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

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)