Antipsychotics Flashcards
Antipsychotics are used to treat _____
psychosis, mania, bipolar depression, and treatment resistant unipolar depression
DSM-V Schizophrenia and Other Psychotic Disorders
Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated):
-delusions*
-hallucinations*
-disorganized speech*
-grossly disorganized or catatonic behavior
-negative symptoms
* = at least one of the symptoms must be one of these
Symptoms must have been present at least part of the time in the last 6 months
Positive symptoms of schizophrenia
Hallucinations, delusions, formal thought disorders, bizarre/disorganized behavior.
Antipsychotics very effective in tx here
Negative symptoms of schizophrenia
Decreased eye contact, decline in grooming/hygiene, flat/blunted affect, poverty of speech, thought blocking, social withdrawal, avolition
Mesolimbic pathway (DA)
VTA -> nucleus accumbens. Hyperactive D2 from ventral tegmental area to nucleus accumbens is associated with positive symptoms of schizophrenia. Apathy and anhedonia are secondary negative symptoms of D2 antagonism.
Mesocortical pathway (DA)
VTA -> DLPFC & VMPFC. Regulates cognition and emotion. Increasing dopamine activity here can reduce negative symptoms and improve cognitive function. Hypoactivity in the DLPFC and VMPFC may be linked to negative symptoms (anhedonia, social withdrawal); hypoactivity in the DLPFC linked to cognitive symptoms; hypoactivity in the VMPFC linked to affective symptoms. D2 antagonist or partial agonist would worsen these symptoms.
Tuberoinfundibular Pathway
hypothalamus -> pituitary gland. Controls prolactin secretion. D2 antagonism here can cause hyperprolactinemia (associated with: gynecomastia, galactorrhea, and amenorrhea), but serotonin antagonism can help modulate this effect.
Nigrostriatal Pathway
substantia nigra -> dorsal striatum. Theoretically unaffected in untreated schizophrenia. Controls motor function. D2 antagonism in this pathway leads to extrapyramidal symptoms (EPS) or drug induced Parkinsonism (DIP), but 5-HT2A antagonism can reduce this risk by increasing dopamine release in the nigrostriatal tract.
Dopamine theory of schizophrenia
psychosis is linked to hyperactivity of dopamine transmission, particularly in the mesocortical tracks and mesolimbic pathway, which is associated with positive symptoms (hallucinations, delusions)
Nicotine in schizophrenia
Nicotine may improve cognitive appearance, parkinsonism, and decrease positive symptoms (tobacco inducer of CYP 450 enzyme 1A2)
Delusions
false, fixed beliefs (persecutory, referential, grandiose, erotomanic, nihilistic, and somatic)
Drug induced Parkinsonism (DIP)
Blockade of D2 receptors prevents DA from binding here → motor effects (drug induced Parkinsonism). Symptoms = tremor, muscle rigidity, slowing or loss of movement, akathesia, dystonia.
Treatment: anticholinergics
Typical antipsychotics
“First generation” antipsychotics. D2 antagonists. Reduces positive symptoms. Potential for acute & chronic extrapyramidal symptoms. Potential for worsened negative symptoms. Still used in patients that do not respond to newer drugs for psychosis and in patients requiring injections. Antagonism in the tuberoinfundibular pathway can cause hyperprolactinemia, leading to sexual dysfunction, galactorrhea, and gynecomastia
Drugs: Chlorpromazine (Thorazine), Fluphenazine (Modecate), Haloperidol (Haldol), Perphenazine (Trilafon), Thioridazine (Mellaril)
Atypical antipsychotics
“Second-generation”. 5HT2A antagonists/D2 antagonists with higher affinity for 5HT2A receptors. Treats both positive and negative symptoms of schizophrenia. Reduced risk of extrapyramidal symptoms and hyperprolactinemia. Increased risk of metabolic side effects (cardiovascular disease and weight gain).
Drugs: Clozapine (Clozaril), Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel), Aripiprazole (Abilify), Ziprasidone (Geodon), Lurasidone (Latuda)
[Clozapine is now THIRD LINE due to its adverse effect of agranulocytosis (reduced neutrophils to severely low level); Ziprasidone and lurasidone are favored because they’re seen as “weight neutral”]
Currently used to treat: schizophrenia, PD psychosis, dementia-related psychosis, negative symptoms of psychosis, motor side effects, and hyper-prolactinemia
Antipsychotic side effects
Blockade of muscarinic cholinergic receptors is associated with: Dry mouth, blurred vision, risk of paralytic ileus; CAN’T SEE CAN’T PEE side effects
Blocking H1 histamine receptors is associated with: Weight gain, sedation
Blocking Alpha1 adrenergic receptors is associated with: Sedation, cardiovascular side effects (orthostatic hypotension)
Many D2 antagonists have ALL of the above actions
Drug-induced acute dystonia
Involuntary contraction of the muscles in the face, neck, trunk, pelvis, extremities, or eyes.
Treatment: IM anticholinergic injection (effective within 20 min)
Akathisia
subjective (mental unease, dysphoria) and objective (rocking from foot to foot, marching in place, pacing) feelings of restlessness
Treatment: beta-blockers, benzodiazepines, or serotonin 2A antagonists
Neuroleptic malignant syndrome
Extreme muscle rigidity, high fevers, coma, and possible death. Medical emergency requiring muscle relaxers (e.g., dantrolene and dopamine agonists) and intensive support medical treatment.
Tardive dyskinesia (Tardive syndromes)
Chronic blockade of D2 receptors in the nigrostriatal dopamine pathway. Acute dystonia, akathisia, or medication-induced Parkinsonism
Assess with: Abnormal Involuntary Movement Scale (AIMS) at baseline & every 6-12 months OR with onset/exacerbation of abnormal movements
Treatment: vesicular monoamine transporter 2 (VMAT2):: Deutetrabenazine, valbenazine, tetrabenazine [Deutetrabenazine and Valbenazine preferred over Tetrabenazine (shorter half life and greater rates of depression); Valbenazine use if severe renal impairment]
Serotonin hypothesis of Schizophrenia
Clinical trials show that adding selective 5HT2A antagonists to drugs with D2
antagonism/partial agonism may improve positive symptoms of psychosis in schizophrenia. Also, there is some indication that the more potent a 5HT2A/D2 antagonist is for 5HT2A receptors compared to potency for D2 receptors, the lower
the degree of D2 antagonism that may be necessary to treat positive symptoms, and also the better tolerated the drug might be.
Clozapine
A highly effective antipsychotic for treatment-resistant schizophrenia but carries a risk of agranulocytosis (dangerously low white blood cell count), requiring regular blood monitoring.
Chronic levodopa administration outcome in PD
chronic levodopa administration in Parkinson’s disease can lead to levodopa-induced dyskinesias that look very similar to tardive dyskinesia, and may share a similar pathophysiology of aberrant striatal plasticity and abnormal neuronal “learning.”
Anticholinergic burden symptoms
Constipation, blurred vision, cognitive dysfunction, dry mouth, drowsiness.
Reciprocal relationship of dopamine and acetylcholine
Dopamine and acetylcholine have a reciprocal relationship in the nigrostriatal dopamine pathway. Dopamine neurons here make postsynaptic connections with the dendrite of a cholinergic neuron. Normally, dopamine binding at D2 receptors suppresses acetylcholine activity
