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Pharmacological treatment of treatment resistant psychosis - Coggle Diagram
Pharmacological treatment of treatment resistant psychosis
What is treatment resistance?
'Inadequate' response
At least moderate symptom severity
Persistent (most weeks)
Frequent (3x/day
Function/health impact
PANSS score 4+
Despite two 'adequate' trials of antipsychotic treatments
Each at BNF (British National Formulary) therapeutic dose
Each 6 weeks+
Evidence of adherence
check prescriptions, boxes, plasma levels
in patient treatment, depots
How common?
13-43% (depending on criteria used)
In FEP, 15-20%
Biology
Lack of elevated DA function in mesolimbic system
Consistent with elevated baseline DA and its metabolite (HVA) predicting good treatment response
Replication by Jauhar et al. 2019 - in associative striatum
Initial DA synthesis capacity associated with improvement in +ve symptoms
Indicates +ve symptoms have different mechanism (not extra DA in these areas) in treatment-resistent psychosis
Demjaha et al. 2014 - PET DA imaging of striatum
Higher DA synthesis capacity in responders vs controls but not non-responders
Significantly higher glutamate in treatment-resistant group
Issue: can't tell whether differences = consequences of poor response, since it's cross-sectional
Elevated glutamate in anterior cingulate compared to responders (Egerton et al. 2012)
Though only small mean difference - not a biomarker
Replicated Egerton et al 2018
Differences present before treatment initiated
But are these causes or effects of treatment resistance?
How to assess?
STRATA (South London) is working on predicting it
FEP
Non-response in first weeks predicts eventual non-response
Though could be poor adherers - need to check up
Evidence: Kinon et al. 2010; Agid et al. 2011
Indicates 6+ week requirement is overkill
Non-response to 1st med predicts non-response subsequently (Agid et al. 2011)
Does it develop over time?
Demjaha et al. 2017 longitudinal study indicates not
predictors (Demajaha et al 2017)
SCZ rather than e.g. affective psychosis
-ve symptoms
younger age of onset
longer DUP
How to manage?
Assess reasons for poor response
Wrong diagnosis
Non-adherence (plasma levels)
Fast metaboliser
Comorbidities that need treating
Consider options
Case conference (MDT)
Talk to family/carers
Engage, explore patient's concerns
DON'T
Not treat
Suicide/deterioration risk
Combine antipsychotics
Increases side effects
Doesn't improve symptoms
Evidence
Essock et al 2011
No difference between monotherapy and polypharmacy in change in PANSS score up to 6 months
Effects of switching
Stay on poly -> weight gain
Higher all-cause discontinuation if switched, though
Switch to mono -> weight loss
Increase antipsychotic dose
Unless evidence insufficient drug to target site
Rapid metabolism
smoking
interaction with other drug
genetics
Inadequate absorption
e.g. gastrointestinal problem
Check with blood plasma level
Otherwise increases side effect burden
EPSEs
Metabolic side effects
Sedation
Cognitive impairment
Some FGAs: cardiac arrhythmia
Requires monitoring
Could explain evidence of higher mortality in elderly/dementia patients - pre-existing cardiac risk
Doesn't improve response
Kinon et al. 2008
Lack of dose-response relationship
NICE guidelines
Then offer clozapine
Offer non-clozapine SGA
But not being met
SLAM records 2006-2010 (Howes et al 2012)
got clozapine average 47.7 months after eligible for it
Polypharmacy had been tried in 36%
High dose tried in 34%
Why?
More monitoring burden with clozapine
Clinicians worried about clozapine side effects (myth)
Clozapine
Evidence for efficacy
Lower motality
Tihonen et al. 2009, 2016
Risk of death lower for all causes and suicide
Greater clinical improvement than FGAs and SGAs in treatment resistance
Cochrane review (Wahlbeck et al 2000)
Siskind et al. (2016) systematic review/meta-analysis of trials comparing clozapine to other antipsychotics
Clozapine better
Positive symptoms
Total and negative symptoms in the short term
If higher baseline psychosis
Responsiveness rate
Lower doses needed
Clozapine worse
Side effects like tachycardia, seizures, fever, dizziness
No difference
Weight gain, hypotension, headache
Issue for trials
Side effects of clozapine mean hard to blind
Dosing
Different for men, women, smokers
Cautious titration
Monitor blood pressure and pulse in case of postural hypotension
Plasma testing
Trough of 350 ng/mL = adequate trial
Clozapine:norclozapine (metabolite) ratio
Shows adherence
< 0.5 = poor compliance in preceding day(s)
Adverse effects
Orthostatic hypotension
Especially when starting
Weight gain/lipids/glucose metabolism
One of the worst antipsychotics for this
Sedation
Can impair functioning
Nausea/constipation/headache
Dry mouth/increased salivation
Meds can help
Blurred vision
Increased heart rate, sweating
Some of these impact self-confidence, e.g. weight gain, swealing, drooling
Agranulocytosis (1%)
Immune system compromised
Monitored via blood tests
Seizures (2-3%)
If high plasma levels
Monitor via blood tests
If high, drop dose and give anti-epileptic medication
Myocarditis/cardiomyopathy
Do cardiology reviews/ECHO cardiograms if thought a risk
Less likely to cause EPSEs, though
Response time
May be a delay in response (Meltzer 1992)
3 months: 20%
6 months: 10-20%
6 weeks: 30%
Trial is attempted for 6 months
Future treatments
Glycine site modulators
Mechanism: increase activity in NMDA glutamate receptors
Evidence
Meta-analysis for D-serine
Issues?
Negative phase III studies
Metabotropic 2/3 glutamate receptor agnoists
Mechanism: reduce presynaptic glutamate
Evidence?
Preclinical rationale
Issues?
Negative phase III studies
Anti-inflammatory/antibiotic glutamatergic agents
Mechanism: reduces inflammatory cytokines
Evidence
Meta-analysis for minocycline
Issues?
Small studies
Rationale for glutamatergic meds
Different underlying neurobiology in treatment resistant people?
Cannabidiol
CBD blocks induction of psychotic symptoms by THC
(Englund et al, 2012)
McGuire et al 2018: early evidence reduces psychotic symptoms in SCZ
Benefits
Young people interested in trying it
Few side effects