Depressive disorders

What pneumonic is used for clinical presentation for depressive disorders?

SIGECAPS

What does SIGECAPS mean?

Sleep disorders Intrest loss Guilt Energy deficit Concentration Appetite Psychomotor fluctuations (impaired movement, agitation) Suicidal Idealation

what is the diagnostic criteria for depressive disorders?

5 or more SIGECAPS symptoms, having been present in the same 2 week period including depressed mood or anhedonia With impairment in multiple settings - not caused by drugs or physiological abnormalities

What is anhedonia?

Absence of pleasure

What drugs can cause drug-induced depression?

antihypertensives- Beta blockers, clonidine, methyldopa CNS depressants - Alcohol, barbiturates, anti-epileptics hormonal agents- steroids, contraceptives, tamoxifen Interferon - Hep C med Isotretinonin - accutane Efavirenz - HIV protease inhibitor

what are the 5 types of depression?

1. Dysthymic disorder 2. Major depression with psychotic features 3. Seasonal affective disorder 4. Melancholic depression 5. Atypical depression

What is dysthymic disorder?

depressed mood on most days for 2 years never been w/out symptoms less severe than MDD - not meet criteria for MDD at least 2 symptoms of SIGECAPS

What is major depression disorder with psychotic features?

Most severe form of depression + hallucinations & delusions at least 5 symptoms of SIGECAPS

What is seasonal affective disorder?

relationship to seasons Winter depression with less sun less happy :(

what is melancholic depression?

Lack of pleasure in all or most activity OR lack of reactivity to usually pleasurable stimuli seen with grief, worse in AM, significant anorexia, early morning awakenings, excessive guilt, slow movements

what is atypical depression?

Mood brightens with + events significant weight gain, hyper-insomnia, leaden paralysis, interpersonal rejection sensitivity

What are acute risk factors for a suicide risk assessment?

seizures insomnia anxiety life stressors psychosis anxiety

What are the chronic risk factors for a suicide risk assessment?

Disability FH of suicide previous suicide attempts isolation w/out social support

What is defined as a response to medication?

~50% decrease in symptoms

What is defined as remission from depression?

no depressive symptoms

What is defined as a relapse in depression?

depressive symptoms after a period of remission ~50% of people relapse 5 years after their 1st episode ~70% of people relapse after 2 episodes

What are some rating scales for depression?

PHQ-9 Hamilton-depression rating scale 8-15 mid, 16-27 mod, >27 severe Montgomery-Asberg depression rating scale 7-19 mild, 20-34 moderate, >34 severe

What are examples of monoamine NTs?

Serotonin, norepinephrine, epinephrine, dopamine, histamine

What NTs are catecholamine?

Dopamine, norepinephrine, and epinephrine

What NT is indoleamine?

Serotonin

What is the rate limiting step in the production of dopamine?

tyrosine hydroxylase

Describe how dopamine is synthesized and released?

packaged into vesicles by VMAT2 by exocytosis - Ca dependent

What 2 receptors does dopamine act on?

1. D1 receptor 2. D2 receptor

How is dopamine reuptake done?

By VMAT2 or the D/NE transporter

What enzymes Metabolize dopamine?

COMT & MAO

Where are D1 receptors located in the synapse?

presynaptic

Where are D2 receptors located in the synapse?

postsynaptic

What is the effect of dopamine in the Mesolimbic tract?

Feeling of reward, learned behavior

what is the effect of dopamine in the Mesocortical Tract?

Higher order and cognitive processess *imp for psychosis and ADHD

What is the effect of dopamine in the Nigrostriatal Tract?

Movement and locomotion

What is the effect of Tuberinfindubular Tract?

Prolactin Secretion

How is NE taken back into the cell( what enzymes or ways)?

NET (norepinephrine transporter), autoreceptor, VMAT

Where are NE receptors highly concentrated?

Prefrontal cortex (important for emotions) Limbic areas of brain

What is the affect of NE on awakeness?

Increase arousal, vigilance, learning, cognition

What are the effects of NE deficiency on the limbic system?

Reduced conc, affects working memory, psychomotor retardation, apathy, symptoms of depression

Where is the serotonin synthesized?

from tryptophan - serotonin located in vesicles released by Ca exocytosis

What are kind of receptors are serotonin receptors?

G coupled protein receptors except 5-HT3 receptor bc its ionic

What enzyme is responsible for serotonin reuptake?

SERT ** where SSRIs effect

How is serotonin metabolized?

by MOA - resevered MAOi therapy bc lots of D-D interactions

What serotonin receptors are excitatory?

2,3,4,6, and 7

What 2 NTs dysfunctions are responsible for reduced + affects?

DA & NE

What 2 NT dysfunctions are responsible for increased negative affect?

5-HT and NE ** many men have this presentation (increased hostility, irritability, and loneliness)

What part of the synapse does MAOis work at?

MAO

Overall describe the effects depressants can have on NTs?

block reuptake, metabolism, receptor binding increase levels of NT in presynatic neurons

Where do SSRIs work in the synapse?

5-HT reuptake via SERT increases levels of serotonin

Where does mirtazipine work?

antagonism of alpha-2 receptors in the pre-synaptic cell leads to release of more NT

What affect do TCAs have on NE and 5-HT?

Increased 5-HT reuptake so increased 5-HT levels increased NE reuptake --> increased levels of NE

What are 3 non-pharm therapies for treatment resistant/refractory depression?

Vagus Nerve Stimulation Transcranial magnetic stimulation (TMS) Electroconvulsive therapy --> very effective

What should every patient with depression recieve?

Fucking therapy any kind (family, marital, interpersonal, CBT)

What is the Black Box warning on antidepressants for MDD?

increased suicide risk younger people are more likely <25 weeks 2-3 especially children and adolescents

Name some TCA drugs?

Amitriptyline - Elavil Imipramine - Tofranil Desipramine - Norpramin Nortriptyline - pamelor

Name some MAOis?

Selegiline - EMSAM Phenelzine - Nardil Isocarboxazid - Marplan

Name some Serotonin/NE reuptake inhibitors (SNRIs)?

Duloxetine - Cymbalta Venlafaxine - Effexor Desvenlafaxine - Pristiq Levomilnacipran - Fetzima

Name some 5-HT2 antagonists?

Trazodone - Desyrel Nefazodone - Serzone

Name some 2nd generation antipsychotics?

Aripiprazole - Abilify Quetiapine - Seroquel Brexpiprazole - Rexulti Olanzapine/Fluoxetine - Symbyax

Name the alpha2 antagonist drug?

Mirtazapine - Remeron

Name some Selective Serotonin Reuptake Inhibitors (SSRIs) medications?

Citalopram - Celexa Escitalopram - Lexapro Fluoxetine - Prozac Paroxetine - Paxil Sertraline - Zoloft Vilazodone - Viibryd Vortioxetine - Trintellix Fluvoxamine - Luvox

What drug is an aminoketone?

Buprorion - Wellbutrin

What was the 1st antidepressant on the market?

Fluoxetine - Prozac

What are the mechanisms of action for SSRIs?

1. Block reuptake of serotonin 2. increase somatodentric serotonin 3. desensitized autoreceptors - no negative fedfback for storage 4. Neuronal impulses are turned on 5. Increase in serotonin from axon terminals (pre-synatic) 6. Desensitization of postsynaptic neurons 7. Downstream increases Neurotropic factors 8. Neurogenesis

Why are SSRI's usually preferred over TCAs?

SSRI are selective TCAs effect both 5-HT & NE --> SE

What are the most common ADE of SSRI that can be tolerated*?

N/V (5-HT rec in gut/vomiting center) * Sexual Dysfunction Insomina (fluoxetine activating) (paroxetine sedating) Headache (5-HT affects vasodilation/spasms)* Anxiety/Activation*

What is a warning with ALL SSRIs about seizures?

Lower the seizure threshold to a small degree

What are the key functional groups of SSRI class drugs?

two phenyl groups basic nitrogen

What is the concern w/ a SSRI w/ a short T1/2? a. less potency b. withdrawal reactions c. increased risk of D-D interactions d. needs to be titrated

B

What SE can cause intolerance to therapy w/ SSRI?

Discontinuation Syndrome Hyponatremia (risk old/female) Bleeding risks (platelets brain/gut increase bleeding risks esp if on DOAKs or anticoagulation therapy) Extra-pyramidal symptoms (EPS) Weight gain - worst with paroxetine (few kg) SIADH - syndrone of inappropriate secretion of ADH - decreases Na/H2O

What is discontinuation syndrome?

withdrawal syndrome from discontinuing antidepressants

What does discontinuation syndrome present like?

Dizziness Nausea Tingling of hands/feet Anxiety Insomnia Flu-like symptoms

What about SSRIs in pregnancy?

Most are class C What is Class D in pregnancy -Paroxetine

What genetic polymorphism affects the concentrations of SSRIs?

CYP 2D6

Main metabolism CYP enzymes for Fluoxetine?

2D6 and 2C9

Main metabolism CYP enzymes for Sertraline?

2D6 and 2C9

Main metabolism CYP enzymes of Paroxetine?

2D6

Main metabolism of CYP enzymes of Citalopram?

2C19 and 3A4

Main metabolism of CYP enzymes of Escitalopram?

2C19 and 3A4

What is the longest T1/2 to shortest of the SSRIs?

Fluoxetine, Citalopram, Escitalopram, Sertraline, Paroxetine

What habit affects some metabolism of drugs via CYP 1A2?

smoking

Which CYP is the most used for SSRIs and which?

2D6 Fluoxetine, Paroxetine, Sertraline - w/ strong inhibiton

What are some PD interactions with serotonin?

Triptans Linezolid MAOis Dextromethorphan Tramadol Synthetic analgesics (fentanyl, oxycodone, methadone) Drugs of abuse (cocaine, amphetamines, LSD)

What is Serotonin syndrome?

A severe adverse effect of multiple seratongeric therapies Can be deadly and life threatening toxicity

What is the progression of symptoms for serotonin syndrome?

mild GI symptoms, Akathisia, Tremor, Altered mental state, Clonus (inducible), Clonus (sustained), Life threatening toxicity

What are bad symptoms of serotonin syndrome?

Tremor Hyperreflexia Clonus Autonomic instability - fluctuation in BP wide pupils agitation change in mental status increased bowel sounds

How do you treat Serotonin syndrome?

Remove offending agent supportive care - BDZ for anxiety/agitation - watch for hypotension and tachycardia Cyproheptadine 8mg Q6h Prevention is helpful

What is the starting dose of citalopram and titration frequency?

20 mg/d 10 mg every 2 weeks

What is the inital target dose and Max daily dose for citalopram?

20-40 mg MDD: 40mg

What is the starting dose and titration frequency of escitalopram?

10 mg/d 10 mg every 2 weeks

What is the initial target and max daily dose of escitalopram?

10-20 mg MDD: 20 mg

What is the starting dose and titration frequency of fluoxetine?

20 mg 10-20 mg every 2 weeks

What is the initial target and max daily dose of fluoxetine?

20-40 mg MDD: 80 mg

What is the starting dose and titration frequency of Paroxetine?

20 mg/d 10-20 mg every 2 weeks

What is the initial target and max daily dose of paroxetine?

20-40 mg MDD: 60 mg

What is the starting dose and titration frequency of Sertraline?

50 mg/d 50-100 mg every 2 weeks

What is the initial target and max daily dose for sertraline?

50-150 mg MDD: 200 mg

Why are Vilazoone (Viibryd) and Vortioxetine (Trintellix) different from other SSRI/SNRIs?

they are SPARIs (serotonin partial agonist reuptake inhibitor)

What reuptake enzymes does Viibryd and Trintellix affect and what happens?

NET and DAT (NE and dopamine) and SERT (5-HT)

What are the adverse effects of Viibryd?

Higher rates of N/V (take w/ food Increase bioavaliability Sim to SSRIs (GI SE) Possibly lower rates of sexual dysfunction

What is the T 1/2 of Viibryd and titration target?

T 1/2 ~25 hrs 20-40 mg/day

What are adverse effects of Trintellix?

Similar to SSRIs less cognitive adverse effects improvement in sexual dysfunction GI affects biggest complaint

What is the T1/2, metabolism and therapeutic dose of Trintellix?

T 1/2 ~66 hrs CYP 2D6 substrate 10-20 mg/ day - very expensive tho $420/month

Serotonin and Norepi reuptake inhibiters consists of what two classes of medication? (old/new)

TCA = older gen (non selective, tolerability difficulties)nmore effective at NE SNRI = new gen (serotonin-norepinephrine reuptake inhibitors)

SNRI MOA?

Serotonin - effect sim to SSRI NE effects lead to cascade (some cross over to DA once NET is saturated)

TCA MOA?

Serotonin - sim to SSRI NE effects lead to cascade (some cross over to DA once NET is saturated) Blockade of cholinergic, histaminergic, and alpha 1 receptors

What adverse effects arise from TCA action upon cholinergic, histaminergic, and alpha 1 receptors?

CNS effects DEADLY OD - possible arrhythmia (Na channel blocker) orthostatic hypotension weight gain (paroxetine) sexual dysfunction withdrawal effects (cholinergic mediated , GI: diarrhea/N) Decreases seizure threshold

What is the difference between amitriptyline and nortriptyline?

Amitriptyline: 5-HT >NE / tertiary amine Nortriptyline: NE>> 5-HT / secondary amine

What is the initial dosing and titration frequency of Nortriptyline?

25 mg increase by 25 mg every 2 weeks

How are TCAs metabolized?

CYP 2D6

What is the initial target and max daily dose of Nortriptyline?

50 - 100 mg MDD: 150 mg

What is the starting dose and titration frequency for amitriptyline?

25-50 mg increase by 25-50 at 1 week intervals

What is the initial target and max daily dose of amitriptyline?

100- 300 mg MDD: 300 mg

What are SNRIs role in therapy?

1st line but often used after SSRIs

What are adverse effects of SNRIs?

Nausea (+/- bs SSRI) - Cymbalta - barf Cardiovascular effects* increase BP monitor Sexual dysfunction - can be slightly better pseudoanticholenergic effects: dry mouth, constipation, urine retention

What are the T1/2, metabolism, and CYP inhibition of venlafaxine and duloxetine?

Venlafaxine: T1/2 ~2 hr, CYP 2D6 Duloxetine: T1/2 ~6 hrs, CYP 2D6 & 1A2*

What is the starting dose and titration frequency of venlafaxine?

37.5 -75 mg 37.5 -75 mg every 2 weeks

What is the initial target and max daily dose of venlafaxine?

75-150 mg MDD:225-375 mg

What is the starting dose and titration frequency of duloxetine?

30-60 mg 30 mg every 1-2 weeks

What is the initial target and max daily dose of duloxetine?

60 mg MDD: 60 mg (120 mg)

What is the newest MOAi, and why are they reserved 3rd line therapy?

Selegiline complex D-D/D-food interactions and restrictions Tolerability is the main issue

Where is MOA located in a cell?

intracellularly and on the mitochondria

What does inhibition of MOA-A/B cause?

greater increases in monoamines increase in 5-HT, NE, DA, Tyramine

What are adverse effects of MOAis?

Orthostatic hypotension (spilt dose) Sexual dysfunction Minor anti-cholinergic properties

What dose tyramine do when it reacts with MAOis?

Increases release of NE lead to dangerous elevation in BP

What foods have high tyramine content?

Dried, aged, smoked, fermented, spoiled, improperly stored (meat, poultry, and fish)

What are signs of a hypertensive crisis in a person on MOAi?

Occipital headache - radiate to front Palpitation Neck stiffness N/V --> sweating

How do you treat a hypertensive crisis with MAOis?

Phentolamine (Regitine) 5mg IM/IV non-selective alpha 1 blocker or rapid acting CCB

What medications used with MAOis can lead to a hypertensive crisis?

Decongestants (Phenylephrine, Ephedrine, Pseudophedrine) Stimulants (amphetamines, methylphenidate) Appetite suppressants Certain antidepressants (TCAs, SNRIs, buproprion)

Which medications used with MAOis can lead to serotonin syndrome?

Antidepressants (SSRI, TCA, SNRI - increase 5-HT) TCA like compounds (carbamazepine & cyclobenzaprine) Appetite suppressants Synthetic opioids (methadone, tramadol, fentanyl) Triptans - ABSOLUTE COUNTERINDICATION

What formulation is Selegiline (EMSAM)?

Transdermal patch - decreases risk of D-D interactions removes 1st pass effect decreases risk of tyramine reactions

What is the starting dose and titration frequency of selegiline?

6 mg increase by 3 mg no less than every 2 weeks

What is the initial target and max daily dose of selegiline?

6 mg MDD: 12 mg

What additional action to SARIs (serotonin antagonist/reuptake inhibitor) have over SSRIs?

Still block reuptake 5-HT Block 5-HT 2A/C - improving some SE and AE

What is the MOA of Trazodone?

5-HT2 receptor antagonist 5-HT reuptake inhibitor at higher doses Histamine antagonism and alpha 1 blockade

What are Adverse effects of Trazodone?

Orthostatsis (histamine/ alpha 1 blockage) Sedation Dizziness Priapism (painful long erection considered medical emergency lololol)

What are the two different states that high and low dose trazodone treat?

High: antidepressant Low: hypnotic - short T1/2 requires multiple doses (25-100)

what is Mirtazapine (Remeron) considered in treatment?

1st line

What is the MOA for Mirtazapine?

Alpha -2 blockade (increase prod of 5-HT) 5-HT antagonist does affect histamine 1 receptor

How is Mirtazapine metabolized and T1/2?

CYP 1A2, 2D6, 3A4 substrate 20-40 hrs

What are the adverse effects of mirtazipine?

Sedation (dose related - lower doses more sedating) lipid abnormalities (triglycerides) increase in appetite and weight gain (histamine receptor)

How is Trazodone metabolized and T1/2?

CYP 3A4 6-11 hrs (require more freq dosing)

What is the starting dose and titration frequency for mirtazapine?

15 mg 15 mg every 1-2 weeks

What is the initial target and max daily dose for mirtazapine?

15-45 mg MDD: 45 mg

What is the starting dose and titration frequency for Trazodone?

50-100 mg QHS - or- 150 mg TID increase by 50 mg every 3-4 DAYS

What the initial target and max daily dose for Trazodone?

150 mg- 300mg MDD: 400 mg (outpatient) - 600 mg (inpatient)

What is the MOA for bupropion?

Blocks NE & DA transporters (NO EFFECT ON 5-HT) presynaptic release of NE/DA binds to VMAT2

What is bupropions (wellbutrin) place in therapy?

1st line

What is bupropions T1/2, metabolism, and inhibiton?

T1/2 = 20-21 hrs Metabolism CYP 2B6 Inhibitor of CYP 2D6

What is bupropion have FDA approval to treat?

Smoking cessation Major Depressive Disorder Seasonal Affective disorder

What is the starting dose and titration frequency of bupropion?

150-200 mg increase by 150 mg every 3-7 days

What is the initial target and max daily dose for Wellbutrin?

150-300 mg MDD: 300-400 (SR), 450 mg (IR/XL)

What are ADE of bupropion?

CNS activation Tremor Weight loss Few sexual SE Dose related risk of seizures (reduces threshold) - low risk w/ controlled-release preperations agitation (dopamine)

What is an ABSOLUTE CONTRAINDICATION to bupropion?

Eating D/O Seizures

What is considered a resonable trial of antidepressants?

Maximum effective dosing for 4-6 weeks balance tolerability vs. efficacy

How long do you continue therapy of antidepressants?

At least 4-9 monts With increase in episode its and increase in time 1 episode = 12 months 2 episodes = 24 months 3 episodes = 36 months

What is good practice when switching from a MAOi to another therapy?

Must have 14 day wash out period

Why is cross-titration a good practice?

Prevent discontinuation syndrome (withdrawal) TCA cholinergic rebound (wet)

What are therapy options for refractory patients?

Augmentation (Lithium/T3, antipsychotics, combotherapy) Esketamine (spravato)

what are off label medications used for depressive disorders?

Stimulants (methylphenidate/ amphetamine) Buspirone (BuSpar) Modafinil (Provigil) 2nd gen antipsychotics (not FDA approved)

When is St. John's Wort efficacious and why is it not used much?

mild-moderate depression It is a 3A4 inducer - lots of D-D intx

What are AE with St. John's Wort?

Mild GI upset Fatigue/Restlessness Phototoxic rash (w/ increased dose) rare events of mania seratonin syndrome

What is a typical dose of St. John's Wort?

300 - 900 mg BID

What safe therapy has been proven to help those afflicted with seasonal affective disorder?

early light therapy (10,000 Lux, for 30 min)

When is pharmacotherapy indicated in pediatric patients?

Moderate to severe depression mild-mod psychotherapy

Which 2 drugs are FDA approved to treat depressed pediatric patients?

Fluoxetine and Escitalopram Fluoxetine most substantial evidence