SZ- Antipsychotics Flashcards
Antipsychotic Medication
1st generation antipsychotics – typical
2nd generation antipsychotics – atypical
3rd generation antipsychotics – partial agonists
Novel targets for cognition
Dopamine receptors
Two main families of dopamine receptor: D1- and D2-like
Regions of the brain usually have opposing densities of each subtype
The D1-like receptor family contains the D1 and D5 receptor subtypes
Dopamine D1-like receptors are coupled to stimulatory G-proteins and they have a stimulatory effect on neurotransmission when bound by an agonist
D2-like family contains the D2, D3 and D4 subtypes
The D2-like receptors are coupled to inhibitory G-proteins, and have an inhibitory effect on NT when bound by an agonist
D2 receptors can be seen as pre-synaptic auto-receptors, reducing release when high DA in synapse
D1 and D2 receptors are much more prevalent than D3/4/5
What are the 4 major dopamine pathways in the brain?
Mesolimbic pathway
Mesocortical pathway
Nigrostriatal pathway
Tubero-infundibular pathway
Typical antipsychotics (neuroleptics)
E.g. Haloperidol, chlorpromazine
High affinity for dopamine D2 receptors (antagonists)
Effective against the positive symptoms
Ineffective against the negative symptoms and cognitive deficits
Typicals (more than atypicals) cause motor control impairments, due to their increased blockade of dopamine D2 receptors
Dopaminergic adverse effects with typicals
The nigrostriatal pathway projects from the substantia nigra to the striatum, contains 80% of the brain’s dopamine, and controls movement
Parkinson’s disease is due to a lack of dopamine in this pathway
Blocking D2 receptors can cause Parkinson-like or extra-pyramidal symptoms (EPS) and tardive dyskinesia (TD)
Other adverse effects of typicals
Worsen negative and cognitive symptoms – due to blocking D2 in mesocortical pathway
Galactorrhoea caused by increased levels of prolactin – due to blocking D2 receptors in tubero-infundibular pathway
Also cause side effects not related to D2 blockade
Receptor action (non-DA) & their side effects
- Blocking H1 receptors- Drowsiness and can cause weight gain
- Blocking alpha-1 receptors- CV side effects e.g. dizziness, hypotension
- Blocking muscarinic receptors- Dry mouth, blurred vision, constipation, cognitive deficits
Atypical antipsychotics (2nd generation)
e.g. Clozapine, risperidone, olanzapine
Higher affinity for serotonin 5-HT2 receptors than dopamine D2 receptors
“Rich” pharmacology
Effective against the positive symptoms
Some efficacy against the negative symptoms and cognitive deficits
Less likely to cause EPS side effects
Adverse effects of atypicals
- Weight gain & metabolic syndrome caused by 5-HT2c blockade- affects compliance
- CV & obesity related conditions e.g. diabetes and hypertension
- Agranulocytosis with clozapine- check blood every 2 weeks
Risk of weight gain:
Hight risk: Clozapine, Olanzapine
Moderate risk: Risperidone, Quetiapine
Minimal risk: Ziprasidone, Ariprazole
Explain the pharmacology of typicals vs atypicals
All antipsychotics have affinity for D2 receptors
Atypicals are usually 5HT2A antagonists but usually have affinity at many other receptors
What is the hit & run hypothesis (with regards to adverse effects)
Older medicine e.g. Haloperidol bind tightly to the Dopamine D2 receptors in cell membrane and thus create their antipsychotic activity but risk adverse EPS. Once done they slowly come off and unbind from the membrane.
New atypical antipsychotic e.g. Quetiopine loosely bind to the cell membrane, then create their antipsychotic activity without adverse EPS. But the main difference being that they come off fast, allowing them to unbind from the membrane quickly.
Nigrostriatal pathway with atypicals
Seratonin (5HT) normally inhibit DA release via action at the 5HT2A receptor
Atypicals block pre-synaptic 5HT2A receptors causing more DA to be released
DA can then compete with the antagonist for the D2 receptor causing less EPS side effects
What are the advantages & disadvantages of Typical (Classical) antipsychotics- that have high-affinity D2 antagonists.
Advantages- Reduces and prevents recurrence of psychotic symptoms.
Disadvantages- Limited efficacy against negative and cognitive symptoms. High rates of extra-pyramidal (EPS) symptoms and tardive dyskinesia (TD).
What are the advantages & disadvantages of Atypical antipsychotics- that have mixed neuroreceptor antagonists; low affinity D2, high affinity 5HT2A.
Advantages- Reduces and prevents psychotic symptoms; broader efficacy against negative and cognitive symptoms(?); may prevent illness progression. Less EPS and TD.
Disadvantages- Various side effects including blood problems, weight gain, increased glucose, and triglycerides; more expensive. Actual benefits??
What are the advantages & disadvantages of Atypical antipsychotics- that have mixed neuroreceptor antagonists; low affinity D2, high affinity 5HT2A.
Advantages- Reduces and prevents psychotic symptoms; broader efficacy against negative and cognitive symptoms(?); may prevent illness progression. Less EPS and TD.
Disadvantages- Various side effects including blood problems, weight gain, increased glucose, and triglycerides; more expensive. Actual benefits??
What are Third generation antipsychotics?
Aripiprazole (2002) - first effective D2 partial agonist
Cariprazine (2015) – D2 and D3 partial agonist
No EPS even at 80% D2 occupancy
Stabilises the dopamine system
No increase in plasma prolactin
Cognition of third generation antipsychotics?
Schizophrenia patients perform on average 1.5 to 2.5 standard deviations below unaffected populations
Impairment appears before the onset of psychosis and carries on throughout a patients life
Previous studies have shown cognitive benefits of 2nd generation antipsychotics
BUT:
1. the effect size was not large
2. the sample size used was very small
3. a number of trials had higher doses of atypicals causing a result bias
Executive function:
- Working memory
- Cognitive flexibility
- Inhibitory control
Important for:
- Attention
- Organising and planning
- Initiating tasks and maintaining focus
- Regulating emotions
- Self monitoring
Treating the unmet clinical need - cognition
- Clinical Antipsychotic Trials of Intervention Effectiveness
[CATIE Study] - Cognitive Effects of Antipsychotic Drugs in First-Episode Schizophrenia and Schizophreniform Disorder: A Randomized, Open-Label Clinical Trial.
- NIMH –MATRICS Consensus Statement on Negative Symptoms
“no drug has received Food and Drug Administration (FDA) approval for an indication of negative symptoms, and available data indicate that second-generation antipsychotic medications have not met early hopes for a highly effective treatment for alleviation of negative symptoms”.
- NYAS 2011—New Molecular Targets for Schizophrenia
There would be no “magic bullet” that would treat all three symptom domains of schizophrenia.
Instead, he proposed that research should find adjunctive therapies to treat negative and cognitive symptoms, which likely stem from problems different from those underlying positive symptoms.
Because antipsychotics already treat positive symptoms with some success, the challenge will be to find adjunctive therapies that won’t undermine the benefits of other drugs.
Cognitive domains- MATRICS
Check slide 20 part 2 of SZ for table that includes the Cognitive domains, their tests (/animal models) and their MATRICS clinical batter.
Cognition- Glutamate/ GABA
Hypofunction of NMDA receptors on GABA neurons, directly disrupts the synchronization of neural circuits in the γ frequency range by altering inhibitory control of pyramidal cell networks
γ synchronization may also be indirectly disrupted by excitotoxic injury to pyramidal cells as a result of reduced inhibition and the ensuing dendritic shrinkage and synaptic attrition
Axon initial segment (AIS) of the pyramidal neurons are occupied by α2/α3 subunit containing GABAA receptors
Schizophrenia patients have low GABAergic signalling at the pyramidal neuron (reduced oscillatory regulation)
Could α2/α3 subunit selective compounds facilitate such signalling by binding to the GABAA receptor at the AIS of pyramidal neurons, resulting in improvement of cognition?
Check slide 23 for further reading
What is Lurasidone?
FDA approved for schizophrenia in 2010 and for depression in 2013
Potent antagonist at D2 and 5-HT2A receptors
Antagonist at 5-HT7 receptors and partial agonist at 5-HT1A receptors, these are likely to affect cognition and mood
Note that prescriptions for Lurasidone have been growing steadily over the last few years
Nicotinic targets
Nicotinic acetylcholine receptors (nAChRs) consist of 5 subunits which form an ion channel
Expression of α7 and α4β2 nAChRs is reduced in patients with schizophrenia and these subtypes are important for cognition
Thought to act by increasing dopamine in the PFC
Examples: GTS-21 (α7 agonist) and TC-1827 (α4β2 agonist)
mGluR targets
Metabotropic receptor targeting provides a way for modulating glutamate tone
Activation of Group II mGluRs is a mechanistically novel and promising approach (Muguruza et al., 2016)
