Antidepressants and Antipsychotics

Catch me on ketamine this weekend

depressed mood, loss of interest/pleasure

What are the 2 core symptoms of depression

A functional decrease in monoamine transmission contributes to depression

What is the monoamine theory of depression (not 100% accurate)?

Blocks the vesicular monoamine transporter

What is the MOA for an OG the hypertension and antipsychotic drug, Reserpine?

increase in monoamine neurotransmission

What is the primary MOA for MOST antidepressant drugs?

Monoamine Oxidase (MAO)

What enzyme degrades dopamine, NE, and E inside the presynaptic cleft?

increase

By blocking MAO what happens to the levels of monoamines in the synaptic cleft?

MAO-a is distributed in the gut and liver

Why do patients taking MAOIs have GI related ADRs?

rasagiline, selegiline, isocarboxazid, phenelzine, tranylcypromine

MAOIs on the market

Orthostatic hypotension (stop the NE, lower the bp), decreased sexual functional, sleep disturbances, weight gain)

Side effects of MAOI inhibitors

block dopamine reuptake

What is the MOA for tricyclic depressants?

amitriptyline, desipramine, doxepin, imipramine, notriptyline, protriptyline, trimipramine

TCAs on the market

promiscuous (block lots of receptors - M1, H1, alpha)

Why do TCAs have lots of side effects?

dry mouth, blurred vision, constipation, urinary retention, impotence

Muscarinic associated ADRs of TCAs

sedation, weight gain

Histamine associated ADRs of TCAs

orthostatic hypotension

Adrenergic alpha associated ADRs of TCAs

Selective Serotonin reuptake inhibitor

What is the 1st rationally designed class of psychotropic mediations that specifically blocks the 5-HT re-uptake transporter?

fluoxetine hydrochoride, nefazodone HCl, sertaline HCl, duloxetine, flueoxamine maleate, escitalopram oxalate, proxetine HCl, venlafaxine HCl

SSRIs on the market

decreased libido, sexual dysfunction

5HT2 associated side effects of SSRIs

GI side effects (N/V/D)

5HT3 associated side effects

increased serotonin over time leads to plasticity leading to an antidepressant effect

What is the theory as to why it takes 6 weeks to see therapeutic effects with SSRIs?

bupropion, trazodone, brexanolone, ketamine

Examples of atypical antidepressants

Blocks the reuptake of NE and dopamine

What is the MOA for wellbutrin

seizure

ADRs of bupropion

Blocks specific serotonin receptors (5HT2C and 5HT2A) and leaves 5HT1A open

MOA for trazodone (nefazodone)

Brexanoline

What atypical antidepressant is approved for post-partum depression and does NOT target monoamine transmission?

modulates the inhibitory transmission

MOA for brexanolone

antagonist for glutamate

MOA for ketamine

nothing has worked

When would you use ketamine in the treatment of depression?

hallucinations, out of body experiences, abuse potential

ADRs of ketamine (special K)

hippocampus

What areas of the brain are associated with depression and may play a role in antidepressant efficacy?

schizophrenia

A debilitating disease affecting 1% of the population that has a late onset usually in late adolescence or early adult hood

hallucination, delusion, disorganized thinking

“Positive” symptoms of schizophrenia

positive

What symptoms of schizophrenia respond to current treatment?

flat affect, anhedonia (lack of interest), social withdrawal

“Negative” symptoms of schizophrenia

slow thinking, difficulty understanding, poor concentration, poor working memory

Cognitive symptoms of schizophrenia

yes (also environmental triggers)

Is there a genetic component for schizophrenia?

electroconvulsive therapy (ECT)

1st approved treatment for schizophrenia

trans-orbital lobotomy

A procedure used in the 1940s-50s in which an ice-pick through the upper eyelid and into the patients head and worked in 1/3 of patients

methylene blue

What is the precursor to all psychiatric drugs

promethazine

What was the 1st sedative that came from methylene blue and is a centrally acting H1 agonist?

chlopromazine (thorazine)

What was the original antipsychotic that was derived from promethazine

haloperidol, chlorpromazine, perphenazine

Examples of 1st generation typical antipsychotics

blocks dopamine D2

MOA for typical antipsychotics

schizophrenia

An increased transmission of dopamine is consistent with

Gotta block post synaptic D2s which are found in multiple places,

Why do antipsychotics take week for maximal theurapeutic efficacy even though the D2 blockade is rapid?

mesolimic, mesocortical, nigrostriatal, tuberoinfundibular

Dopamine pathways

Mesolimbic

Hyperactivity in what pathway is thought to underlie positive symptoms of schizophrenia and regulates emotion/pleasure?

blocking dopamine in the mesocortical pathway contributes to these symptoms

Why are typical antipsychotics ineffective at treating negative and cognitive symptoms

Block dopamine receptors in the nigrostriatal pathway

Why do 1st gen typical antipsychotics result in an increase of Parkinson’s related symptoms like resting tremor, ridigity, bradykinesia, or tardive dyskinesia?

prolactin release is not inhibited

Why does the blockage of D2 receptors in the tuberoinfundibular pathway result in galactorrhea, amenorrhea, and sexual dysfunction?

neuroleptic malignant syndrome, supportive care

26 y/o patient presents to the ER with altered mental status. Family reports that the patient is not making any sense and has been more agitation. On a physical exam, the skin is extremely warm to the touch, pulses are fast and vary between strong and thready, and muscles are rigid. Family reports the patient was recently diagnosed with schizophrenia and is taking haloperidol. Labs are fine except for an elevated CK and myoglobin. What is this rare ADR known as? Treatment plan?

Dopamine agonist (bromocriptine (overcome the antagonist)), muscle relaxant (dantrolene)

What medications can you used to help treat Neuroleptic malignant syndrome, but may lead to positive schizophrenia symptoms?

No (they suck to be on)

Is there any worry about tolerance or dependence with 1st gen antipsychotics?

low chance to cause Parkinsonian symptoms, no dystonia, no tardive dyskinesia

What makes an antipsychotic atypical?

ratio of 5-HT2A/D2 affinities

What factor distinguishes typical from atypical antipsychotics?

inhibits dopamine in nigrostriatal but not mesolimbic

What is the point of having a 5HT2 antagonistic affect in a antipsychotic drugs?

Action at the H1 receptor

Why do atypical antipsychotic have an ADR of weight gain?

QT prolongation

What side effect of atypical antipsychotics are due to the a blockage of HERG K+ channel?

olanzapine, apriprazole, asenapine, clozapine, Iloperidone, lurasidone, paliperidone, quetiapine, repseridone, ziprasidone

Example of atypical antipsychotics

olanzapine

What atypical antipsychotic was slightly better than the other drugs but associated with significant weight-gain as a side-effect?

Perphenazine

What 1st gen antipsychotic was equally effective and as well tolerated as the 2nd gen drugs in the CATE trial?