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Pharmacological treatment of psychosis - Coggle Diagram
Pharmacological treatment of psychosis
Main dopaminergic pathways
Mesolimbic
Mid-brain DA neurons in VTA project to striatum (basal ganglia)
Prediction error (surprise)
Increased presynaptic DA -> worsening positive symptoms
Risk factors seem to increase this, e.g. childhood adversity
Howes et al. (2012) Robust effect - higher presynaptic DA in people with SCZ vs controls
Antipsychotics aim at blocking this
Mesocortical
Different mid-brain DA neurons project to different areas of PFC
Some evidence (but not much) that reduced levels of DA here is lined to negative and cognitive symptoms
Or possibly imbalance in excitatory and inhibitory signalling in PF areas -> negative and cognitive symptoms
Side effects of antipsychotics: relatively few D2 receptors, but agonists could make negative and cognitive symptoms worse
Nigrostriatal
Substantial nigra pars compacta projects to parts of the striatum
Antipsychotics blocking this may -> adverse motor effects
Extrapyramidal side effects
Dystonia
Muscle stiffness
Rigidity
Spasms
Parkinson symptoms
Shuffling gait
Tremor
Rigidity
Akathisa
Restlessness
Agitation
Compulsion to move
Tardive dyskinesia
Mostly from 1st gen
Involuntary orofacial movements
Tuberoinfundibular
Hypothalamus -> anterior pituitary
DA inhibits release of prolactin
Blocking with medication -> increased prolactin (hyperlactinaemia)
-> side effects e.g. SD in men
Check prolactin at baseline and after meds
Highest concentration of D2 receptors in striatum and anterior pituitary
PFC has high concentrations of non-D2 DA receptor types
Receptor types
D1
Effect of binding is usually excitatory
D2
Positive symptoms mostly linked to these
In all 3 subdivisions of striatum
Effect of binding is usually inhibitory
Pharmacological basis of treatment response
Agid et al (2007):
Striatal D2 receptor occupancy predicted response of positive symptoms
Increased occupancy -> improved positive symptoms
Onset of side effects
Narrow treatment window
Kapur et al 2000: double-blind of 2 doses of haloperidol in FE SCZ
Need to titrate up, as dose for high occupancy/no side effects is different for every individual
Slow metabolisers
Younger, lower BMI, antipsychotic naive
Rapid metabolisers
high smokers (hydrocarbons induce enzymes that break down antipsychotics
At 78% occupancy, extrapyramidal side effects
Improved global impression score (CGI) with D2 occupancy increase
Kapur & Seeman (2001)
First gen vs second gen
1st gen
D2 antagonists
But also
Muscarinic cholinergic M1 antagonists (-> dry month, constipation, cognitive problems)
histamine H1 antagonists (-> sedation, , weight gain)
Alpha 1 adrenergic antagonists (-> sedation)
See Stahl notes for weaknesses
2nd gen
Most have affinity for seratonic 5HT2A receptor
SA usually reduces DA release in the striatum - blocking it and competing with D2 receptor agonist -> less binding -> less EPS
SA promotes prolactin release, so inhibiting its receptors mitigates hyperprolactinemia (Stahl)
More importantly, low affinity for D2 receptor
Means can unblind when natural physiological surge of DA
Clozapine is one of those with lowest affinity
So opens up therapeutic window (details in Stahl)
Sounds great, but difficult to find balance between agonism and antagonism (Stahl)
e.g.s
Quetiapine
Antidepressant properties depending on dose
Aripiprazole
D2 partial agonist
Stops excess DA getting full response
Weight gain and sedation less likely than with e.g. quetiapine, clozapine
Did their introduction -> increased cardiovascular mortality in SCZ patients 1991-1995? (Tilhonen et al. 2009)
National register study, Finland
Mortality gap vs general population comes from death at young age
Long-term treatment leads to lower mortality than patients not using them
Varies a lot among SGAs - clozapine
reduces
mortality
Maybe due to monitoring -> higher treatment compliance
Study design does have limitations
Evidence base
Different drugs have similar effectiveness on positive symptoms
(Kahn et al 2008)
More people stopped Haloperidol vs 2nd generation
Leucht et al 2012 meta-analysis - replicates in many studies
Except clozapine - better than some others
So should weigh up potential benefits and adverse effects of each treatment
Little response of negative symptoms to antipsychotics
Negative symptoms could be coincidentally comorbid or due to e.g. medication
Negative symptoms might be secondary to positive symptoms
But cariprazine shows promise
Partial agonist of D2 and D3 receptors
Also 5HT1A receptors, giving it antidepressant effects
D3 receptor binding could affect negative symptoms
Nemeth et al 2017
Multicentre RCT
Cariprazine reduced negative symptoms more than risperidone (after several months)
Also greater improvement in Personal and Social Performance Scale
Suggests the effect is clinically relevant
Good side effect profile: not too much weight gain, sedation or effects on cariometabolic measure (some transient akathisia)
Commonly a good response in FEP
But this can lead people to discontinue taking meds
Chen et al. 2010 showed stopping meds associated with increased risk of relapse
Replicates (Leucht et al 2012 meta-analysis)
So maintenance treatment benefits patients
It's just because people rebound when they're taken away
Though maintenance treatment doesn't affect functioning (employment)
12-month RCT in Hong Kong
Maintenance quetiapine vs placebo
Relapse risk 41 for Q, 79% for placebo
Limitation: sample were people expected to have a good outcome
1/3 won't respond -> clozapine
Predictors of relapse
Discontinuation of antipsychotics
Use of illicit substances
More recent meta-analysis indicates meds do differ in efficacy
Huhn et al 2019
Highest overall change in symptoms = clozapine
Some antipsychotics have antidepressant properties
Probably due to affecting secondary negative symptoms
In patients with prominent negative symptoms, no clinically significant improvement (Fusar-Poli et al 2015)
Even for 2nd gen drugs
Treatment in prodromal phase?
No firm evidence
Promising early results for cannabidiol
Common adverse effects
Extrapyramidal side effects
Dystonia
Muscle stiffness
Rigidity
Spasms
Parkinson symptoms
Shuffling gait
Tremor
Rigidity
Akathisa
Restlessness
Agitation
Compulsion to move
Tardive dyskinesia
Mostly from 1st gen
Involuntary orofacial movements
Sedation
Metabolic effects
High risk e.g. clozapine
increase appetite
Affect glucose metabolism and lipids
Moderate risk e.g. risperidone
Low risk e.g. aripiprazole
Big push to monitor physical health of mental health patients
Harder to lose weight than gain it
Need to avoid prescribing high risk drugs if the person already has poor cardiometabolic health
Lifestyle factors due to psychosis increase risk
Lack of exercise, smoking
Using antipsychotics is associated with increased CVD incidence (Correll et al 2017)
But treatment reduces all-cause mortality versus no treatment (Tihonen et al. 2009, 2016)
Mechanisms of action
Drugs can be
Partial agonist
Caps response at a certain level
Blocks natural neurotransmitter binding to reduced overall response
"dimmer switch"
Some antipsychotic, e.g. 2nd genaripiprazole
Full agonist
Full response at high enough concentration
Can get above 100% response by blocking reuptake or enzymic degradation
e.g. naturally occurring neurotransmitter
Neutral antagonist
Blocks receptor
Reduction in response
Common in 1st gen e.g. haloperidol
Inverse agonist
Reduces cell's activity below baseline, e.g. antihistamines