Antipsychotics 1&2

Behaviors, thoughts, or sensory experiences added to a person’s reality

Positive symptoms

Abilities, feelings, or behaviors that are subtracted or missing from a person’s baseline functioning

Negative symptoms

List of positive symptoms

Hallucinations

Thought disorder

Abnormal behavior

Aggressiveness

List of Negative symptoms

Poor hygiene

Withdrawal

Avolition (decreased initiation of goal-directed behavior)

Alogia (decrease speech fluency)

Two or more symptoms with social or occupational dysfunction >6 months

DSM-IV-TR diagnosis

Increased & dysregulated levels of DA neurotransmission in the brain

Schizophrenia

What is used to relieve schizophrenic symptoms by decreasing DA levels

D2 Receptor Antagnoists

What occurs in the mesolimbic system which can affect emotions & memory

Hyperactivity → positive symptoms

Excess dopamine receptor activation results in which symptoms

Positive symptoms

Mesocortical system

Affected attention, planning, and motivated behavior

Decreased DA activity → negative symptoms

How does schizophrenia affect Glutamate

Reduced concentrations and receptor densities

What drugs can exhibit psychotic symptoms by blocking glutamate receptors and mimic negative symptoms

NMDA receptor antagonists (PCP “angel dust,” ketamine, dizocilpine/MK-801)

Which neurotransmitter dysfunction can produce hallucinatory effects

5-HT (2C)

What drug class can be used to antagonize 5-HT receptors

Antipsychotics

Antipsychotics effect on Basal Ganglia

Antagonize DA in forebrain

Reduce motor activity

Antipsychotics effect on Limbic system

Affects mesolimbic and mesocortical systems

Antipsychotics effect on Cerebral cortex

Interact with dopaminergic projections to prefrontal and deep-temporal regions

Antipsychotics effect on Hypothalamus & Endocrine system

• Blocks pituitary actions of Tuberoinfundibular Dopaminergic neuron

• Reduce Gonadotrophin secretion & sex steroids

• Amenorrhea

• Sexual dysfunction or infertility in men

What receptors do Typical Antipsychotics (first gen/neuroleptics) bock

D2 → parkinsonism

Cholinergic (M1) → dry mouth, constipation, urinary retention, blurred vision

Alpha-1 Adrenergic → orthostatic hypotension

H1 Histaminergic → weight gain, sedation

What side effects can be caused by Typical Antipsychotics

Extrapyramidal Symptoms (EPS) via D2 blockage in Nigrostriatal pathway

• acute dystonia, akathisia, pseudoparkinsonism, tardive dyskinesia

Neuroleptic malignant syndrome (NMS)

Prolactin secretion

Involuntary muscle contractions (repetitive/twisting movements) that occurs within few hours to days of Tx

Dystonia

Motor restlessness that occurs days to weeks of Tx

Akathisia

Parkinsonian symptoms

Activate the indirect pathway

Bradykinesia, rigidity, tremor within weeks - months of FGA

Amantadine & Cholinergic drugs used as non-dopaminergic parkinson’s treatment

Repetitive, involuntary, stereotyped movements of facial muscles, arms, and trunk that may be irreversible if prolonged use of FGA

Tardive Dyskinesia

Neuroleptic Malignant Syndrome (NMS)

Rare life-threatening syndrome characterized by catatonia, stupor, fever, and autonomic instability via high D2 affinity in Hypothalamus

• can also cause Rhabdomyolysis (skeletal muscle damage via myoglobin released in plasma)

Result of D2 antagonist action in Pituitary Gland

Prolactin secretion → Hyperprolactinemia

• may cause osteoporosis in women

• Breast swelling, pain & lactation in men & women

T/F: high dose antipsychotics increase extrapyramidal, muscarinic & alpha adrenergic effects

False; only extrapyramidal

T/F: Low dose antipsychotics have more prominent anti-cholinergic and anti-adrenergic effects

True

FGA/Typicals drug interactions

• inhibits anti-parkinsons drugs → worsen Sx

• Potentiate sedative effects of Benzos & Antihistamines

• Increase effects of analgesics, alcohol, hypnotics, and cold remedies

• Chlorpromazine increases effects of Morphine and respiratory depression of Opiates

Which FGAs/Typicals have an anti-emetic action

Haloperidol & Prochlorperazine

What receptors are antagonized by Atypical antipsychnotics (2nd gen)

D1 & D4 (low affinity for D2), and 5-HT

Fewer adverse effects

Which antipsychotic is more effective to treat negative symptoms of schizophrenia

Atypical antipsychotics

Typical antipsychotic therapeutic efficacy and extrapyramidal adverse effects correlates directly to ____

Affinity to D2 receptors

Typical psychotics MOA

Blocks D2 Receptors

Antagonism of Mesolimbic system & Mesocortical D2 receptors

First generation antipsychotics (FGA) / Typical antipsychotics that are in the Phenothiazine structural class

Chlorpromazine

Fluphenazine

Perphenazine

Thioridazine

Trifluoperazine

FGAs that are in Butryophenone structural class

Haloperidol (Haldol)

Which generation antipsychotics help reduce positive symptoms of schizophrenia & is less effective when controlling negative symptoms

FGA/Typical

Haloperidol & Prochlorperazine anti-emetic MOA

Blocks D2 of chemoreceptor trigger zone (CTZ) of medulla

Treats nausea from chemotherapy

Haloperidol therapeutic actions

Delirium, severe agitation in hospice

T/F: FGA binds extremely tightly to D2 receptors compared to SGA

True

SGA that is used to decrease suicidality in schizophrenic patients

Clozapine (Clozaril)

Clozapine (Clozaril) AEs

• 1-2% risk of Agranulocytosis (low WBC)

  • Must be nationally registered for monitoring of low WBC & absolute neutrophil count (ANC)

• Myocarditis, seizures, orthostatic hypotenion

• Contraindicated in severe heart disease

Clozapine (Clozaril) pharmacogetics

Primarily metabolized by CYP1A2, additional contribution by CYP2D6 and CYP2C19

Olanzapine (Zyprexa) therapeutic actions

Antipsychotic

Bipolar disorder

Olanzapine (Zyprexa) AEs

Anticholinergic Symptoms

• sedation, wt gain, prolactin secretion

Olanzapine can be combined with which mu-opioid receptor antagonist

Samidorphan

Olanzapine can be combined with which mu-opioid receptor antagonist

Samidorphan

Although has dopaminergic & serotinergic antagonist activity, this SGA has preferential activity of alpha 1&2 adrenergic receptors

Quetiapine (Seroquel)

Quetiapine (Seroquel) Therapeutic actions

As efficacious as Haloperidol for positive symptom Tx

Antidepressant monotherapy (XR for major depressive and biopolar disorders)

Quetiapine (Seroquel) AEs

Risk of cataract development

Hypothyroidism

Suicidal thoughts

Metabolite via CYP2D6 that has similar pharmacological activity as Risperidone

9-hydroxyrisperidone

Half life of Risperidone (Risperdal) + metabolite

3-6 days

Risperidone (Risperdal) AEs

High risk of increased prolactin

Fewer EPS than FGAs

Risperidone (Risperdal) therapeutic actions

• more effective than Haloperidol for positive Sx

• Preventing relapse of active phase of disease

• Bipolar disorder

• Long acting injection via microspheres

Paliperidone (6-hydroxyrisperidone) ER formulation

Invega (once daily PO)

Paliperidone (6-hydroxyrisperidone) AEs

• high blood sugar & DM

  • Routine blood test (FH of DM)

• Increased QT

• Dose-dependent increase prolactin secretion

Ziprasidone (Geodon) MOA

Inhibit SE & NE reuptake

• antidepressant / anxiolytic properties

Ziprasidone (Geodon) CI

• avoid in QTc prolonging meds

• Myocardial infarction, heart problems

• Antiarrhythmics

Lurasidone (Latuda) therapeutic use

Major depressive episodes associated with bipolar disorder

• monotherapy

• Adjunctive with lithium or valproate

Lurasidone (Latuda) AEs

Leukopenia, neutropenia, agranulocytosis (sometimes fatal) → periodic blood count assessment

Prolactin secretion

Which SGA is a D2 partial agonist & dopaminergic antagonist in mesocortical pathway (and also 5-HT(1A) partial agonist & 5-HT(2A) antagonist)

Aripiprazole (Abilify)

Aripiprazole (Abilify) therapeutic actions

treats positive & negative symptoms of psychosis & mood Sx

Bipolar disorder

Aripiprazole (Abilify) AEs

NMS

High blood sugar in DM

Which SGA is a partial agonist of 5-HT(1A) and D2 receptors

Brexipiprazole (Rexulti)

Brexipiprazole (Rexulti) Therapeutic actions

Schizophrenia

Major depressive disorder (adjunct)

Dosage adjustment for CYP2D6

Brexipiprazole (Rexulti) AEs

Extrapyramidal Sx & Akathisia

Asenapine AEs

Orthostatic hypotensino, sedation, wt gain, prolactin secretion

Asenapine formulations

Transdermal (Secuado)

Sublingal (Saphris)

Cariprazine (Vraylar) MOA

Partial agonist → 10x affinity D3 than D2, 5-HT(1A)

Antagonist → 5-HT (2A, 2B, 2C), H1

Cariprazine (Vraylar) Therapeutic actions

Schizophrenia

Acute manic or mixed episodes with bipolar disorder

Cariprazine (Vraylar) AEs

Leuko/Neutro-penia, agranulocytosis

Lumateperone (Caplyta) MOA

Partial agonist: D2 (presynaptic), D1

Antagonist: 5-HT(2A), D2 (postsynaptic)

Enhance glutamate

Serotonin reuptake inhibitor

Which SGA is used for schizophrenia only in adults

Lumateperone (Caplyta)

Lumateperone (Caplyta) AEs

Blood dyscrasia (leuko/neutropenia, agranulocytosis)

Weight gain

Pimavanserin (nuplazid) MOA

selective inverse agonist of 5-HT(2A) used for parkinson’s psychosis

Pimavanserin (nuplazid) AEs

CNS depression

Xanomeline & Trospium (Cobenfy) MOA

Xanomeline → M1 & M4 agonists → reduced psychotic Sx

Trospium → muscarinic antagonists → does not cross BBB; minimize GI effects

Treats both positive & negative Sx

Xanomeline & Trospium (Cobenfy) AEs

Urinary retention, increased HR, decreased gastric movement

Xanomeline & Trospium (Cobenfy) CI

Liver impairment

Gastric retention

Untreated narrow-angle glaucoma

T/F: FGA has higher metabolic effects (DM, hypercholesterolemia, weight gain)

False; SGA

T/F: FGA have more neurological side effects

True

Which generation is FDA approved for maintenance therapy to prevent relapse

second generation antipsychotics