Exam 4

Question 1

What are the general considerations for schizophrenia and the drug therapy of schizophrenia?

Answer 1

Schizophrenia - most debilitating of psychotic disorders. It affects 1% of population. The onset is typically 15-20 years old.
- Antipsychotic, neuroleptic, and anti-schizophrenic are all synonymous

Positive symptoms - respond well to drug therapy. Ex. hallucinations, delusions, etc.

Negative symptoms - little response to drug therapy. Ex. blunted emotion, poor self care, social withdrawal, etc.

*also decrease in cognitive function

Question 2

Which neutrotransmitters are thought to be involved with schizophrenia? (Hypotheses)

Answer 2

α1, D2, 5HT2A, M1,3, H1 receptors are all targeted by therapies. The effectiveness of targeting each receptor varies by patient.

Serotonin -
- LSD and mescaline are 5HT agonists, which cause hallucinations
- 5HT2A receptors modulate dopamine release in the cortex, limbic region, and striatum
- 5HT2A receptors modulate glutamate release and NMDA receptors

Glutamate
- Excitatory
- Phencyclidine and ketamine are noncompetitive inhibitors of NMDA receptors that exacerbate psychosis and cognition
- GlyT inhibitors and Glu agonists are effective in schizophrenia

Dopamine
- D2 receptors highly involved
- Dopaminergic agents exacerbate symptoms of schizophrenia
- D2 receptor antagonists initially increase metabolites in the CNS, then later decrease metabolites
- D2 antagonists - want to target the mesolimbic system, risk of motor effects and EPS

Question 3

When do drug-induced movements occur, what target is responsible, which drugs are likely to cause them, and how can they be treated?

Answer 3

Extrapyramidal Symptoms (EPS) - Occurs in 30-50% of patients
- Occurs in the early days/weeks of treatment
- Reversible!!
- Symptoms: dystonia (increased muscle tone), pseudoparkinsonism (muscle rigidity), tremor, akathisia (restlessness)
- Target responsible: D2 antagonist causes DA/ACh to be off
- Treatment: Anticholinergics, antihistamines, DA releasing agent, propranolol (for akathisia)

Tardive Dyskinesia - Occurs in 20-40% of patients
- Occurs late months/year
- IRREVERSIBLE
- Symptoms: rhythmic involuntary movements with mouth, irregular jerking movements (choreiform), athetoid (worm-like) movements, axial hyperkinesias (to and fro)
- Target responsible: Unclear. Maybe supersensitivity of receptors to dopamine?
- Treatment: Need to PREVENT. Monitor and use lowest possible doses; Reduce doses, change drug, eliminate anticholinergics; VMAT inhibitors (indirectly blocks dopamine release)

Neuroleptic Malignant Syndrome (NMS) -
- Serious and rapid; 10% fatality
- Symptoms: EPS with fever, impaired cognition, muscle rigidity
- Treatment: Restore dopamine balance; D/c drug, used DA agonists, diazepam, or dantrolene (skeletal muscle relaxant)

Question 4

What are the adverse pharmacological effects associated with antipsychotic drugs? (autonomic, CNS, endocrine system, other)

Answer 4

autonomic -
- anticholinergics: loss of accomodation, dry mouth, difficulty urinating, constipation
- α adrenoceptor blockade: orthostatic hypotension, impotence, failure to ejaculate

CNS -
- DA receptor blockade: parkinson’s syndrome, akathasia, dystonias
- Supersensitivity of DA receptors: tardive dyskinesia
- Muscarinic blockade: toxic-confusional state
- H1 receptor blockade: sedation

Endocrine -
- DA receptor blockage resulting in hyperprolactinemia: amenorrhea-galactorrhea, infertility, impotence

Other -
- H1 + 5HT2C blockade: Weight gain

Question 5

What are some precautions and contraindications for antipsychotic drugs?

Answer 5

Cardiovascular (most will prolong the QTc interval)
Parkinson’s Disease
Epilepsy (clozapine will lower seizure threshold)
Diabetes (for newer agents)

Question 6

What does it mean to have a high or low 5-HT2A/D2 ratio? Which drugs have a high or low 5-HT2A/D2 ratio?

Answer 6

High - mostly binding D2 (not 5HT2A); High D2 blockade is associated with extrapyramidal symptoms (dystonia, pseudoparkinsonism, tremor, akathisia)

Low - binds similarly to both receptors (D2 and 5HT2A)

Drugs with very high: thiothixene
Drugs with very low: clozapine, risperidone, quetiapine

Question 7

What are the pharmacological target, action, and side effects of Chlorpromazine, Promethazine, and Thioridazine?

Answer 7

1st gen antipsychotics - strong D2 blocks, which can cause more movement problems (EPS & TD)

Chlorpromazine (Thorazine) - is the 1st antipsychotic, has antihistamine side effects

Promethazine (Phenergan) - has antihistamine side effects and is an antiemetic

Thioridazine (Mellaril) - can cause many side effects, such as sedation, hypotension, anticholinergic side effects, sexual dysfunction, cardiovascular, etc.

Question 8

What are the pharmacological target, action, and side effects of Fluphenazine, Prochlorperazine, and Perphenazine?

Answer 8

1st gen antipsychotics - strong D2 blocks, which can cause more movement problems (EPS & TD)

Fluphenazine (Permitil, Prolixin) - lots of EPS

Prochlorperazine (Compazine) - Antiemetic

Perphenazine (Trilafon) - has similar efficacy, less weight gain, and is cheaper than several of the newer agents when used with anticholinergic

Question 9

What are the pharmacological target, action, and side effects of Thiothixene, Haloperidol, Molindone, and Pimozide?

Answer 9

1st gen antipsychotics - strong D2 blocks, which can cause more movement problems (EPS & TD)

Thiothixene (Navene) - Has modest EPS

Haloperidol (Haldol) - EPS

Molidone (Moban) - Has moderate EPS

Pimozide (Orap) - Used for Tourette’s disease to suppress motor and vocal tics

Question 10

What are the pharmacological target, action, and side effects of Clozapine, Olanzapine, and Loxapine?

Answer 10

atypical/2nd gen antipsychotics - Reduced EPS, enhanced 5HT2A receptor antagonism, more metabolic problems

Clozapine (Clozaril) - 1st atypical, very effective; Has anticholinergic and antihistamine side effects, can cause agranulocytosis, increases diabetes risk

Olanzapine (Zyprexa) - Causes weight gain, less likely to cause N/V, less likely to cause movement disorders, increases diabetes risk

Loxapine (Loxitane) - Older agent. The parent agent is an antipsychotic, but its metabolite is an antidepressant (useful with psychosis + depression)

Question 11

What are the pharmacological target, action, and side effects of Quetiapine, Risperidone, Paliperidone, Iloperidone?

Answer 11

atypical/2nd gen antipsychotics - Reduced EPS, enhanced 5HT2A receptor antagonism, more metabolic problems

Quetiapine (Seroquel) - Has 5HT2A + D2. Has low antimuscarinic properties, low EPS, can cause hypotension and sedation, increases diabetes risk

Risperidone (Risperidol) - Designed to be 5HT2A and D2 antagonist, relatively low EPS at <8mg/day, causes weight gain and some sedation

Paliperidone (Invega) - Add hydroxyl group on 9th carbon of risperidone

Iloperidone (Fanapt) - Structurally related to risperidone, very potent at α1 receptors

Question 12

What are the pharmacological target, action, and side effects of Ziprasidone, Asenapine, Lurasidone, Pimavanserin?

Answer 12

atypical/2nd gen antipsychotics - Reduced EPS, enhanced 5HT2A receptor antagonism, more metabolic problems

Ziprasidone (Geodon/Zeldox) - 5HT2A. D2, α1 affinity, prolongs QT interval

Asenapine (Saphris) - 5HT2A and D2 (also α and histamine receptors)

Lurasidone (Latuda) - 5HT2A, D2. Less weight gain and metabolic effects compared to olanzapine, fast onset, higher doses don’t usually increase effectiveness, rapid titration

Pimavanserin (Nuplazid) - Inverse agonist on 5HT2A, used for Parkinson’s disease psychosis since it doesn’t bind D2

Question 13

What are the pharmacological target, action, and side effects of Aripiprazole, Brexpiprazole, Cariprazine, Lumateperone?

Answer 13

Aripriprazole (Abilify) - atypical, high affinity for 5HT2A and D2, causes weight gain and has low risk of D2 effects because it has partial agonist activity

Brexpiprazole (Rexulti) - D2/D3 partial agonist with less akathisia than aripiprazole. Used for schizophrenia and as an adjunct to antidepressants

Cariprazine (Vraylar) - D2/D3 partial agonist with greater affinity to D3. Has a lot of akathisia. Used for schizophrenia, mania, and bipolar disorder

Lumateperone (Caplyta) - partial D2 agonist and 5HT2A antagonist

Question 14

What are the key structural features of the phenothiazine antipsychotics?

Answer 14

• 3 rings
• R2 is important for potency (ex. Cl, CF3, SCH3)
• R10 requires a 3 atom chain to bind to the receptor

Question 15

What are the adverse pharmacological effects associated with antipsychotic drugs? (autonomic, CNS, endocrine system, other)

Answer 15

autonomic -
- anticholinergics: loss of accomodation, dry mouth, difficulty urinating, constipation
- α adrenoceptor blockade: orthostatic hypotension, impotence, failure to ejaculate

CNS -
- DA receptor blockade: parkinson’s syndrome, akathasia, dystonias
- Supersensitivity of DA receptors: tardive dyskinesia
- Muscarinic blockade: toxic-confusional state
- H1 receptor blockade: sedation

Endocrine -
- DA receptor blockage resulting in hyperprolactinemia: amenorrhea-galactorrhea, infertility, impotence

Other -
- H1 + 5HT2C blockade: Weight gain

Question 16

What the key features that define psychotic disorders?

Answer 16

Positive symptoms:
- Delusions: fixed, false beliefs that are not changed even with conflicting evidence
- Hallucinations: Perception-like experiences that occur without an external stimulus (usually auditory, also visual, tactile, or olfactory)
- Disorganized thinking and speech: switching from one topic to another, unrelated answers to questions
- Disorganized or abnormal motor behavior

Negative symptoms: losing interest in motivations and relationships, etc.

Question 17

When do men and women usually develop schizophrenia?

Answer 17

Men - late teens/early 20s (this is earlier than women by 5-10 years)

Women - late 20s/early 30s (estrogen is protective)

Question 18

What does smoking have to do with schizophrenia? What effect can marijuana, cocaine, and amphetamine use have on schizophrenia?

Answer 18

Smoking - more than 75% of people with schizophrenia use tobacco
- Smoking induces 1A2 due to hydrocarbons that are produced and inhaled. This DECREASES serum concentration of 1A2 substrate antipsychotics (olanzapine, asenapine, clozapine, loxapine)!!!!!

Marijuana, cocaine, and amphetamine can hasten the onset of schizophrenia, exacerbate symptoms, and reduce time to relapse

*important to treat substance use with schizophrenia

Question 19

What is the most commonly used typical antipsychotic? What important side effect is more common with the typicals? How do the typicals affect positive and negative symptoms of schizophrenia?

Answer 19

Haloperidol is most commonly used, whether thats PRN or maintenance; Also given as a long-acting injection q4 weeks

EPS is common with the higher potency typicals

Typical antipsychotics are great for treating positive symptoms, but are likely to worsen negative symptoms and cognitive symptoms

Question 20

What are the clinical pearls for these atypical antipsychotics: Clozapine (+REMS requirements), Iloperidone, Lumateperone, Lurasidone, and Olanzapine

Answer 20

Clozapine - the MOST EFFECTIVE antipsychotic, requires REMS monitoring due to agranulocytosis, may cause cardiomyopathy, hypersalivation, hypotension, metabolic syndrome, and dose-related seizures. Is a 1A2 substrate
- REMS: monitor ANC weekly x 6 months, biweekly x 6 months, then q4 weeks.

Iloperidone - boxed warning for QTc prolongation, causes orthostatic hypotension. Is a 2D6 and 3A4 substrate.

Lumateperone - Is a D1/D2 partial agonist. Take with food to enhance absorption. Is a UGT and 3A4 substrate.

Lurasidone - MUST take with food to improve bioavailability. Higher risk of akathisia, lower risk of weight gain/metabolic syndrome. Is a 3A4 substrate.

Olanzapine - high risk of sedation, weight gain, hyperglycemia, hyperlipidemia, metabolic syndrome, anticholinergic effects at high doses. Is a 1A2 substrate.
- REMS

Question 21

What are the clinical pearls for these atypical antipsychotics: Paliperidone, quetiapine, risperidone, ziprasidone

Answer 21

Paliperidone - ER dosage can come out as a ghost tablet. Renally eliminated, so dose adjust in renal impairment, higher risk of EPS and hyperprolactinemia, moderate weight gain/metabolic syndrome

Quetiapine - boxed warning for QTc prolongation, risk of sedation, moderate weight gain/metabolic syndrome. Is a 3A4 substrate

Risperidone - Higher risk of EPS and hyperprolactinemia, moderate risk of weight gain/metabolic syndrome. Is a 2D6 substrate (produces paliperidone)

Ziprasidone - MUST be taken with food for bioavailability, lower risk of weight gain/metabolic syndrome and akathisia. No P450 metabolism

Question 22

How do you use the Asenapine transdermal patch (Secuado)? What are the warning and metabolism interactions?

Answer 22

Apply one patch every 24 hours, rotate patch site to minimize application site reactions.

Has a warning for QTc prolongation

UGT and 1A2 substrate (reduce the dose of the patch if it’s given with strong 1A2 inhibitors (ex. fluvoxamine))

Question 23

Which medication is approved for the treatment of hallucinations/delusions in a patient with Parkinson’s? What is its MOA and what is its metabolism interactions?

Answer 23

Pimavanserin
- MOA: inverse agonist and antagonist at the serotonin 5HT2A receptor (not DA)
- 3A4 substrate

Question 24

What is Samidorphan used for? What’s its MOA?

Answer 24

Samidorphan is used to mitigate the weight gain and metabolic syndrome of olanzapine (given as olanzapine/samidorphan)
- MOA: opioid antagonist with preferential activity at the mu opioid receptor

Question 25

What must be done with Risperdal Consta when initiating treatment? What kind of injection is Perseris and what metabolism interactions does it have?

Answer 25

Risperdal Consta (IM injection) - It MUST be supplemented with oral risperidone (or another oral antipsychotic) for the first few weeks of treatment. Until the 3rd injection, which is week 4. Perseris - LAI of risperidone, abdominal SQ injection; 3A4 substrate, use 120mg dose if 3A4 inducer or may need oral supplementation.

Question 26

How do you initiate Invega Sustenna and how is it eliminated? How do you initiate Invega Trinza and at what CrCL is it not recommended? When can you initiate Invega Hafyera and where is the injection?

Answer 26

Invega Sustenna - paliperidone (IM) - Initiation: loading dose, then booster, then injection q4 weeks starting 5 weeks after the loading injection. *the initial loading dose and booster dose must be given in the deltoid to improve absorption consistency **if loading strategy was followed, we don't need oral antipsychotic overlap - renally eliminated, so may require dose adjustment in moderate to severe renal impairment Invega Trinza - paliperidone (IM) - Initiation: Can be initated for a pt who has been on a stable monthly IM injection of Invega Sustenna for at least 4 doses; This is a q3mo IM injection *recommended to be given in deltoid, gluteal lowers Cmax - Not recommended in CrCL < 50mL/min Invega Hafyera - paliperidone (IM - gluteal) - Can be initiated after 4 months of Invega Sustenna or one 3 month dose of Invega Trinza *gluteal injection ONLY

Question 27

What is a serious side effect of Zyprexa Relprevv?

Answer 27

Zyprexa Relprevv - Olanzapine injection - PDSS: post-dose delirium sedation syndrome - on REMS program due to similar side effect of olanzapine (high risk of sedation, weight gain, hyperglycemia, hyperlipidemia, metabolic syndrome, anticholinergic effects at high doses)

Question 28

How can you initiate Abilify Maintena and where is it to be injected? When do you need to make dosage adjustments for Abilify Maintena?

Answer 28

Abilify Maintena - aripiprazole injection - MUST overlap with oral aripiprazole (or other oral antipsychotic) for at least 14 days after the first injection - Deltoid or gluteal injection - Dosage adjuments: If taking 2D6 inhibitor or 3A4 inhibitor or inducer for more than 14 days as concomitant therapy (lower dose with inhibitors, don't use with inducers)

Question 29

How can you initiate Aristada?

Answer 29

Aristada - aripiprazole lauroxil (prodrug) - overlap with oral aripiprazole for 3 weeks after the first injection

Question 30

What do we use for psychiatric emergencies? (immediate release antipsychotic injections)

Answer 30

- Haloperidol, chlorpromazine, fluphenazine are used, but haloperidol is used most commonly - Olanzapine IR IM CANNOT be given at the same time as benzodiazepine IR injection due to boxed warning for respiratory depression!! - Loxapine for inhalation is not commonly used due to REMS

Question 31

What are the 4 manifestations of EPS and how do we treat them?

Answer 31

acute dystonia - muscle group reaction that is not life-threatening, but very frightening. Give IM anticholinergic NOW dose (ex. benztropine 2mg, diphenhydramine 50mg) drug-induced parkinson's - oral anticholinergic (benztropine, trihexyphenidyl, diphenhydramine) akathisia - feeling of restlessness, increases risk for suicidal thinking/behaviors. Use beta-blocker (propranolol is 1st line), benzodiazepine (usually lorazepam) tardive dyskinesia - VMAT inhibitors

Question 32

What VMAT inhibitors can we use and what are the important side effects and metabolism interactions?

Answer 32

tetrabenazine - not FDA approved for TD, boxed warning for suicidality/depression, causes QTc prolongation valbenazine - FDA approved, causes QTc prolongation, 2D6 and 3A4 substrate deutetrabenazine - FDA approved, causes QTc prolongation, 2D6 substrate

Question 33

What is neuroleptic malignant syndrome?

Answer 33

Neuroleptic malignant syndrome - life-threatening medical emergency that is caused by the effects of antipsychotics on dopamine blockade. Symptoms include hyperpyrexia, tachycardia, labile blood pressure, muscle rigidity, significantly elevated CK, myoglobinuria Treatment is supportive, d/c antipsychotics, consider DA agonists Future antipsychotic use is NOT contraindicated (you can even use the same drug, but likely switch to another antipsychotic)

Question 34

What are the adverse effects of metabolic syndrome? Which agents have the most/least risk of this?

Answer 34

metabolic adverse effects - hyperglycemia, hyperlipidemia, hypertension, etc. Most - clozapine & olanzapine Mid - quetiapine, risperidone, paliperidone, asenapine, iloperidone, cariprazine, brexpiprazole Least - Ziprasidone & Lurasidone & Aripiprazole

Question 35

When do we monitor personal/family hx, weight, waist circumference, blood pressure, A1c, and fasting lipids for metabolic monitoring?

Answer 35

personal/family hx - at baseline & yearly weight - baseline and q4 weeks-q3 months waist circumference - baseline & yearly BP - baseline, q3 months & yearly A1c - baseline, q3 months & yearly fasting lipids - baseline, q3 months, q5 years

Question 36

What are important warnings for all antipsychotics?

Answer 36

- Boxed Warning: increased risk of death in elderly pts treated with antipsychotics for dementia w/ related behaviors - Metabolic adverse effects - EPS - Risk of somnolence, postural hypotension, and motor/sensory instability increases fall risk *fall risk assessment should be performed for pts at higher risk of falling

Question 37

What are the general considerations for depression? What's the basis behind the individual hypotheses? (biogenic amine, neurodendocrine, neurotropic)

Answer 37

clinical features - when the physiological symptoms (decreased sleep, appeptite changes, fatigue, etc) and psychological symptoms (dysphoric mood, worthlessness, excessive guilt) and cognitive symptoms (decreased concentration, suicidal ideation) get so severe that they interfere with your life biogenic amine hypothesis - due to depletion of NE and 5HT. We've seen that reserpine, which causes depletion of NE and 5HT from vesicles causes depresison. We also know that agents that increase 5HT and NE treat depression. Also mutations in the SERT, NET, and DAT (minor) transporters can affect depression. Additionally, alterations in 5HT1A/2C and α2 receptors neuroendocrine hypothesis - overactivity of HPA and elevated CRF is found in almost all depressed pts and can lead to other negative effects. Antidepressants and ECT reduce CRF levels neurotropic hypothesis - decreased BDNF is related to depression. Decreased volume of the hippocampus is also involved (regulates HPA + memory). Loss of BDNF = less dendritic sprouts for neurological processes

Question 38

How are the individual hypothesis of depression integrated with each other? Esp. involving BDNF and HPA axis

Answer 38

- HPA and steroid abnormalities regulate BDNF levels (more BDNF is good, overactivity of HPA is bad) - During stress, hippocampal glucocorticoid receptors are activated by cortisol, which results in a decrease in BDNF - BDNF is increased with chronic activation of monoamine receptors for over 2 weeks - Chronic activation of monoamine receptors also downregulates HPA axis

Question 39

What are the proposed MOAs associated with these antidepressants: MAOIs, TCAs, SSRIs, SNRIs

Answer 39

MAOIs - Block the breakdown of NE and 5HT by monoamine oxidase (MAO), thus increasing their concentration in the synapse - non-selective MAO inhibitors (irreversible): phenelzine, tranylcypromine - MAO-B selective (reversible): selegiline - MAO-A selective (reversible): moclobemine TCAs - - tertiary amines inhibits NE and 5HT reuptake through NET and SERT (also muscarinic, histamine, and adrenergic antagonists); Ex. imipramine, amitrytyline (both of these have active metabolites), doxepin, clomipramine - secondary amines are more selective for NE than 5HT; Ex. desipramine, nortriptyline, protriptyline, and maprotiline; These cause less side effects SSRIs - Blocks reuptake of 5HT through SERT, which allows serotonin to stay in the synapse for longer - fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram SNRIs - NET & SERT inhibitors - venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran

Question 40

What are the proposed MOAs associated with these antidepressants: 5-HT2 antagonists, tetracyclic and unicyclic antidepressants, NSRIs

Answer 40

5-HT2 antagonists - - trazodone is a 5HT2a antgonist and weak SERT inhibitor. Almost always used for sleep, not depression tetracyclic and unicyclic antidepressants - - Maprotiline is a NET inhibitor (4º) - Mirtazapine is an α2 antagonist, 5HT2/T3 antagonist, and H1 antagonist (4º) - Bupropion is a DAT inhibitor, NET/SERT inhibitor (1º) NSRIs - norepinephrine selective reuptake inhibitors; These are very similar to secondary amine TCAs, but have less side effects - reboxetine (can't be used in the US) - atomoxetine (not approved for depression, used for ADHD)

Question 41

Which receptors are associated with the side effects of antidepressants?

Answer 41

MAOIs - headache, drowsiness, dry mouth, weight gain, orthostatic hypotension, sexual dysfunction *avoid foods with tyramine TCAs - QTc prolongation (extremely dangerous), sedation, anticholinergic, autonomic effects, weight gain - secondary amines have a better side effect profile than the tertiary amines SSRIs - N/V, headache, sexual dysfunction, anxiety, insomnia, tremor (these are all pretty modest), serotonin syndrome risk *avoid abrupt d/c SNRIs 5-HT2 antagonists tetracyclic and unicyclic antidepressants

Question 42

What newer antidepressants (dual/multiple actions or rapidly acting) may have advantages or different applications compared to the other agents?

Answer 42

SSRI + HT1A partial agonists - vilazodone (Viibryd), vorioxetine (Brintellex) - these have reduced sexual side effects vs. pure SSRIs, but as a whole are pretty similar to the SSRIs NMDA antagonists - ketamine at subanesthetic doses, esketamine (intanasal, REMS); These are rapid acting

Question 43

How does Brexanolone work for post-partum depression?

Answer 43

allopregnanolone levels are increased during pregnancy. It's thought that GABA-A receptors may desensitize during this. Postpartum, allopregnanolone levels return the normal. Brexanolone resensitizes these GABA-A receptors.

Question 44

How does filbanserin (addyi) work?

Answer 44

Filbanserin - agonist at 5HT1A, antagonist at 5HT2A/C - used for hypoactive sexual desire disorder, but it was developed as an antidepressant - selective at prefrontal cortex *controversial approval

Question 45

What are the major structural differences between MAOIs, TCAs, and SSRIs?

Answer 45

MAOIs - one ring with carbon chain TCAs - 3 ring structure SSRIs - don't look like a 3 ring connected structure. Usually has at least one-two aromatic rings

Question 46

What therapeutic agents are available for the treatment of mania/bipolar disorder and what are their important side effects and when do they occur?

Answer 46

lithium - very dirt drug. Mechanism is not clearly understood, but involves depletion of PIP2 & its associated signaling. Also modulate GSK2. - SE: anticonvulsants - - valproate increases GABAergic tone, block Na+ channels, block T-type Ca2+ channels, inhibits histone deacetylase (HDAC5) - carbamazepine/oxcarbazepine work on Na+ channels - lamotrigine works on Na+ and Ca+ - topiramate works on Na+ and may enhance GABA atypical antipsychotics - these are dirty drugs (but not as dirty as lithium) - olanzapine, quetiapine, risperidone, ziprasidone, lurasidone, aripiprazole

Question 47

What are the risk factors for depression? What does SIGECAPS represent? What are risk factors for suicide?

Answer 47

Risk factors for depression - feelings of guilt, chronic fatigue/headache, sleep disturbances, loss of sexual interest, agitation, anxiety, hopelessness S - sleep (too much or not enough) I - interest (loss of interest in things they used to like) G - guilt (excessive guilt) E - energy (not enough) C - concentration (unable to stay concentrated) A - appetite (over/under) P - psychomotor (move slower, no motivation to keep moving) S - suicide Risk factors for suicide - have a detailed plan, anniversary or loss, widowed/unmarried, substance misuse, increasing age, unemployment, gender (more women when younger, more white men when older), living alone, physical or mental illness, family history, lack of social support, PRIOR ATTEMPTS

Question 48

What are the two diagnostic criteria for depression?

Answer 48

1. depressed mood most of the day nearly every day 2. markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day

Question 49

What medications can contribute to depression symptoms?

Answer 49

- beta blockers - hormonal therapy - isotretinoin - CNS depressants - interferon-beta - levetiracetam - atomoxetine - indomethacin

Question 50

What are the natural products for depression? What metabolism interactions are there?

Answer 50

- St. John's wort: CYP450 3A4 inducer, causes photo toxicity - SAMe (S-adenoxyl-L-methionine) These two agents can also increase the risk of serotonin syndrome, leading to severe N/D, dizziness, headache, agitation, tachycardia, hallucinations

Question 51

what is the step-wise approach to treatment of depression?

Answer 51

Week 1 - better appetite Week 2 - better sleep/energy *in weeks 1/2, anxiety will be increased, so anxiolytics may be needed Week 4 - better mood Week 6 - increased mood (the goal is absence of symptoms) Months 2-3 - efficacy can be properly assessed Months 4-9 - continuous phase (goal is to eliminate residual symptoms/prevent relapse) Months 12-36 - (goal is to prevent the recurrence of depression)

Question 52

What warning do all antidepressants have for patients age 24 or younger?

Answer 52

Increased risk of suicidal thinking and behavior *there's actually a protective factor for ages ≥65 years old **medguides are required for all antidepressants

Question 53

Which antidepressants are serotonergic?

Answer 53

Amphetamines Buspirone Cocaine Dextromethorphan Fentanyl Lithium Linezolid LSD Serotonin agonists (ex. triptans) Serotonergic antidepressants - SSRIs, SNRIs, TCAs, etc. St John's Wort Tramadol

Question 54

What are the clinical pearls for these SSRIs: citalopram, escitalopram, fluoxetine, paroxetine, sertraline,

Answer 54

citalopram - high rates of QTc prolongation, which is why it requires dose adjustment in elderly, doses above 40mg are most effective for antidepressant effect escitalopram - has less QTc prolongation than citalopram, but it's still significant fluoxetine - has stimulating effect (insomnia, resting tremor), has the longest half life of SSRIs, Sarafem is used for PMDD paroxetine - Brisdelle is for moderate-severe vasomotor symptoms that are associated with menopause. This is anticholinergic and ALWAYS needs to be tapered *lean away from this one sertraline - preferred for patients with cardiac risk, this is the best tolerated

Question 55

Which P450 interactions do these drugs have: Fluoxetine, Fluvoxamine, Paroxetine, Bupropion

Answer 55

Fluoxetine - 2D6, 2C19 Fluvoxamine - 1A2, 2D6, 2C19, 3A *pretty much only used for OCD Paroxetine - 2D6 Bupropion - 2D6

Question 56

What happens when we discontinue SSRIs? (esp. abruptly)

Answer 56

F - flu-like symptoms L - lightheadedness U - uneasiness S - sleep disturbances H - headaches

Question 57

What are the clinical pearls of these SNRIs: venlafaxine, desvenlafaxine, duloxetine, levomilnacipran

Answer 57

venlafaxine - can increase BP and QTc, it in the preferred agent in combination with tamoxifen, it's most likely for a patient to switch into mania with this one, need at least 150mg/day to get the NE benefit desvenlafaxine - better 5HT/NE balance than venlafaxine, has no CYP interactions duloxetine - can be used for musculoskeletal diagnoses, has high affinity for reuptake sites and has more balanced activity between the two levomilnacipran - has more emphasis on NE than 5HT, which increases tolerability with sexual dysfunction

Question 58

What is bupropion's MOA, adverse effects, clinical pearls, and dosing for depression?

Answer 58

MOA - dopamine norepinephrine reuptake inhibitor (DNRI) - AEs: weight loss, decreases seizure threshold, insomnia - Pearls: contraindicated in pts with hx of seizures, disordered eating, or recent alcohol/sedative withdrawal. Also has risk of abuse. It's a good alternative if pt is having sexual dysfunction with other antidepressants. Contrave is used for weight management Dosing: - Daily dose limits: 450mg IR/XL, 400mg for SR - Single dose limits: 150mg for IR, 200mg for SR, 450mg for XL

Question 59

What are the 2 SARIs for depression and what are their clinical pearls?

Answer 59

SARI - serotonin antagonist reuptake inhibitors trazodone - has dose-related priapism, mostly used for sleep, requires dosing of 300-600mg for antidepressant effect nefazodone - has black boxed warning for liver failure

Question 60

What are the multi-modal antidepressants (3) and what are their clinical pearls?

Answer 60

mirtazapine - makes you hungry, happy, and sleepy. fors at H1, 5HT, and a stimulating effect at higher doses *one of the favs to adjunct with SSRIs vilazodone - can cause nausea, take with food, less sexual dysfunction voritoxetine - less sexual dysfunction *vilazodone and voritoxetine increase serotonin reuptake, push serotonin into the synaptic gap, should work in treatment-resistant depression due to to dual mechanisms

Question 61

What are the adverse effects of TCAs? What is the titration process?

Answer 61

Tricyclics - Amitriptyline, Imipramine (most weight gain), Doxepin - AEs: anticholinergic effects such as sedation, weight gain, orthostasis, anticholinergic effects, and CARDIAC TOXICITY Dosing taper: - start with 25mg/qHS and increase by 25-50mg every 3-4 days until response - 1g can be considered FATAL (potassium changes and seizure risk) - MUST TAPER over 1-2 weeks

Question 62

How can we switch/taper these: serotonergic to serotonergic, SNRI to SSRI, fluoxetine to d/c, paroxetine to anything else

Answer 62

serotonergic -> serotonergic = can directly switch SNRI -> SSRI = must taper the SNRI when we switch to an SSRI because we aren't covering norepinephrine with the new medication fluoxetine -> d/c = has a long half life, so we don't have to taper paroxetine -> d/c = must ALWAYS be tapered due to cholinergic rebound and flu-like symptoms

Question 63

What are the MAO inhibitors for depression? What type of diet is necessary for MAO inhibitors? How can we switch to MAOIs? What's different about the selegiline patch?

Answer 63

MOAIs are very last line for depression due to side effects! - phenelzine, tranylcypromine, isocarboxazid, selegiline Need tyramine diet because tyramine is increased with MAOIs, which increases BP. With this diet, you CANT eat: - smoked, aged, pickled meats or fish, sauerkraut, aged cheeses, yeast extracts, etc. Need to have at least 14 day wash out period between serotonergic agents (5 weeks with fluoxetine) Selegiline patch doesn't require the tyramine diet for the 6mg dose, but 9mg and 12mg do require the diet

Question 64

What is esketamine used for? What are some clinical pearls about esketamine? What warnings are associated with it?

Answer 64

Esketamine (spravato) is an NMDA receptor antagonist that is used for treatment resistant depression and acute suicidality. - It MUST be used as adjunct (not monotherapy) - It is an active metabolite of ketamine - REMS *this is one of the 3 drugs that reduces suicidality Warnings: dissociation or perceptual changes, sedation, misuse, BP elevations, short-term cognitive impairment, etc.

Question 65

What is serotonin syndrome?

Answer 65

When there is too much serotonin, it can cause serotonin syndrome, leading to severe nausea, dizziness, headache, diarrhea, agitation, tachycardia, and hallucinations. SSRIs, SNRIs, TCAs are serotonergic MAOIs can contribute to serotonin syndrome

Question 66

What antidepressants can we or can we not combine? Ex. SSRI + SNRI, + bupropion, + mirtazapine, +atypical antipsychotics

Answer 66

SSRI + SNRI = do not combine due to duplicate MOAs + bupropion = can add if the pt would benefit from the side effects, such as increased motivation, stimulation, or decreased appetite. Don't add if the patient is already not eating or sleeping + mirtazapine = add if the pt would benefit from the side effects, such as increased appetite and sedation. Avoid if the pt is overeating, obese, or sleeping too much + atypical antipsychotics = lurasidone, quetiapine, and brexpiprazole are FDA approved as adjunct to antidepressants

Question 67

What medication can be used for post-partum depression? How is this medication given?

Answer 67

Brexanolone - positive allosteric modulator of GABA-A receptors. - REMS program due to excessive sedation and loss of consciousness - Given as a 60 hour infusion post-partum

Question 68

What changes have been made in the DSM-5 related to diagnostic criteria?

Answer 68

DSM-5TR had further SDOH and cultural factors in diagnosis. They dropped the multi-axial assessment and reorganized to reflect disorders across a continuum based on developmental and lifespan considerations. - neurodevelopmental disorders: disorders previously referred to as childhood diagnoses (ex. ADHD, autism, etc.) - schizophrenia: now a spectrum - anxiety: anxiety disorders and obsessive-compulsive, trauma, and stressor related disorders are separate - substance use disorders: have set criteria - neurocognitive disorders: includes dementia, alzheimer's, etc.

Question 69

What do these rating scales assess and it is clinician or patient-rated: patient health questionnaire (PHQ-9), beck depression inventory (BDI), mood disorders questionnaire (MDQ), hamilton depression (HAM-D, HDRS), montgomery-asberg depression rating scale (MADRS), young mania rating scale (YMRS), hamilton anxiety rating scale (HAM-A)

Answer 69

PHQ-9: depression and suicidal thinking, patient BDI: attitudes and characteristics of depression, patient MDQ: bipolar I (mania and depression), patient HAM-D, HDRS: depression research, clinician MADRS: depression research, clinician YMRS: symptoms of bipolar disorder and generalized anxiety at baseline and over time, clinician HAM-A: psychic and somatic anxiety, clinician

Question 70

What do these rating scales assess and it is clinician or patient-rated: positive and negative syndrome scale (PANSS), brief psychiatric rating scale (BPRS), simpson-angus (SAS), barnes akathisia scale (BARS), abnormal involuntary movement scale (AIMS), extrapyramidal symptoms rating scale (ESRS), clinical global impressions (CGI), global assessment of functions (GAF)

Answer 70

PANSS: schizophrenia symptoms and antipsychotic efficacy, clinician BPRS: very similar to PANSS, clinician SAS: drug-induced parkinsonian symptoms, clinician BARS: observation of akathisia, clinician AIMS: tardive dyskinesia, clinician ESRS: parkinsonian symptoms, akathisia, dystonia, TD, clinician CGI: overall psychiatric functioning, clinician GAF: overall psychiatric functioning, clinician

Question 71

What are the 4 main characteristics of bipolar disorder?

Answer 71

Mood - euphoric Activity - impulsive behavior - challenging cognitive - grandiosity

Question 72

Which medications can cause/contribute to drug-induced mania?

Answer 72

amphetamines antidepressants (MAOIs, TCAs, 5-HT/NE/DA reuptake inhibitors, 5-HT antagonists) caffeine decongestants dopamine agonists hallucinogens (LSD, PCP) steroids (anabolic, ACTH, corticosteroids theophylline thyroid meds *a toxicology screen should be done prior to starting treatment to rule out drug-induced mania

Question 73

What is lithium FDA-approved for in bipolar disorder? What are the therapeutic and toxic serum concentrations? What drug interactions could increase or decrease lithium serum concentration? What are important counseling points? Can we use in pregnancy?

Answer 73

- FDA approved for acute mania and maintenance therapy. It is effective for acute bipolar depression. It has a slower onset (steady state is reached after 3 days, onset of action is 1-2 weeks) - Cannot use in CrCL under 30mL/min - therapeutic goal = 0.6-1 mEq/L, 0.8-1.2 mEq/L for mania - toxic levels > 1.5mEq/L (N/V/D -> death if >2.5) - increase risk of toxicity: dehydration, use of diuretic, excessive use of alcohol, fever (may need dialysis if conc is too high) - increase conc: NSAIDs, ACEi/ARBs, thiazides, caffeine - decrease conc: osmotic diuretics, caffeine - decreases CrCL by 2mL/min per year while on lithium - pregnancy: Ebstein's Anomaly causing heart defects; but it can be used during breastfeeding *lithium is like salt. it follows water

Question 74

What is the difference between mania and hypomania? Why does it sometimes take longer for an appropriate bipolar diagnosis?

Answer 74

mania - distinct period of abnormally and persistently elevated, expansive, or irritable mood & abnormally and persistently increased activity/energy, lasting as least 1 week and is present for most of the day, every day. Has qualities of grandiosity, euphoria, and impulsivity. hypomania - abnormal mood/energy lasts 4 days. Has qualities of mild euphoria, expansive speech, and a reduced need for sleep. Hypomania does not affect social/work functioning and does NOT cause psychosis or hospitalization

Question 75

What is the difference in bipolar I and II?

Answer 75

bipolar I - at least 1 episode of mania that significantly impairs social/work functioning, causes psychosis or delusions, or requires hospitalization WITH bouts of intense depression bipolar II - at least one episode of HYPOmania (at least 4 consecutive days) and at least one depressive episode

Question 76

What are the choices for mood stabilizers?

Answer 76

lithium - FDA approved for acute mania and maintenance therapy. It decreases suicide risk by 8-10x. Can be very toxic >1.5 mEq/L. Can't be used in pregnancy. valproic acid - FDA approved for acute mania and maintenance therapy. Can't be used in pregnancy. Hyperammonemia is a big concern. carbamazepine - 2nd or 3rd line. Don't use in pregnancy. HLA*1502 testing needed. Big CYP450 inducer oxcarbazepine - 2nd or 3rd line. Don't use in pregancy. HLA*1502 testing needed. May be used as adjunct. More hyponatremia than carbamazepine, but less hematologic effects. lamotrigine - one of the best options for bipolar 2. 1st line for DEPRESSIVE symptoms, but not useful for acute or manic treatment. Huge SJS risk!! topiramate - used as adjunctive treatment. Need slow dose titration due to cognitive deficits. Teratogen. atypical antipsychotics - chlorpromazine for acute mania, quetiapine/lurasidone/cariprazine for bipolar depression, aripiprazole/olanzapine for maintenance. *we CAN combine mood stabilizers (provides better response & long-term prevention of relapse **don't use more than one atypical antipsychotic at one time

Question 77

What is the therapeutic serum concentration of valproate? What are the drug interactions, boxed warnings, and adverse effects of valproate? Can it be used in pregnancy?

Answer 77

Valproate is FDA approved for acute mania and maintenance therapy. Most formulations are NOT interchangeable. - therapeutic range: 50-125mcg/mL (levels need to be at least 60 to see efficacy, steady state is reached after 3 days) - drug interactions: lamotrigine, phenytoin (hepatotoxicity and/or hyperammonemia), warfarin (elevated INR) - boxed warnings: hepatoxocity (esp. children <2yo), pancreatitis, pts with mitochondrial disease, teratogenicity (decreases IQ, neural tube defects), pts with migraines - adverse effects: hyperammonemia, weight gain, alopecia, PCOS, pancreatitis, sedation/ataxia *always check for acute changes in mental status and get an ammonia level **can't be used in pregnancy

Question 78

What are the FDA-approved drugs for bipolar depression? What is the best choice for depression symptoms, but not mania for bipolar disorder? Which agents should we avoid and why?

Answer 78

FDA-approved: lurasidone, quetiapine, cariprazine Depression (not mania) symptoms: lamotrigine Avoid: TCAs and venlafaxine - risk of manic switch - antidepressants may not be very effective for depression in bipolar disorder

Question 79

What 3 medications can decrease suicidal ideation?

Answer 79

Clozapine Lithium Esketamine

Question 80

Bipolar disorder: What is first line for acute mania? What is first line for acute bipolar depression? What is first line for maintenance?

Answer 80

Acute mania - quetiapine, + divalproex OR lithium; 2º is switching divalproex and lithium; 3º is carb/oxcarb Acute depression - divalproex, atypicals, lamictal, olanzapine/fluoxetine; 2º switch from these; 3º carb/oxcarb Maintenance - lithium, olanzapine, divalproex

Question 81

What is the difference between a sedative, anxiolytic, hypnotic, are narcotic?

Answer 81

sedative - calms anxiety, decreases excitement and activity, does not produce drowsiness or impair performance anxiolytic - relieves anxiety without sleep or sedation (not all anxiolytics are sedatives) hypnotic - induces sleep, implies restful, refreshing sleep (sleep-inducing) narcotic - sleep producing, but now refers to opioids or illegal drugs

Question 82

How is the reticular formation involved in anxiety and sleep disorders?

Answer 82

The reticular formation (medulla oblongata, pons, midbrain, etc.) is very complex. It contains dopamine, adrenergic, serotonergic, and cholinergic neurons. It regulates sleep-wake transitions and synchronization of EEG.

Question 83

What are the stages of sleep? What are some factors that regulate sleep?

Answer 83

Stages of sleep: - Wakefulness - Non-rapid eye movement (NREM) slow-wave sleep: really deep sleep. Has 4 stages. EEG looks very different. - Rapid eye movement (REM) sleep: EEG looks almost as if you are awake Factors that regulate sleep: - Age: sleep decreases w/ age due to changes in activity of reticular formation - Sleep history: rebound of REM sleep - Drug ingestion: acute and withdrawal produce rebound effects - Circadian rhythms: "normal sleep cycle"

Question 84

What are the neurotransmitters and neuromodulators that are biological regulars of sleep?

Answer 84

Neurotransmitters - Almost all of them regulate sleep - catecholamines - serotonin - GABA (main target for current medications, GABA-A, GABA-B, GAT-1, GABA-T) - etc. Neuromodulators: - Growth hormone - Prolactin - Melatonin - Cortisol - etc.

Question 85

Where do benzodiazepines find on the GABA receptor? How do they work for anxiety/sleep disorders? What are the Z-Hypnotics and where do they bind? Which Z-hypnotic is approved for long-term use?

Answer 85

Benzodiazepines bind to an allosteric site in the α1 and γ2 sites on the GABA receptor. This binding site is called the BZD receptor. Benzos facilitate GABA action by increasing frequency. Z-Hypnotics (zolpidem, zalepon, and eszopiclone) bind to BZ1 receptors on the α1 subunit of GABA. - These are more safe because they only bind to the BZ1 region. - only eszopiclone is approved for long-term use, but we see all of them used in practice. - these are better for sleep than benzos, but need to warn about sleep-driving, sleep-cooking, sleep-sex, etc. *-flumazenil is a BZD antagonist that is used for overdose treatment of the benzos and z-hypnotics

Question 86

How do BZDs, barbiturates, and alcohol modulate the GABA-A receptor?

Answer 86

BZDs - increase frequency of channel opening Barbiturates - increase duration of channel opening and have direct effects on GABA-A at high doses alcohol - enhances actions of GABA on GABA-A receptor. Alcohol is very dirty

Question 87

What is important to know about the metabolism of benzodiazepines? Which drugs have slow, intermediate, and rapid elimination rates?

Answer 87

- benzodiazepines can be metabolized at position 1. This is a source of active metabolites. This can be the difference between some benzos having a long vs short half life *diazepam has a long half-life (oxazepam is an active metabolite of diazepam). This is why it's used for seizures. *clonazepam has an intermediate elimination rate and is used as an anticonvulsant *midazolam is rapidly eliminated, thus it's used as anesthesia

Question 88

What makes benzos and barbiturates different?

Answer 88

- Benzos are safer than barbiturates because there is a plateau of CNS effects. The most you could do is anesthesia. But these decrease REM and stage 3-4 sleep. - Barbiturates can cause coma and death because there is not this plateau *benzos also can be antagonized by flumazenil, which makes it safer

Question 89

Which barbiturates are long acting vs. short-intermediate acting? What are some of the dangerous side effects of the BBTs?

Answer 89

long - phenobarbital (anticonvulsant) short-intermediate acting - pentabarbital (sedative/hypnotic) *risk for respiratory depression -> death

Question 90

What are the differences between the BZDs, BBTs, and Z-Hypnotics in terms of where they bind to GABA-A and their risk for patients?

Answer 90

benzodiazepines (BZDs) - bind to all GABA-A α1-5; these increase the frequency of GABA-A channel opening. These have a medium risk barbiturates (BBTs) - bind to all GABA-A α1-5; these increase the duration of channel opening and also have direct effects on GABA-A at higher doses. These have a high risk Z-Hypnotics - bind to GABA-A BZ1 receptors of α1. these increase the frequency of GABA-A channel opening. These have a low risk

Question 91

What are drugs that can cause anxiety?

Answer 91

albuterol caffeine (high dose) decongestants (pseudoephedrine, ephedrine) levothryroxine steroids stimulants (ADHD meds)

Question 92

How does buspirone work in anxiety? What is it approved for? What is the target dosing and how long does it take to work?

Answer 92

buspirone - 5HT-1a receptor agonist - Approved for generalized anxiety disorder - Dosing: 30-45mg total/day, so 10-15mg TID (need to titrate up due to side effects) - May take up to 3-4 weeks for initial efficacy. Technically only works long-term.

Question 93

How is benzodiazepine use for anxiety viewed? What are some warnings/recommendations? What are some of the side effects?

Answer 93

Due to misuse potential, benzodiazepines are usually not supported. But they have shown to be more effective than serotonergic agents. - Long term use is not recommended - Acute withdrawal of benzos may lead to seizures that can be life-threatening (requires a slow taper over weeks-months) - There is overdose risk and a warning against using benzodiazepines + CNS depressants Side effects: - sedation - paradoxical excitement - swallowing difficulties - impairment of memory and recall - psychomotor impairment

Question 94

Which 4 BZDs do not have an active metabolite? Which 3 BZDs have a long-acting active metabolite? Which 3 agents are preferred if needed to use in elderly?

Answer 94

No active metabolite: COAL (less likely to accumulate, so less of a fall risk) - clonazepam - oxazepam - alprazolam - lorazepam Long-acting active metabolite: DCC - diazepam - clorazepate - chlordiazepoxide Eldery - LOT - lorazepam - oxazepam - temazepam

Question 95

What is hydroxyzine approved for in anxiety? How is it used? What are some side effects? What patient population should we avoid using hydroxyzine in?

Answer 95

Hydroxyzine - approved for generalized anxiety disorder - Used PRN for anxiety or insomnia instead of a BZD - Side effects: sedation, anticholinergic side effects, QTc prolongation risk (not the biggest issue) - avoid use in elderly due to anticholinergic side effects and fall risk

Question 96

How is propranolol used in anxiety? What comorbidities to we need to evaluate before prescribing?

Answer 96

Propranolol - useful for performance and situational anxiety as PRN. Use low doses - Evaluate for history/current asthma and cardiovascular conditions

Question 97

What are some of the natural products we can use for anxiety? Which product do we want to avoid due to hepatotoxicity?

Answer 97

- St. John's Wort (watch for 3A4 interactions, since it's an inducer) - Passionflower (avoid in pregnancy) - Valerian (avoid in pregnancy) - Chamomile AVOID Kava

Question 98

What are the 1st line therapies for anxiety disorders? When can gabapentinoids be considered for anxiety?

Answer 98

1st line - SSRIs/SNRIs are 1st line for all anxiety disorders - buspirone can also be used 1st line for GAD - BZDs are FDA approved to treat anxiety disorders, but guidelines suggest against them *Consider in pts with bipolar disorder who have anxiety or comorbid neruopathic pain

Question 99

What is the DSM-5 criteria for generalized anxiety disorder?

Answer 99

Generalized Anxiety Disorder - excessive anxiety/worry present for at least 6 months Symptoms: (at least 3 of the following) - restlessness/feeling keyed up or on edge - being easily fatigued - difficulty concentrating or mind "going blank" - irritability - muscle tension - sleep disturbances

Question 100

How do we treat generalized anxiety disorder?

Answer 100

1º maintenance treatment - SSRIs (takes 2-4 weeks to work) If pt also has a pain syndrome - SNRIs - can use benzos as a bridge therapy to cover the time until the onset of SSRI/SNRI, but MUST taper if the pt has been taking them long term to avoid withdrawal - buspirone or PRN hydroxyzine may also be useful

Question 101

What is the DSM-5 criteria for social anxiety disorder? How do we treat it?

Answer 101

Social anxiety disorder - persistent fear about social and/or performance situations in which the patient fears embarrassment or humiliation that is unreasonable - duration of symptoms is at least 6 months 1º SSRIs (SNRI if failure of SSRI) - beta blockers may be useful in non-generalized performance-related SAD

Question 102

What is the DSM-5 criteria for panic disorder? How do we treat it?

Answer 102

Panic disorder - recurrent, unexpected panic attacks. At least one attack has been followed by one month or more of persistent concern about addition attacks or significant maladaptive change in behavior related to the attacks. 1º SSRIs - venlafaxine (SNRI) is FDA approved - benzos shouldn't be considered first line unless there has been an inadequate response to serotonergic drugs

Question 103

What is the DSM-5 criteria for obsessive-compulsive disorder? How do we treat it?

Answer 103

Obsessive-compulsive disorder - obsessions and compulsions that are excessive/unreasonable 1º SSRIs (can expect 25-50% reduction in symptoms) 2º clomipramine (TCA) if patient has failed a few trials of different SSRIs - antipsychotics are not FDA-approved, but can be used as adjunct with SSRIs/SNRIs (risperidone & aripiprazole)

Question 104

What is the DSM-5 criteria for posttraumatic stress disorder? How do we treat it?

Answer 104

Posttraumatic stress disorder - exposure to real or threatened death, serious injury, or sexual violence (either victim, witness, discovery, exposure to details of traumatic event). Pt experiences flashbacks, reexperiencing, avoidance, hypervigilance. This causes negative alterations in mood or cognition. 1º SSRIs/SNRIs (these are the only drugs that are FDA approved for PTSD) - prazosin may be helpful for sleep or nightmares at low doses - benzodiazepines are NOT recommended - polytherapy is common - substance use is common - CBT and eye movement desensitization and reprocessing may be helpful *drug therapy may be more effective in civilian trauma (one-time event) vs combat trauma, so non-drug treatments are especially useful

Question 105

Why do we want SSRI/SNRI doses to start lower in anxiety than in depression?

Answer 105

Jitteriness can result from SSRIs/SNRIs when treating anxiety, so initial doses should be lower.

Question 106

What are the differences between GABA-A and GABA-B? Which drugs target the different receptors?

Answer 106

GABA-A: chloride ion channel - BZDs, BBTs, z-hypnotics GABA-B: Gi coupled (inhibitory); located in brain and limbic system - it's a heterodimer with a unique binding site. Need GABA to bind to B1, then B2 will be activated for Gi action. - agonist: baclofen, GHB - antagonist: mostly for research purposes; phaclofen, saclofen, 2-hydroxysaclofen

Question 107

GHB - how/where does it work, what are concerns with it

Answer 107

GHB is a very dirty drug. It hits GABA-B, GABA-A, etc. The mechanisms isn't really known. It can cause CNS depression (dizziness, drowsiness, coma) Concerns: - No antagonist - Date-rape drug - amnesia

Question 108

How does ramelteon work? What do we use it for? Does it cause dependency/withdrawal?

Answer 108

Ramelteon - melatonin agonist. It binds to MT1 and MT2. - Treats insomnia characterized by difficulty with sleep onset - No abuse, no withdrawal, no dependency!

Question 109

How does suvorexant work?

Answer 109

Suvorexant - orexin antagonist. Orexin is at the hypothalamus. This signal is promoting wakefulness. In order for people to go to sleep, we want to reduce orexin signaling. Antagonizing this receptor can reduce reward stimulti via receptors that mesolimbic projections between the VTA and nucleus accumbens.

Question 110

What OTC antihistamines are used for sedation?

Answer 110

diphenhydramine doxylamine pyrilamine

Question 111

Which neurotransmitters are involved with anxiety?

Answer 111

Norepinephrine - stimulates autonomic nervous system. NE is dysregulated in GAD and other types of anxiety. It projects to the amygdala (fear center). GABAergic system - GABA/glutamate balance is important. glutamate is converted to GABA by glutamic acid decarboxylase. We want more GABA signaling in anxiety. Serotonin - 5HT1A receptors are effective Corticoptropin-releasing factor (CRF) and the HPA axis - hyperregulation is bad.

Question 112

Which disease states, medications, and substances are associated with insomnia? (9)

Answer 112

anxiety amphetamines beta agonists beta blockers bupropion decongestants methylphenidate modafinil mood disorders thyroid meds

Question 113

What is the DSM-5 criteria for insomnia disorders? How do we treat it?

Answer 113

Insomnia - difficulties with sleep initiation (latency), sleep maintenance, and/or early morning awakening. - at least 3x per week for at least 3 months 1º is non-pharm treatment (behavioral therapies, sleep hygiene) - Z-hypnotics (zolpidem, eszopiclone, zaleplon) are the most commonly used *initial dose of zolpidem is lower in women (5mg) *z-hypnotics are 3A4 substrates

Question 114

what are the two melatonin agonists we use for insomnia disorders? What are the contraindications and side effects, FDA approvals, and metabolism interactions for these agents?

Answer 114

Ramelteon - - contraindicated with fluvoxamine - side effects: GI upset, next day somnolence, hyperprolactinemia, prolactinoma Tasimelteon - FDA approved for non-24 sleep-wake disorder in adults - same side effects as ramelteon *1A2 substrates

Question 115

What are the 3 orexin receptor antagonists? How much sleep do pts on these need to have? What are their contraindications?

Answer 115

suborexant lemborexant daridorexant These all need the pt to get 7 hours of sleep. These are all contraindicated in narcolepsy due to causing narcolepsy-like side effects.

Question 116

How are doxepin and trazodone used in insomnia disorders?

Answer 116

doxepin - TCA - low doses exert H1 antagonism, causing sedation - anticholinergic side effects trazodone - not FDA approved for insomnia - long-half life, may see daytime hangover - this is very common, but not in guidelines

Question 117

How are mirtazapine and quetiapine used in insomnia disorders?

Answer 117

mirtazapine - not FDA approved for insomnia - clinically used as a sleep agent, especially in pts with depression who have difficulty sleeping - if pt has depression as well as insomnia, use mirtazapine instead of a z-hypnotic quetiapine - low dose quetiapine is not recommended for use in insomnia unless there is a co-morbid psychiatric disorder

Question 118

How are the OTCs, such as diphenhydramine/doxylamine and melatonin/valerian/chamomile used in insomnia disorders?

Answer 118

diphenhydramine/doxylamine - not recommended to use melatonin/valerian/chamomile - melatonin can be considered in jet lag and in pts with low melatonin levels *melatonin is 1A2 substrate *chamomile can cause allergic reaction in pts with daily or ragweed allergies

Question 119

What is the DSM-5 criteria for obstructive sleep apnea? When can't patients do a home test to test for sleep apnea?

Answer 119

Obstructive sleep apnea - patient must have evidence of at least 5 obstructive apneas per hour of sleep confirmed by polysomnography - many patients may have both apnea AND insomnia. Both need to be treated, but apnea should be treated first. - patients can do a home test, but they MUST so polysomnography if they are on chronic opioids, have severe insomnia, cardiorespiratory disease, respiratory muscle weakness due to a neuro-muscular condition, hx of stroke, or sleep-related hypoventilation

Question 120

How do we approach treatment for sleep apnea?

Answer 120

- Weight loss, smoking cessation, avoid alcohol and CNS depressants, sleep on side rather than back - excessive daytime sleepiness can be treated with modafinil or armodafinil (but reveiw CPAP adherence and RLS or PLMS) *if patient is obese and is coming in for insomnia, should test for sleep apnea before starting treatment for insomnia

Question 121

What is the narcolepsy tetrad?

Answer 121

EDS - (excessive daytime sleepiness) occurs in ALL patients, generally more severe in Type I narcolepsy, which is narcolepsy with cataplexy or hypocretin deficiency syndrome Cataplexy - sudden loss of muscle tone triggered by emotion (75% of patients) Hallucinations - 30-60% of patients Sleep paralysis - 25-50% of patients *10-33% of patients have all 4 symptoms

Question 122

How do we treat narcolepsy?

Answer 122

cataplexy - sodium oxybate (GHB) is most effective - Xywav can be used for adults and children >7yo, also for idiopathic hypersomnia in adults EDS - sodium oxybate (GHB) - pitolisant and solriamfetal - recently FDA approved

Question 123

Pitolisant - contraindications, metabolism interactions, when to avoid use; Solriamfetol - when to adjust dosing, what is it indicated for, warnings

Answer 123

Pitolisant - FDA approved for EDS - contraindications: severe hepatic impairment - 2D6/3A4 substrate, weak 3A4 inducer (think about oral contraceptives) - avoid use with centrally acting H1 receptor antagonists (OTC antihistamines) solriamfetol - indicated for improvement in wakefulness in adults with EDS due to narcolepsy or OSA - requires dose decrease in renal impairment - warnings: BP & HR increases, so avoid in unstable CV disease and arrhythmias; caution in pts with psychosis or bipolar disorder, decrease dose or d/c if psychiatric symptoms develop; caution with dopminergic drugs

Question 124

What drugs can we use to treat shift work sleep disorder and restless less syndrome?

Answer 124

Shift work sleep disorder - modafinil and armodafinil (take 1 hour before work period starts) *DON'T use sleep medications, want to help wakefulness Restless leg syndrome - - 1º dopamine agonists - gabapentin enacarbil (prodrug of gabapentin) is FDA approved, so may be considered 1st line - iron supplementation may be considered

Question 125

What is the DSM-5 criteria for anorexia nervosa?

Answer 125

Anorexia - restriction of energy intake leading to a significantly low body weight. Involves an intense fear of gaining weight or becoming fat. - Restricting type: during the last 3 months, pt has NOT engaged in recurrent episodes of binge eating or purging. The weight loss is accomplished primarily through dieting, fasting, and/or excessive exercise - Binge-eating/purging type: during the last 3 months, the individual has engaged in recurrent episodes of binge eating or purging *BMI under 18.5kg/m2 is considered to be on the low end of normal mild = >17 moderate = 16-16.99 severe = 15-15.99 extreme = <15

Question 126

What are the health consequences of anorexia nervosa?

Answer 126

*lack of energy to perform daily functions, body slows down down to preserve energy - slow HR/BP, cardiac muscle atrophy, hypotension, arrhythmias - decreased bone density, low estrogen, amenorrhea, infertility - fainting, fatigue, decreased metabolic weight, weakness - dry skin, hair loss, hypercarotenemia - severe dehydration - downy layer of hair all over body - cold intolerance - delayed gastric emptying, constipation

Question 127

How do we treat anorexia? What is the biggest thing we are trying to avoid with treatment of anorexia?

Answer 127

Treat - slowly increase calories, correct electrolyte and fluid deficits, cognitive behavioral therapy *bupropion is contraindicated Re-Feeding syndrome!!! Results from a shift from fat metabolism to glucose metabolism - hypokalemia, water retention, severe edema - end result is multiple organ failure!!

Question 128

What are the severity specifiers for binge-eating disorder?

Answer 128

mild: 1-3 episodes per week moderate: 4-7 episodes per week severe: 8-13 episodes per week extreme: ≥14 episodes per week *related to episodes, not BMI *not related to recurrent use of inappropriate compensatory behavior

Question 129

What are the health consequences of binge eating disorder?

Answer 129

- hypertension - elevated cholesterol - cardiovascular disease - type 2 diabetes - gall bladder disease

Question 130

What medication is approved for treatment of binge eating disoder?

Answer 130

Lisdexamfetamine (vyvanse) - approved for moderate or severe binge eating disorder (mod = 4-7 episodes; severe = 8-13 episodes) - CBT + medications provides best outcomes

Question 131

What are the severity specifiers for bulimia nervosa? What are the health consequences?

Answer 131

mild: 1-3 episodes per week moderate: 4-7 episodes per week severe: 8-13 episodes per week extreme: ≥14 episodes per week - recurrent bingeing and purging can affect the entire digestive tract (tooth decay, fastric rupture, electrolyte imbalances, irregular bowel movements, physical sores, etc.) - amenorrhea - orthostatic hypertension - bradycardia - arrhythmias - osteopenia - osteoporosis

Question 132

What are the 5 methods of purging with bulimia nervosa? What is the FDA approved medication for bulimia nervosa?

Answer 132

- vomiting - laxatives - diuretics - excessive exercise - diabulimia (taking less insulin than they need to promote weight loss) Fluoxetine is FDA approved for bulimia nervosa. CBT + medication provides best benefit.