Antipsychotic Agents - Filtz

Question 1

Define Psychoses

Answer 1

Mental disorders characterized by rifts in rational thought, inappropriate processing of sensory information, and disturbed views of reality and self. Psychotic symptoms are generally not recognized as such by the sufferer.

Question 2

Define Nueroses

Answer 2

Abnormal reaction to an external state that is generally recognized as abnormal by the sufferer.

Question 3

Psychotic markers, “positive” or overt symptoms

Answer 3

Delusions and/or paranoia, hallucinations (mostly auditory), Disordered thoughts/loose ideation, inappropriate emotional responses

Question 4

Psychoses in disease states

Answer 4

Schizophrenia, delirium in dementia, manic psychoses, secondary to severe depression, post-traumatic stress disorders, drug-induced

Question 5

Drug Induced psychoses

Answer 5

Amphetamine, steroid, LSD, ketamine, PCP, sedative/hypnotics

Question 6

Schizophrenia

Answer 6

Disease with psychotic symptoms affecting 1% of the population (men and women affected equally; there are multiple and varied subtypes)

Age of onset varies from 15-25 years (odd behaviors and other symptoms often precede onset of psychoses)

Clinical presentation and course are highly variable

High mortality (10%) with poor long term prognosis

Question 7

Negative or residual symptoms of schizophrenia

Answer 7

Flat affect; anhedonia and apathy; anxiety; lack of volition; social and emotional withdrawal; disorganized speech, thinking and behavior; impaired attention; poor self-care

Question 8

Etiology of schizophrenia

Answer 8

Neurodevelopmental disorder (cause unknown)

Genetic and environmental factors in causation (twin studies show a genetic predisposition, perinatal insults and traumatic early life events increase susceptibility)

Anatomic irregularities (enlarged cerebral ventricles, reduced cortical mass, hypofrontality)

Question 9

Hypofrontality

Answer 9

Reduced processing in the prefrontal cortex

Question 10

Treatment options for Schizophrenia

Answer 10

Frontal lobotomy (used in 40s and 50s, calmed patients but was permanently debilitating)

Psycotherapy (ineffective by itself)

Cognitive behavioral therapy (improves social skill, life skills and may improve ability to self-assess)

Self medication with nicotine

Antipsychotics

Question 11

Antipsychotic Agents

Answer 11

AKA Neuroleptics or major tranquilizers

Most effective means of treating psychotic symptoms with much less effect on emotional and social problems

Effective in 70% of psychotic patients (reduces frequency and obtrusiveness of hallucinations and delusions; reduces the 12 month relapse rate from 90% without drugs to 40% with drugs; additional affects included improved mood, reduced anxiety and improved sleep)

Not anesthetics but can supplement anesthesia

Do NOT cure schizophrenia and are usually life-long treatments

Question 12

Latency of effectiveness of anti-psychotics

Answer 12

Calming (tranquilizing) effects may be seen within minutes to hours

Diminished psychotic symptoms within 24-28 hours

Full antipsychotic effects evolve over 2-8 weeks

Improvement may continue for up to 6 months (fewer hallucinations, less paranoia and more rational thinking can significantly improve functioning)

Question 13

D2 Antagonism correlation with antipsychotic pharmacology

Answer 13

All antipsychotics are D2 dopamine receptor antagonists or weak partial agonists

Antipsychotic affinity for D2 receptors correlates wtih average clinical dose (an approximation of potency)

Question 14

Dopaminergic Pathways

Answer 14

Mesocortical (VTA to frontal and prefrontal cortex)

Mesolimbic (VTA to nucleus accumbens in limbic area)

Nigrostriatal (Substantia nigra to striatum in the basal ganglia)

Tuberoinfundibular (hypothalamus to pituitary)

Question 15

Dopamine Theory of Psychosis

Answer 15

Psychoses resulting from over-stimulated dopamine receptors in the cortex (reasoning) and limbic (emotional) areas

> drugs that increase dopamine levels (e.g. amphetamine) can induce or exacerbate psychoses
drug that block dopamine release decrease psychoses (reserpine)

Dopamine “hypofrontality” refers to a hypothesized lack of dopamine in the mesocortical pathway

Positive symptoms seem to be a result of dopamine hyperactivity

Question 16

Serotonin signaling in psychosis

Answer 16

LSD is a serotonin partial agonist

Newer antipsychotics have higher affinity for serotonin 5HT2 receptors

Negative symptoms may be associated with dysfunction in the serotonin (and dopamine) systems

Question 17

Glutamate signaling in psychosis

Answer 17

NMDA receptors:

> Glutamate antagonists (Ketamine and PCP) can exacerbate or produce psychoses
Potential new antipsychotics affecting glutamate signaling have not moved beyond Phase 3 clinical trials yet

Question 18

1st Generation Antipsychotics

Answer 18

Phenothiazines and related thioxanthines (Chlorpromazine - the grandparent of all antipsychotics, Thioridaine, Fluphenazine, Thiothixene)

Butyrophenones and related are more D2 selective (Haloperidol, Pimozide)

Question 19

2nd Generation Antipsychotics

Answer 19

Dibenzapines (Clozapine, Loxapine, Olanzapine, Quetiapine)

Others (Risperidone, Ziprasidone, Aripiprazole, Iloperidone, Paliperidone, Lurasidone, Asenapine, Brexpiprazole, Cariprazine)

Question 20

Side Effects: Nigrostriatal Pathway

Answer 20

Initiation and control of movement and muscle tone

Selectively degenerated in Parkinson’s disease

Involved in obsessive and compulsive disorders

Antagonism of D2 receptors in the basal ganglia produces extrapyramidal side effects (EPS)

Question 21

Toxic Dose-Limiting Effects: EPS/Acute Dyskinesias

Answer 21

Akathisia (after a few months) - motor restlessness and distress compels constant movement

Dystonia (early on, within 1-2 doses) - spasms of neck and face muscles including grimacing, torticollus, ocular dysfunction; involuntary, often painful movements and bodily distortions

Respiratory disress - pharyngeal/laryngeal dysfunction

Pseudo-Parkinsonism (occurs around 6 months) - bradykinesia and rigidity, resting treomr of head and hands, flat affect)

Question 22

EPS or Motor Side Effects

Answer 22

Dose related - most common with high dose bolus or initial depo injection

Treat by decreasing dose, changing drugs, adding anti-Parkinson agent

Women more sensitive than men

Lead to irreversible tardive dyskinesias

Less selective antipsychotics (the dirty drugs) cause fewer EPS

In general, 2nd generation drugs cause less EPS than 1st generation drugs

Question 23

Muscarinic Receptor Affinity and EPS

Answer 23

Inverse relationship

In order of increasing EPS frequency:
(Thioridazine < Clozapine < Chlorpromazine < Promazine < Thiothixene Fluphenazine < Haloperidol)

Haloperidol is often given in combination with benzotropine, a muscarinic antagonist, to reduce EPS

Question 24

Muscarinic antagonists in combo with dopamine antagonists (or as properties of dopamine antagonists) work by…

Answer 24

Helping to reset the motor output imbalance caused by D2 antagonists

Question 25

Tardive Dyskinesias

Answer 25

Involuntary movement of the tongue, lips, head and neck (grimacing, tongue rolling, lip smacking, eye rolling)

Occurs in up to 50% of patients long-term (after a few years) of treatment with antipsychotics - resulting from increase of D2 receptors

Frequently irreversible

Severity is related to dose, duration of treatment, and gender

Question 26

Mechanism for Tardive Dyskinesias

Answer 26

Resulting from too many Dopamine (D2) receptors as a result of long term treatment with antipsychotics

Can occur short term

Treatment: Withdraw or reduce antipsychotic, consider a cholinomimetic; Vitamin B6 supplements (100mg pyridoxine/day) used as prevention

Question 27

Tuberoinfundibular Pathway SIde Effects

Answer 27

Pituitary D2 receptors normally inhibit prolactin

Blockade of D2 inhibition leads to increased prolactin (gynecomastia and increased lactation; disturbed thermal regulation; amennorhea, inretility and sexual dysfunction)

Prolactin levels above 100 ng/mL lead to prolactinomas and increased risk of breast cancer (usually don’t see this in antipsychotics)

Question 28

2nd Generation Antipsychotics (general)

Answer 28

Relative to FGAs, SGAs:

One average have a higher affinity for 5HT2 receptors

Have somewhat lower affinity for D2 dopamine receptors (by 5-50 fold)

Generally have lower incidence of EPS and endocrine side effects

Recommended as first line therapies (have other side effects)

Question 29

Serotonergic CNS pathways/antipsychotic theory

Answer 29

Projection from the raphe to the pre-frontal cortex, hypothalamus, limbic areas, spinal reflex areas, and basal ganglia

5HT2 receptors modulate dopamine release

Theory is that there are fewer EPS with antipsychotics that combine 5HT2 antagonism with lower affinity D2 antagonism because 5HT modifies dopamine release in the basal ganglia

*the best possible drug is a DA/HT/muscarinic antagonist but is dirty in nature (blocking of 5HT2 heteroreceptors will result to increased dopamin in cleft with every signal)

Question 30

Autonomic Effects of antipsychotics

Answer 30

A1 adrenergic antagonism

Muscarinic cholinergic antagonism (blind, hot, dry, red, confusion/crazy and other anticholinergic effects)

Question 31

Sedation in Antipsychotics

Answer 31

H1 antagonism leads to drowsiness and sedation, weight gain, and anti-nausea effects on vestibular apparatus

Difficult for patients on prophylactic or chronic therapy

Very useful for acute treatment of florid psychoses with agitation

Question 32

Weight gain/metabolic disorder with antipsychotics

Answer 32

Serotonin, H1 and alpha1 adrenergic receptor blockade causes:

Increased appetite, increased fat storage, sleep apnea, hypocholesterolemia, insulin insensitivity and hypoglycemia

*lipids, weight, HbA1c, and BP should all be monitored in all patients on antipsychotic therapy

**susceptibility varies and we don’t know why

Question 33

Antipsychotics with large weight gain

Answer 33

Clozapine, Olanzapine, Chlorpromazine, Thioridazine

Question 34

Antipsychotics with moderate weight gain

Answer 34

Risperidone, Quetiapine, Paliperidone, Iloperidone

Question 35

Antipsychotics with no weight gain (weight neutral)

Answer 35

Ziprasidone, Aripiprazole, Molindone, Haloperidol, Asenapine

Question 36

Potentially fatal cardiotoxicities with antipsychotics

Answer 36

Increased risk of sudden cardiac death (prolonged QT interval may cause Torsades de pointe arrythmias; highest risk with ziprasionde, pimozide and thioridazine)

Muscarinic and a1 adrenergic antagonist activities

Weight gain and CV disease increase

Smoking

Question 37

Black Box Warning for Antipsychotics

Answer 37

Increased mortality in elderly patients with dementia related psychosis (1.6-1.7 times placebo)

Most deaths appeared to be either CV or infectious in nature (these drugs are not approved for the treatment of patients with dementia-related psychosis)

Question 38

Neuroleptic malignant syndrome

Answer 38

Rare, recurrent with 10% mortality, patients with severe EPS are more vulnerable (could be related to D2 antagonism)

Manifestations include: Hyperthermia and diaphoresis; altered mental status, including catatonia and stupor; flucutating blood pressure and pulse; tremor and muscle rigidity; acute renal failure

Treatment: Immediate discontinuation of all antipsychotic medication; dantrolene may be helpful; bromocriptine may be helpful

Question 39

Hypersensitivity reactions to antipsychotics

Answer 39

Primarily with phenothiazines (5%): Dermal reactions including rash and photosensitivity, ocular opacities of the cornea and lens, jaundice

Alert for Asenapine: Serious hypersensitivity and anaphylaxis alert

Question 40

Clozapine unique efficacy and toxicities

Answer 40

Significant advantage (uniquely effective in 25-30% of treatment-resistant patients; no reported EPS)

Serious toxicities make it a third line agent (Leukopenia can lead to agranulocytosis in 1.3% which can be fatal in 4-16% of patients; myocarditis; CV collapse including hypotension, respiratory or cardiac arrest)

Decreased seizure threshold

Sedation, antimuscarinic effects (severe constipation), etc.

Question 41

Olanzapine

Answer 41

Very similar in structure and profile to clozapine but lacking the unique toxicities

2nd most effective antipsychotic of all

Weight gain is very problematic at effective doses making it a third line agent

Question 42

Quetiapine (Seroquel)

Answer 42

Sedating - making it useful to reduce anxiety and agitation

Low EPS (active metabolite is an anti-muscarinic)

Low adrenergic blockade

Moderate weight gain/risk of metabolic syndrome

Question 43

Risperidone

Answer 43

Lack of sedation is attractive for some patients

Restlessness/agitation is a problem

Dose needs to be controlled to avoid EPS

Approved for irritability in autism spectrum disorders at age 5 and up

Used more often as a maintenance therapy for those looking to function in normal society

Question 44

Paliperidone

Answer 44

Hydroxy metabolite of risperidone (similar pharmcologic profile, including restlessness and EPS)

Sustained release form leads to once monthly dosing

Question 45

Ziprasidone and Lurasidone

Answer 45

Low weight gain, low EPS

Problems including QT prolongation (less with Lurasidone)

Question 46

Iloperidone

Answer 46

Low EPS, low-anticholinergic effects, low weight gain, low tendency for metabolic syndrome

Hypotension is a problem and requires dose titration

Question 47

Asenapine

Answer 47

Minimal weight gain and metabolic disturbance

Extreme sedation from histamine receptor antagonism

Off-label use to treat PTSD

Serious hypersensitivity reactions including anaphylaxis alert issued by FDA in 2011

Concern with EPS due to relatively low affinity for muscarinic receptors

No better efficacy than other antipsychotics and noto as good in some trials

Question 48

Aripiprazole

Answer 48

D2 partial agonist (~30%)

Transient nausea

No endocrine disturbances (slight decrease in prolactin)

No receptor sensitization (low risk for EPS or TD)

Good efficacy (but may increase psychoses in a subset of patients)

Agitating (may be a problem in some patients)

Alpha 1 antagonist (increasing reports of weight gain with time)

Question 49

Brexipiprazole

Answer 49

Newer to market

Similar to aripiprazole but weaker D2 partial agonism (partial agonist at 5HT1, antagonist at 5HT2 receptors; low risk for EPS or TD)

Alpha 1 antagonism

Low affinity for histamine receptors

Common side effects include akathisia and moderate weight gain

Question 50

Cariprazine

Answer 50

Newer to market

Pharmcology similar to Aripiprazole (D2 partial antagonist, 5HT1A partial agonist, 5HT2 antagonist)

D3 partial agonist with higher affinity for D3 than D2

Extrapyramidal side effects in 1/4 to 1/3 patients

Low weight gain

Question 51

American Psychiatric Association top 5 recommendations from the “Choosing Wisely” initiative

Answer 51

Don’t prescribe antipsychotic medications to patients for any indication without appropriate initial evaluation and appropriate ongoing monitoring

Don’t routinely prescribe 2 or more antipsychotic medications concurrently

Don’t use antipsychotics as first choice to treat behavioral and psychological symptoms of dementia

Don’t routinely prescribe antipsychotic medications as a first-line intervention for insomnia in adults

Don’t routinely prescribe antipsychotic medications as a first-line intervention for children and adolescents for any diagnosis other than psychotic disorders

Question 52

Additional Antipsychotic Indications

Answer 52

Tourette’s (uncontrolled vocal outbursts, tics and repetitive movements | too much dopaminergic activity in the nigrostriatial pathway | treat with high affinity D2 antagonist like pimozide)

Neuroleptanesthesia (Innovar = Droperidol plus fentanyl)

Adjunct treatment to anti-depressants (not alone | approved for aripiprazole, quetiapine and olanzapine)

Behavioral problems, including irritability, in autism spectrum disorders (approved for risperidone and aripiprazole)

Bipolar disorder

Question 53

Additional indications-more on these in the GI unit

Answer 53

Severe nausea and vomiting (Promethazine and Prochlorperazine, D2 antagonists block the chemoreceptor trigger zone and increase GI motility, antihistamine and anticholinergic effects block motion sickness)

Intractable hiccups (Thorazine)

Insufficient lactation (Metoclopramide, inhibit D2 inhibition of prolactin release)