Antipsychotics

Question 1

Antipsychotics are used to treat _____

Answer 1

psychosis, mania, bipolar depression, and treatment resistant unipolar depression

Question 2

DSM-V Schizophrenia and Other Psychotic Disorders

Answer 2

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

Question 3

Positive symptoms of schizophrenia

Answer 3

Hallucinations, delusions, formal thought disorders, bizarre/disorganized behavior.
Antipsychotics very effective in tx here

Question 4

Negative symptoms of schizophrenia

Answer 4

Decreased eye contact, decline in grooming/hygiene, flat/blunted affect, poverty of speech, thought blocking, social withdrawal, avolition

Question 5

Mesolimbic pathway (DA)

Answer 5

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.

Question 6

Mesocortical pathway (DA)

Answer 6

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.

Question 7

Tuberoinfundibular Pathway

Answer 7

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.

Question 8

Nigrostriatal Pathway

Answer 8

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.

Question 9

Dopamine theory of schizophrenia

Answer 9

psychosis is linked to hyperactivity of dopamine transmission, particularly in the mesocortical tracks and mesolimbic pathway, which is associated with positive symptoms (hallucinations, delusions)

Question 10

Nicotine in schizophrenia

Answer 10

Nicotine may improve cognitive appearance, parkinsonism, and decrease positive symptoms (tobacco inducer of CYP 450 enzyme 1A2)

Question 11

Delusions

Answer 11

false, fixed beliefs (persecutory, referential, grandiose, erotomanic, nihilistic, and somatic)

Question 12

Drug induced Parkinsonism (DIP)

Answer 12

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

Question 13

Typical antipsychotics

Answer 13

“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)

Question 14

Atypical antipsychotics

Answer 14

“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

Question 15

Antipsychotic side effects

Answer 15

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

Question 16

Drug-induced acute dystonia

Answer 16

Involuntary contraction of the muscles in the face, neck, trunk, pelvis, extremities, or eyes.
Treatment: IM anticholinergic injection (effective within 20 min)

Question 17

Akathisia

Answer 17

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

Question 18

Neuroleptic malignant syndrome

Answer 18

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.

Question 19

Tardive dyskinesia (Tardive syndromes)

Answer 19

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]

Question 20

Serotonin hypothesis of Schizophrenia

Answer 20

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.

Question 21

Clozapine

Answer 21

A highly effective antipsychotic for treatment-resistant schizophrenia but carries a risk of agranulocytosis (dangerously low white blood cell count), requiring regular blood monitoring.

Question 22

Chronic levodopa administration outcome in PD

Answer 22

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.”

Question 23

Anticholinergic burden symptoms

Answer 23

Constipation, blurred vision, cognitive dysfunction, dry mouth, drowsiness.

Question 24

Reciprocal relationship of dopamine and acetylcholine

Answer 24

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

Question 25

5HT/DA Blockers (Antipsychotics) in treatment of Bipolar disorder

Answer 25

Olanzapine/Fluoxetine (Symbyax), Quetiapine (Seroquel), Lurasidone (Latuda), Cariprazine (Vraylar)