Antipsychotics Flashcards
What are some indications of antipsychotics?
- Recurrent suicidal behavior
- Hallucinations/Delusions associated with Parkinson Disease psychosis
What is the dopamine hypothesis?
- Chlorpromazine serendipitously found to have antipsychotic activity
- Direct/indirect DA-agonists provoke psychotic reactions in non-schizophrenics and exacerbate symptoms in schizophrenics
- PET studies have revealed alterations in DA-mediated transmission in schizphrenics
What are positive symptoms of schizophrenia?
- Hallucinations
- Delusions
- Disorganized speech/thinking
- Agitation
- Abnormal motor behavior
What is the anatomy of the mesolimbic pathway in schizophrenia?
- Projections from the ventral tegmental area to the nucleus accumbens
What is the physiology of the mesolimbic pathway schizophrenia?
- Motivation
- Emotions
- Reward
- Positive symptoms of schizophrenia
What is the anatomy of the mesocortical pathway in schizophrenia?
- Projections from the ventral tegmental area to the cortex
What is the physiology of the mesocortical pathway in schizophrenia?
- Cognition and executive functions
- Emotions and affect
What are the implications of the mesolimbic pathway in schizophrenia?
- D2 antagonists reduce positive symptoms of schizophrenia
What are the implications of the mesocortical pathway in schizophrenia?
- Hypofunction of the mesocortical pathway might be related to cognitive and negative symptoms in schizophrenia
What are the negative symptoms of schizophrenia?
- Apathy
- Avolition
- Alogia
- Cognitive deficits
- Social withdrawal
What is the anatomy of the nigrostriatal pathway and EPS?
- Projections from substantia nigra to striatum
What is the physiology of the nigrostriatal pathway and EPS?
- Stimulation of purposeful movement
What are the implications of the nigrostriatal pathway and EPS?
- D2 antagonism induces extrapyramidal symptoms (pseudoparkinsonism)
What is the anatomy of the tuberoinfundibular pathway and prolactin release?
- Hypothalamus to infundibular region
What is the physiology of the tuberoinfundibular pathway and prolactin release?
- Dopamine is released into the portal circulation connecting the median eminence with the anterior pituitary gland
- Dopamine tonically inhibits prolactin release
What are some implications of the tuberoinfundibular pathway and prolactin release?
- D2 antagonism increases prolactin levels
What are the four dopaminergic pathways?
- Mesolimbic pathway
- Mesocortical pathway
- Nigrostriatal pathway
- Tuberoinfundibular pathway
What is the schizophrenia hypotheses?
- Limits to dopamine hypothesis
1. Does not account for all cognitive deficits/negative symptoms associated with schizophrenia
2. Does not fully explain role of other neurotransmitters or other receptors
- What is the glutamate disorder hypothesis?
- NMDA receptor antagonists can manifest select aspects of schizophrenia
- Agents that modulate glycine modulatory site NMDA/AMPA receptor reduce some cognitive symptoms of schizophrenia
- Cognitive symptoms may be due to low activity of NMDA/AMPA receptor on GABA inhibitor interneurons in prefrontal cortex
What is the early-life neurodevelopmental disorder hypothesis?
- Youth/adolescence genetic/environmental impact during pivotal neurodevelopmental stages leads to later-life symptoms and presentation of worsening impacts
What do the therapeutic choices start with when treating psychotic disorders?
- Previous dosing history
- Tolerance to known side effects
What is the minimum therapy necessary in order to evaluate response to therapy?
- 2-3 weeks
- Max benefit may take several months
What is the best for rapid response in treating psychotic disorders?
- Injectable versions
- Acute high doses are not universally beneficial
When is favorable prognosis seen in treating psychotic disorders?
- Shorter duration and less severe symptoms of disease prior to diagnosis/treatment]
- Strong, positive pre-illness functionality
What is the MOA of first generation antipsychotics (FGAs)?
- Primarily block dopamine type-2 post synaptic receptors (D2» 5-HT)
What else does FGAs do?
- Also block one or more other receptors (primarily inducing SE’s)
1. Muscarinic
2. Histaminic
3. Alpha-adrenergic
4. D2 receptors in nigrostriatal and tuberoinfundibular
What are the muscarinic side effects of FGAs?
- Dry mouth
- Constipation
- Urinary retention
- Blurred vision
- Sedation
What are the alpha adrenergic side effects of FGAs?
- Orthostatic hypotension
- Dizziness/syncope
What are the histamine side effects of the FGAs
- Sedation
What are some other side effects of FGAs?
- Rick of QT prolongation and seizure activity
What are some dopamine associated side effects of FGAs?
- Hyperprolactinemia (amenorrhea/galactorrhea/gynecomastia/decreased libido)
- Extrapyramidal symptoms/Tardive dyskinesia
What are some treatments for extrapyramidal symptoms (EPS)?
- Anticholinergic agents (benztropine and trihexyphenidyl)
2. Antihistamine agents (diphenhydramine)
What are some treatment for tardive dyskinesia (TD)?
- Selective vesicular monoamine transporter 2 (VMAT2) inhibitors (valbenazine and deutetrabenazine)
What is the MOA of second generation antipsychotics (SGAs)?
- Not only block dopamine type 2 post synaptic receptors they also block 5HT
- They are stronger 5HT blockers than D2
What are the four broad categories of SGAs?
- 5HT-2A/DA receptor antagonists
- Partial DA/5HT-1A receptor agonists
- Multi-acting receptor target agents
- Inverse serotonin agonist/antagonist
What are some 5HT-2A/DA receptor antagonist drugs?
- Iloperidone
- Lurasidone
- Paliperidone
- Risperidone
- Ziprasidone
What are some partial DA/5HT-1A receptor agonist drugs?
- Aripiprazole
- Brexpiprazole
What are some multi acting receptor target agents?
- Asenapine
- Clozapine
- Olanzapine
- Quetiapine
- Lumateperone
What are some inverse serotonin agonist/antagonists?
- Primavanserion
What are some side effects of SGAs?
- Weight gain
- Metabolic effects
- QT prolongation/ECG changes
- Stroke
What is monitored during antipsychotic treatment?
- Serum glucose
- Lipids
- Weight
- BP
- Waist circumference and personal/family histories of metabolic and CV disease (if possible)
What are some ways to monitor antipsychotics?
- GASS
- AIMS
- BARS
- SAS
What are some rare side effects of SGAs?
- Agranulocytosis (clozapine)
- Drug reaction with eosinophilia and systemic symptoms (DRESS) (olanzapine)
- Neuroleptic Malignant Syndrome (NMS)
What is the treatment of Neuroleptic Malignant Syndrome?
- Dantrolene (malignant hyperthermia)
What may be needed after dose escalation or when switching agents?
- Combination of antipsychotic therapy may be necessary clinically
What is the best for acute agitation?
- Injectable and ODT or SL versions
What is the best treatment of multi-drug resistant disease of psychotic diseases?
- Clozapine
What is critical in treatment of psychotic disorders?
- Adherence
How can non-adherence be managed?
- Long acting injectable agents (LAIAs)
What are some LAIAs?
- Haloperidol
- Fluphenazine
- Risperidone
- Olanzapine
- Aripiprazole
