol
- predictable
- reliable
- works quickly esp with benzo
- dosage flexibility
- sedation clears relatively quickly
FGA’s:
Describe Zuclopenthixol Acetate
Quite sedating on 1st exposure, 24-72hr duration of calming effects
Describe the stabilization phase Tx
- Slow, erratic, gradual improvement over 6-12 weeks (and onward)
- 1-3 weeks: look for decreased intensity of hallucinations, paranoia - improvement sin self-care, anxiety, socialization (pt-specific factors)
- 3-12 weeks: further improvements, likely discharge when “safe” but improvement/regression dependent on ongoing adherence
What is the selection criteria for antipsychotic medication?
- History of response & tolerability: favourable, unfavourable, incomplete
- Medication side effect profile
- Patient characteristics, Sx spectrum
- Hx of response in a family member
- Input from patient/caregiver
- Risperidone injections for 1st break ? (Injections every few weeks ensures adherence compared to pills)
Dosing has to be a balance, describe this.
- Needs to be aggressive enough for safety concerns and to relieve distress VS. concern over impact of side effects
- Neither Pt or MD want to delay relief or extended length of stay VS. a too rapid titration or too high a dose may damage therapeutic alliance and adherence
____ symptoms usually have a much slower response
Negative
Describe stabilization phase Tx (negative symptoms)
- Usually a much slower response
- Often more resistant to medication
- Negative & cognitive symptoms often considered the most devastating, dysfunctional aspects
*Improvement is attainable with sustained “wellness”
Describe DEPOT medication for maintenance treatment
- Ideally not to enforce compliance but to enable adherence
- Deep IM q2,3,4 weeks
- FGA’s (haloperidol, fluphenazine, zuclophenthixol)
- SGA’s also available in “depot” formats - Risperidone, Paliperidone, Ziprasidone & Olanzapine
How does a depot work?
fat soluble in oily vehicle and drug slowly leaches into the system to extend duration of effect
What is the FGA’s efficacy tied to ?
blocking dopamine receptors
FGA’s are effective but we may consider them second line for ___ patients
new
Describe structure and clearance of FGA
lipophilic, hepatically cleared
half lives of FGA’s rather ___
long
SGA’s:
Why are they effective ?
-beneficial effects mediated by “broader” impact on serotonergic and dopaminergic transmission (receptors)
SGA’s:
Describe SE compared to FGAs
Different SE profiles:
- less movement disorders (DA)
- greater metabolic issues
List some FGA’s and state their potency as L, M or H (low, medium, or high)
- Chlorpromazine (L)
- Loxapine (M)
- Perphenazine (M)
- Fluphenazine (H)
- Flupenthixol (H)
- Trifluoperazine (H)
- Haloperidol (H)
- Zuclopenthixol (H)
FGA’s:
What does potency refer to?
In this context, it refers to D2 receptor binding affinity
*just because it’s more potent D2 blockade, doesn’t mean it’s a more effective antipsychotic for SZP
FGA’s:
D2 occupancy > ___% is attainable for all FGA’s
65
FGA’s:
Potentially ________ regardless of D2 blockade “potency” or specificity
equi-effective
FGA’s:
Just because they are dirty, does that make them a bad choice?
No, can’t automatically say dirty is bad
FGA’s:
What are some adverse effects ?
- Anticholinergic - muscarinic antagonism
- CV - alpha 1, muscarinic
- Sedation - H1 antagonism, other
- Neurologic - movement disorders - D2 antagonism in the nigrostriatum (higher potency = higher risk), decreased seizure threshold
- Prolactin elevation - D2 antagonism in tuberoinfundibulnar region
- Hypersensitivity (photosensitivity, temperature dysregulation, cholestatic jaundice, agranuloctyosis)
- Neuroleptic malignant syndrome (NMS)
How does prolactin elevation affect men?
gynecomastia, dysfunction in libido and in sexual function
How does prolactin elevation affect women?
menstrual disturbance, breast engorgement/lactation, hirsutism, osteoporosis
What is Neuroleptic malignant syndrome (NMS)?
*very rare
- Rigidity, tachycardia, increased temp, altered consciousness
- Can be life threatening
- Tx is primarily supportive measures (possibly dantrolene, bromocriptine, Benzo pancuronium, nitroprusside)
Describe ExtraPyramidal Movement Disorders (EPS)
- Dytonic reactions - uncoordinated/spastic innervation of a muscle group
- Akasthisia - motor restlessness, pacing
- Akinesia - decreased muscular movements
- Rigidity - trunk, limbs, digits, facial
- Pisa syndrome (tilts us ?)
- Trmors
- Tardive Dyskinesia and other tar dive manifestations
What does tardive mean ?
Late appearing
Describe the management of EPS
- Prevention & Early Detection
- Anticholinergics - Benztropine, Procyclidine, Trihexyphenidyl, Diphenhydramine
- Propranolol for Akasthisia
- Benzos for Akathisia plus other EPS
Describe the PK of psychotropics
- ADME processes are helpful for a timeframe of SE but have little relevance to antipsychotic effects.
- True anti-schizophrenic effect is due to prolonged presence of drug int he system not based on levels.
What is the Tx resistance with FGA’s ?
15-25% of patients receive no sustained benefit
What is the Tx limitations with FGA’s ?
negative & cognitive symptoms often respond poorly
What do SGA’s offer?
- reduced EPS liability
- improved impact on negative symptoms
- demonstrated effect on positive symptoms
- alternatives for poor responders that don’t do well on FGA
SGA’s have a very different ____ ____ profile which may be more or less tolerable
adverse effect
SGA’s have an increased ____ but overall likely pharmacoeconomic benefit
cost
SGA’s can cause ____ ____
weight gain
List some SGA’s
- Clozapine
- Risperidone
- Olanzapine
- Quietiapine
- Ziprasidone
Why is clozapine a dirty drug? LOL
because it has affinity for so many receptors
Clozapine can cause ______
Agranulocytosis
*Docs should get blood work routinely
“No blood = No drug”
Start of dispensing weekly amounts, over time can quality for q2w or q4w.
Clozapine and Agranulocytosis:
_______ and not related to dose
idiosyncratic
Clozapine and Agranulocytosis:
Is it reversible ?
Yes - if detected early
Clozapine and Agranulocytosis:
When is the highest risk?
week 4-18 of treatment
Clozapine and Agranulocytosis:
______ CBC on initiation
WEEKLY MAN
Clozapine:
Adverse effects
- drowsiness, hyper salivation, tachycardia, dizziness
- constipation
- hypotension, headache, dry mouth, tremor, nausea, fever
- seizure (dose-dependent)
- weight gain/metabolic issues
- the weekly bloodwork may be a deal breaker for some
Clozapine:
Therapeutic serum range
over 350 ng/mL
Clozapine:
Has the best results in ?
Patients with “Treatment-Resistant” schizophrenia and in suicide risk
Clozapine:
How long is an adequate trail
minimum 3 months, but should be 6 months or longer in treatment-resistant populations
Clozapine:
CI and precautions
- Hx of drug-related blood dycrasias or of poorly-controlled seizure disorders
- On Carbamazepine
- Barbiturates, Cimetidine, Lithium, Cannabis should NOT be used with Clozapine
- Other AP are best avoided except in transition or if out of alternatives
What are some first line SGA’s ?
- Risperidone
- Olanzapine
- Quetiapine
- Ziprasidone
What is Risperidone?
-A potent 5HT-2 and D2 blocker
Risperidone:
Compare to FGA’s
- Broader spectrum of efficacy
- Less EPS, but advantage becomes smaller as dosage rises
- Improved tolerability & hopefully adherence
- Likely cognitive benefits with prolonged adherence
Risperidone:
Compare to other SGA’s
- Strongest and tightest D2 affinity and binding - implications on adherence gaps, EPS and prolactin-related AE
- Significant $$ advantage
- Least sedating
Describe Paliperidone
It is the primary active P450 metabolite of Risperidone.
- Food can increase Cmax
- Decreased potential for P-450 interactions
- Simplified dosing but LESS flexibility
- decreased prolactin effects/weight gain (compared to risperidone)
Olanzapine:
When is clearance increased?
by smoking and carbamazepine
Olanzapine:
Adverse effects
- Somnolence, dizziness, weight gain, metabolic syndrome, akathisia
- Lesser frequency: constipation, agitation ALT elevation, rhinitis, headache, postural hypotension, tachycardia, dry mouth
- Seizure risk (low - similar to FGA’s)
ODT
rapid dissolve tabs
Olanzapine:
What are some other effects ?
Hypnotic - both Olanzapine and quetiapine may be very effective for facilitation of sleep
Anxiolytic - both Olanzapine and quietiapine seem to possess direct anxiolytic properties along with anticipated anti-agitation effects
Compare olanzapine to other SGA’s
- greatest adherence
- increased metabolic and weight effects (biggest reason why guidelines are moving away)
- expensive acquisition cost
- sedation, anxiolytic
Quetiapine:
Adverse effects
- sedation
- dizziness, agitation, increased ALT, constipation, dry mouth, tachycardia, tremor
- adherence may be poor due to sedation or complex regimen
Quetiapine XR:
Describe it
- XR tabs prolong Tmax to 6 hours
- Some reduction of adverse effects
- Extends action at D2 receptor somewhat
- Best depression evidence of SGA’s for the XR format
- Indicated for SZP, bipolar, depression
Compare quetiapine to other SGA’s
- sedation can either be good or bad depending on the patient
- anxiolytic
- some weight gain but < olanzapine
- multiple tablets
- not all patients manage once daily
Ziprasidone preferred with ____
food
Ziprasidone: Drug interactions of concern ?
QT prolongation
Ziprasidone has a favorable ______ profile
weight gain, BG, lipids
Describe Aripiprazole
- has mixed antagonist and agonist effects at Da receptors
- less metabolic effects
- effective for SZP but largest role is augmentation of antidepressant Tx
Describe Lurasidone
- Antagonizes 5-HT2 and D2
- Modest metabolic effects
- Prolactin effects < Risperidone
- AE: drowsy, nausea, agitation, akathisia, parkinsonism
- more expensive than SGAs or FGAs
- also indicated for bipolar depression
SZP is usually considered chronic so _____ Tx may be best
lifelong
SZP:
Adherence to Tx correlates with ?
both reduced relapse risk and with continued functional improvement
Antipsychotics:
What does a cross-taper do?
comprise of relapse risk and tolerability
Antipsychotics:
What does starting/stopping do?
increase withdrawal sx and relapse
Antipsychotics:
What does delayed taper do?
minimize relapse risk but may have side effects ?
What’s the difference between adherence and compliance?
Adherence - patient is involved
Compliance - you’re telling them to
Caution antipsychotic use in the _____
elderly
