Term 2 Pharm - Anti-Psychotics Flashcards
Psychotic Disorders
Schizophrenia Schizoaffective, Schizophreniform, Delusional Disorder Bipolar Disorder with Psychosis Major Depression with Psychosis Other – e.g., substance induced, etc.
Domains of Schizophrenia (4)
Positive Symptoms
Negative Symptoms
Disorganization
Cognitive Function
Suicide and Schizophrenia
Suicide attempts = 20 – 40% of schizophrenic population
Rate of suicide = 10% (20 – 50 times general population)
Relationship of Schizophrenia to substance abuse
Lifetime prevalence - 47% of Patients have Any Comorbid Substance Use Disorder in Lifetime
Substance abuse makes this disorder worse but helps reward system so makes ppl feel better although making disease worse
What type of problems does Schizophrenia cause
Schizophrenia is a multiple system disorder ppl die 28.5 years earlier than everyone else (a lot tied with cardiovascular problems)
Current Models of Schizophrenia
2 implications for treatment:
- Neurodevelopmental
- Neurodegenerative
Neurodevelopmental - an abnormality of some sort occurs early in life (maybe in utero on temporal lobes silent effects until puberty… negative symptoms are primary & psychosis is secondary)
Neurodegenerative – possible glutamate abnormalities? Possible explanation for life shortening? Do anti-psychotics have life shortening effects
Neurodevelopmental Model
- Early abnormality (primarily temporal?)
- Development of hypofrontality
- Subsequent mesolimbic hyperactivity
Mesocorticolimbic Dopamine System
(see slide 10)
Neurodegenerative Model (Causes of psychosis)
- PCP (phencyclidine) and psychosis
- NMDA antagonists produce positive and negative symptoms and cognitive deficits
- Glutamatergic dysregulation leads to apoptosis?
What do All Treatments for Psychotic Disorders do?
They ALL block D2 receptor (Dopamine)
Typical antipsychotics
- Chlorpromazine
- Haloperidol Fluphenazine
- Thioridazine
- Loxapine
- Perphenazine
Atypical (novel) antipsychotics
- Clozapine*
- Risperidone
- Olanzapine*
- Quetiapine
- Ziprasidone
- Aripiprazole*
- Paliperidone
- Iloperidone
- Asenapine
- Lurasidone
- Brexpiprazole
Development of Typical Antipsychotics
- Chlorpromazine discovered by serendipity
- Other typical antipsychotics discovered based on effects on movement in animal models
- Importance of blockade of DA D2 receptors recognized later – 2000 Nobel Prize to Arvid Carlsson
- ALL “first-generation” antipsychotics cause extrapyramidal symptoms (EPS)
- high potency results in HIGH EPS
(Blocking dopamine receptors can result in rigidity/tremor)
Typical Antipsychotics (Neuroleptics)
Chlorpromazine (Thorazine)——– low potency
Perphenazine (Trilafon) ———–mid range
Haloperidol (Haldol) —————high potency
Fluphenazine (Prolixin) ———–high potency
(low potency drugs) Have Anti-cholinergic effects Less parkinsons/rigidity symptoms
High potency drugs do not have anti-Ach so it comes with more parkinsons/rigidity symptoms
Dopamine Hypothesis of Schizophrenia
Hypoactivity (Mesocortical pathway) = negative symptoms
Hyperactivity (mesolimbic pathway) = positive symptoms
ALL drugs inhibit prolactin (Tuberoinfundibular pathway)
Effect of Typical Antipsychotics
Days – calm behavior, improve sleep, decrease confusion.
Days – weeks – decrease psychotic symptoms
Weeks – months – improve insight?
Negative symptom improvement minimal
Cognitive improvement usually minimal
Disability may remain
Huge problem with SCZ is problems with insight
Side Effects of Typical Antipsychotics
Low potency
- Dry mouth, blurred vision, constipation, urinary retention, hypotension, sedation, weight gain
- Less acute dystonia, NMS
- Parkinsonism, akathesia, tardive dyskinesia
- Prolactin elevation
High potency
- More acute dystonia, NMS
- Parkinsonism, akathesia, tardive dyskinesia
- Prolactin elevation
Akathesia = restlessness, busy body Tardive dyskinesia (from blockage of D2 receptor, increase activity of DA Treat dystonia with an anticholinergic
Diagnosis of Neuroleptic Malignant Syndrome
Minor Manifestations
- Tachycardia
- Abnormal blood pressure
- Tachypnea
- Altered consciousness
- Diaphoresis
Major Manifestations
- Fever
- Rigidity
- Elevated CPK level
Diagnosed when: three major OR two major and four minor
Typical Outcomes of Antipsychotics
- Limited clinical efficacy
- Relapses common
- Cognitive deficits continue
- Substance use common
- Neurological side effects
Novel (atypical) antipsychotic drugs
- clozapine*
- risperidone (and risperidone long-acting)
- olanzapine* (and olanzapine pamoate)
- quetiapine
- ziprasidone
- aripiprazole* (and aripiprazole long-acting)
- paliperidone (and paliperidone palmitate)
- iloperidone
- asenapine
- lurasidone
- brexpiprazole
- Less EPS
- Less prolactin elevation (except risperidone, paliperidone)
- Releases dopamine in prefrontal cortex
- Weight gain (MOSTLY in Clozapine)
Novel Antipsychotics Potential Benefits
Improved efficacy?
Fewer relapses?
Fewer neurological side effects
Useful in affective psychosis
Role in suicidal patients – clozapine data
Role in comorbid substance use – clozapine data
Clozapine*
An Atypical Antipsychotic Drug
- Introduced over 30 years ago (chemical relative of loxapine), and seen to be effective.
- Caused agranulocytosis (decrease in WBCs, can use, but monitor the WBC count)
- Withdrawn from the market in mid-1970’s.
- Relative safety/efficacy demonstrated in 1988.
- Re-introduced as treatment for treatment for resistant schizophrenia in 1989.
Dramatically effective for positive and some negative symptoms.
Minimal EPS effects.
Minimal prolactin elevation.
Weak DA D2 receptor antagonism; potent antagonism at 5HT2 and NE α2 receptors
Clozapine Side Effects
Agranulocytosis Seizures Myocarditis Weight gain, glucose and lipid dysregulation Tachycardia, hypotension Drooling Sedation Liver function changes
Clozapine vs. olanzapine
Response of Suicidality
Clozapine vs. olanzapine: decreased time to hospitalization to prevent suicide or to a suicide attempt
