Pharmacology of Mood Disorders & Psychosis Flashcards
Absorbption, distribution, and metabolism of anti-psychotics
Oral absorption is incomplete with significant first-pass effect
Highly lipid solubility leads to concentration in the CNS, which extends clinical half-life beyond plasma half-life; crosses placenta
Metabolized to polar substance for excretion by hepatic CYP450; can be excreted in breast milk
Dosage formulations for antipsychotics
Oral - immediate release for chronic dosing, 1-2x/day
IM - for rapid treatment of acute psychosis or for patients who can’t take oral meds
IM depot - improves adherence to maintenance therapy; administered every 2-4 weeks
Typical antipsychotics - Mechanism
High D2/5HT2A blocking ratio
Good D2 block is associated with high efficacy against positive symptoms AND high incidence of extrapyramidal side effects
Typical antipsychotics - agents
Haloperidol - High clinical potency due to greater D2 blocking activity; effective in lower doses but higher risk of EPS
Chlorpromazine - Lower clinical potency due to lesser D2 blocking activity; less risk of EPS but higher doses produce other side effects including antimuscarinic (dry mouth, tachycardia, urinary retention, constipation), alpha-1 blockade (hypotension) and antihistamine (sedation)
Atypical antipsychotics - Mechanism
Low D2/5HT2A blocking ratio - associated with better efficacy against negative symptoms and increased efficacy in treatment-resistant individuals
Atypical antipsychotics - Agents
Clozapine
Risperidone
Olanzapine
Aripiprazole
Clozapine
Atypical antipsychotic effective in patients who are refractory to other drugs
Reserved for this indication due to 1-2% incidence of agranulocytosis
Extrapyramidal symptoms
Caused by dopaminergic blockade; high with Haloperidol
Acute dystonia - treated with antimuscarinic agents
Akathisia - motor restlessness, inability to sit still
Pseudoparkinsonism (tremor, bradykinesia, rigidity) - treated with anticholinergic agents or Amantadine
Tardive dyskinesias
Tardive dyskinesias
Extrapyramidal symptom with onset 3-6 months; characterized by involuntary, repetitive movement of lips and tongue with chorea of arms and legs
May worsen with withdrawal of the antipsychotic drug and is usually irreversible; overall incidence 20-40% with chronic treatment
Other side effects of antipsychotic agents
Metabolic effects via block of hypothalamic DA receptors - Type 2 DM, weight gain, hypertension, hyperglycemia, hypercholesterolemia; more common with atypical agents
Altered thermoregulation via block of hypothalamic DA
Lowered seizure threshold
Tricyclic antidepressants - Agents
Amitriptyline
Imipramine
Desipramine
SSRIs - Agents
Fluoxetine
Paroxetine
Sertraline
Citalopram
Buproprion - Mechanism & Side effects
NE and DA reuptake inhibitor (NDRI)
Side effects: anxiety, insomnia, higher seizure risk; contraindicated in patients with eating disorders or history of seizures
No sexual side effects, weight neutral
Venlafaxine - Mechanism & Side effects
5HT and NE reuptake inhibitor (SNRI)
Side effects: Diastolic hypertension Sweating Sexual side effects Withdrawal syndrome with "electric shock" sensation
Trazodone - Mechanism
Serotonin antagonist / reuptake inhibitor (SARI)
Weak antidepressant, mainly used for insomnia
Side effects: drowsiness, dizziness
TCADs - Mechanism
Blocks reuptake of NE, 5HT and DA (at high doses)
Also blocks H1 histaminic, muscarnic cholinergic, and alpha-1 receptors
SSRIs - Side effects
Acute (diminish over time): Nausea, diarrhea, insomnia, dry mouth
Chronic: Weight gain, sexual dysfunction, cognitive blunting
Flu-like withdrawal syndrome
DDIs with MAOIs & inhibitors of CYP450
TCADs - Side effects
Anticholinergic effects (blurred vision, constipation, dry mouth, urinary retention, glaucoma)
Orthostasis
Weight gain
Sexual side effects
Fatal in overdose due to seizure and cardiac arrhythmia
MAOIs - Mechanism
Blocks degradation pathway for NE and 5HT, allowing greater release into the synapse; inhibition is irreversible and persists after drug is no longer detectable in the plasma
Effective in non-responsive patients, especially atypical depression
MAOIs - Adverse Effects
Anti-cholinergic (dry mouth, constipation, urinary retention)
Sexual side effects
Weight gain
Overdose causing seizures, shock, hyperthermia
MAOI DDIs
Interaction with foods high in tyramine (liver/beer/wine/cheese); tyramine displaces NE from storage vesicles causing excessive NE release leading to hypertensive crisis
Interaction with SSRIs/SNRIs, Medperdine (Demerol), and Dextromethorphan (cough suppressant) causing serotonin syndrome
Serotonin syndrome
Increased serotonin in the CNS causes over-stimulation of 5HT2A receptors
Presents as tremor, tachycardia, hypertension, sweating, dilated pupils, hyperreflexia, clonus, and hyperthermia causing metabolic acidosis, rhabdomyolysis, seizures, renal failure, and DIC
Mirtazapine - Mechanism, Uses, and Side effects
Mechanism: Blocks a-2 receptors on serotonergic and adrenergic neurons, enhancing release of 5HT and NE; does NOT affect reuptake systems
Useful due to additional anti-insomnia and anti-anxiety effects; low incidence of sexual side effects
Side effects: Daytime somnolence, weight gain
Benefits of Lithium
Best studied, best proven drug for bipolar disorder
Effective anti-manic, reasonable preventative agent, some antidepressant and anti-suicidal properties
Neuro-regenerative
Cheap
Lithium - Adverse Effects, and DDIs
GI upset, tremor, metallic taste, cognitive dulling
Decreased urine concentration / diabetes insipidus, due to decreased ADH secretion (20-30%)
Hypothyroidism (5-10%); can cause weight gain
Narrow therapeutic window; toxicity/overdose causes confusion, seizures, stupor, coma
DDIs: Diuretics decrease renal clearance up to 25% causing increased Li+ plasma levels
MAOIs - Agents
Phenelzine, Selegeline
SSRI Indications
Major depressive disorder Generalized anxiety disorder Social anxiety Panic OCD PTSD PMDD
Mania - Pharmacologic Treatment Options
Lithium
All atypical antipsychotics
Divalproex Sodium (Depakote)
Bipolar Depression - Pharmacologic Treatment Options
Olanzapine-Fluoxetine
Quetiapine
Possibly Lithium, Lamotrigine
Bipolar Maintenance - Pharmacologic Treatment Options
Lamotrigine
Aripiprazole
Bipolar Relapse Prevention - Pharmacologic Treatment Options
Lithium
Olanzapine
What is the overall response and remission rate of antidepressants?
67% overall response rate within 8 weeks; 40% of patients do not respond until week 8, thus 8-14 weeks is considered an adequate trial
SSRIs have a 33% rate of remission; all FDA approved antidepressants have comparable rates
Benzodiazepines - Mechanism
Bind to the GABA channel gamma subunit, facilitating channel opening and Cl- influx; does NOT directly initiate Cl- current and requires presence of GABA
No effect on excitatory neurotransmitters - graded, dose-dependent CNS depression with ceiling affect below the level of anesthesia
Barbituates - Mechanism
Prolong the effect of GABA on its receptor (presence of GABA is required); at high doses, interact directly with the GABA receptor
Also depresses excitatory glutamate transmission - capable of inducing surgical anesthesia
Zolpidem - Mechanism & Uses
Selectively interacts with alpha-1 GABA channels in the cortex
Produces hypnosis (sleep) without anxiolysis; less potential for abuse Also used as an anti-convulsant
Side effects: Amnesia, additive CNS depression
Flumazenil
Benzodiazepine binding site antagonist; reverses CNS effects of benzodiazepines in overdose or following surgical use
GABA receptor variants - a1 and a2/a5
GABA receptors with a1 subunits are expressed in the cortex; mediate sleep, anticonvulsant, and amnesia effects
GABA receptors with a2/a5 subunits are expressed in the limbic system and brain stem; mediate muscle relaxation, motor impairing, anxiolytic, and alcohol-potentiating effects as well as tolerance, dependence, and withdrawal
Benzodiazepines - Metabolism
Metabolized by CYP450 prior to elimination in urine
Metabolites of some agents are active, with longer half lives than the parent comopounds leading to accumulation effects such as daytime sedation
Lorazepam and Oxazepam are metabolized directly to inactive compounds; better choice in elderly patients or patients with hepatic dysfunction
Benzodiazepines - Adverse Effects
Extension effects: More likely with high doses, longer half life agents, elderly patients, patients with hepatic dysfunction
Sedation
Performance impairment (drowsiness, incoordination, decreased concentration, cognitive deficits)
Anterograde amnesia
Physical / Psychologic Dependence
Withdrawal syndrome
Barbituates - DDIs
Barbituates are inducers of CYP450 enzymes; major source of clinically significant DDIs leading to declining use
Buspirone
Partial agonist of 5HT1A, located pre-synaptically on nerve terminals
Anxiolytic effect only; NO sedation, anticonvulsant, or myorelaxant action
Requires 2 weeks for onset of effect and 4-6 weeks for maximal efficacy; must be administered daily (not prn); useful in chronic anxiety
Treatment of GAD
- Antidepressants - SSRIs, SNRIs
- Benzodiazepines - Alprazolam/Lorazepam/Oxazepam (shorter acting) vs. Diazepam (longer acting) if both hypnotic and daytime anxiolysis are desired
