Exam 1 - Antidepressants Flashcards
Depression Treatment Key Takeaways:
Medications are only one part of treatment
R/O bipolar disorders prior to initiating antidepressants
Certain medications may work for some people and not for others
Macro level data does not show superiority of any agent
Greater depressive sx predicts greater response to medication, in general
Side effects can often be troubling
Adherence issues are common
Treatment with more than one antidepressant or treatment with one antidepressant and one additional agent for augmentation is often reasonable
Major Depressive Disorder
SIG-E-CAPS:
Sleep changes
Interest (loss of)
Guilt
Energy (lack of)
Cognition/concentration
Appetite
Psychomotor
Suicide/death thoughts** (high risk of this in depression, always assess)
Treating Depression
Mild Depression: Non-pharmacologic interventions (e.g. CBT, guided self help, interpersonal psychotherapy and other lifestyle and psychosocial interventions.
Severe-chronic depression: Consider antidepressant
Depression w/ psychotic features: Antipsychotic and an antidepressant or ECT.
Factors that impact antidepressant selection
Previous patient or family member response to antidepressants (if any)
Impact on psychiatric or medical comorbidities
Clinician familiarity
Patient preference
Safety in overdose
Availability
Cost
Drug to drug interaction
Top distressing side effects: Sexual dysfunctions, sleep disturbance, weight gain
Theories of Depression: Monoamines
Monoamine hypothesis
Deficit of monoamines (serotonin, norepinephrine, dopamine)
Delayed onset of therapeutic response to antidepressants (2 to 6 weeks)
Changes in receptors takes time
Problems with the monoamine hypothesis
Theories of Depression: Neurogenic
Neurogenic theory
Neurons become damaged, a neurodegenerative process
Genetic vulnerability + stress = disorder
Medication, therapy, etc. can Increases BDNF (brain-derived neurotrophic factor) “fertilizer for the brain cells” to help repair neurons and connections
BDNF can be increased via medication, therapy, or other interventions (exercise) to some extent
Neurotransmitters/Monoamine Hypothesis
Depression=↓Serotonin; ↓Dopamine; ↓NE
Monoamine Hypothesis: Deficient brain 5HT and/or NE results in depression
Antidepressants
Etiology:
Dysregulation in 1 or more biogenic amines (i.e. 5HT, NE, DA)
Low level precursor tryptophan
Target Symptoms: Depressed mood, sleep/rest distress, anxiety, irritability, impaired concentration/memory, appetite disturbances, agitation, anhedonia, impaired energy/motivation.
Classes: SSRI, SNRI, NDRI, SPARI, TCA, MAOI
Antidepressants
General Information:
All antidepressants have similar response rates but differ in safety and side effect profiles.
60-70% of patient with MDD will respond to antidepressant meds.
Most antidepressants require a trial of at least 3-4 weeks for effect and in some cases 6-8 weeks for noticeable effects.
Maintenance therapy: 6-13 months
Most antidepressants have a withdrawal phenomenon= Educate patients not to stop abruptly
Dizziness, headaches, nausea, insomnia, anxiety, electric-like shocks “zaps”, malaise
Depends on dose and half-life
Antidepressants
Factors affecting drug choice= Cost, patient symptoms, previous treatment of patient or family member, side effect profile, comorbid conditions, risk of suicide
Side Effects: Sexual dysfunction (25-30%), GI (nausea/diarrhea)-Give w/ food, insomnia, headaches, anorexia/weight loss, Akathisia
Lab Monitoring: TSH, CBC, Chemistry, Folate and vitamin B12 , UA
STAR-D Study Implications
The longer a person goes without responding to treatment, the less likely response becomes overall
Switching medications to a different class or to a different SSRI is a reasonable strategy but provides only modest improvement for most
On a macro level, any antidepressant is just as likely to be effective as any other antidepressant
Individual responses can be hard to predict
High relapse rates for chronic depression
More complex individuals have more difficulty with response/remission (e.g. other psychosocial stressors, medical issues, etc.)
The Major Categories
SSRIs – commonly used d/t safety and tolerability
SNRIs
Heterocyclic antidepressants (i.e. TCAs and tetracyclic)
MOAI
Atypical/Miscellaneous antidepressants
Selective Serotonin Reuptake Inhibitors (SSRIs)
Mechanism of Action:
Inhibit presynaptic serotonin reuptake pumps = ↑ availability of 5HT in synaptic clefts.
Cause downstream effects increasing brain plasticity – explains the delay of antidepressant effect.
1st line
Most prescribed class d/t
Low incidence of side effects – most resolve with time
No food restrictions
- Safer in overdose
Better tolerated
May initially worsen anxiety or panic attacks
Selective Serotonin Reuptake Inhibitors (SSRIs)
Low incidence of side effects
Transient (lasting 1-2 weeks especially GI)
Side Effects: Sexual dysfunction (30-40%)- decreased libido, anorgasmia, delayed ejaculation – occurs weeks to months (typically do not resolve)
GI (nausea/diarrhea)-Give w/ food, insomnia, headaches, anorexia/weight loss, Akathisia, sedation, agitation, Hyponatremia / SIADH, decreased platelet aggregation-risk for bleeding and bruising
Seizures- rare
BLACKBOX WARNING: Increased suicidality in children, adolescents and young adults
NOTE: Remember FFPECS
Common result of blocking serotonin reuptake is enhancement of postsynaptic serotonin activity at all serotonin receptors in the brain
5-HT1 = antidepressant and anxiolytic
5-HT2 and 5-HT3 = adverse effects
5-HT2 = insomnia, anxiety, agitation, and sexual dysfunction
5-HT3 = nausea
The SSRIs
Fluoxetine(Prozac) 20-80mg
Longest half –life =2-3 days(no need to taper)
Safe in pregnancy
Approved in use of Child/Adolescent
Approved for Buliemia
Can be dosed 1x/wk
Can elevate levels of antipsychotics – watch for increased side effects
Consider in patients w/ poor adherence d/t long half life
Activating” or energizing effect (Stahl, 2013)
Combination with olanzapine for psychotic depression
The SSRIs
Fluvoxamine(Luvox) 50-300mg
FDA approved for OCD
Common S/E: Nausea, vomiting
The SSRIs
Paroxetine (Paxil) 20-50mg
Considered “dirty” -
Potent CYP26 Inhibitor = several drug to drug interactions
Common side effects – Anticholinergic and sexual dysfunction
Short half-life = withdrawal phenomenon
Fairly significant side effects including sexual s/e
“Paxil packs on the pounds”
Can be sedating, take around dinner time
The SSRIs
Escitalopram (Lexapro) 10-20mg
Levo-enantiomer of citalopram, similar efficacy
Dose dependent QTc prolongation
Fewer drug –drug interactions.
The SSRIs
Citalopram (Celexa)
20-40mg
Associated with dose dependent QTC prolongation in doses 40+mg
Max dose in Geriatrics= 20mg.
Fewer drug interactions
Most Lethal in OD
The SSRIs
Sertraline(Zoloft) 50-200mg
Has the most GI side effects
Very few drug interactions
Give with food
Activating (Agitation, anxiety)
Favored during pregnancy and nursing (MCPAP for Moms, 2014)
Activating Antidepressants – good for patients who want to avoid medications that cause tiredness – e.g. Fluoxetine
Advantage of SSRIs over other classes of meds
When choosing an SSRI= Consider the inhibition of CYP-450 isoenzymes (induction vs. inhibition) – be familiar with these concepts
Most lethal SSRI in overdose ? (Citalopram) consider cardiac effects
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
Consider w/ patients who have significant fatigue or comorbid chronic pain
Mechanism of Action: Inhibits dual reuptake of NE and 5HT = ↑ extracellular concentrations of NE and 5HT
Side Effects: Sustained elevation in BP Nausea, diarrhea, dizziness, anticholinergic
All SNRI can increase blood pressure, cause tremor (beta receptor stimulation)
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)-
Venlafaxine (Effexor ) 75-375mg BID
MDD, GAD, neuropathic pain
Useful in treating anxiety and panic attacks in depressed patients
XR available
New form Desvenlafaxine (Prestiq)= expensive
Short half life
Very hard to taper and d/c
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)-
Duloxetine (Cymbalta) 40-120mg/day
Can increase LFTs
Used for depression, neuropathic pain and in fibromyalgia
Hepatotoxicity (monitor LFTs)
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)-
Levomilnacipran(Fetzima)
20-120mg /day
Associated w/ more side effects (HTN, decrease appetite, Palpitations, diaphoresis etc.)
Norepinephrine- Dopamine Reuptake Inhibitor (NDRIs)
Mechanism of Action: Inhibits reuptake of NE and DA
Side Effects: Headache, tremors, tachycardia, insomnia, anxiety, decreased appetite
Most helpful for target sx of low energy, anhedonia, low concentration, or if having sexual s/e from SSRI
Norepinephrine- Dopamine Reuptake Inhibitor (NDRIs)
Bupropion (Wellbutrin) 150-450mg
Used in ADHD and smoking cessation d/t effects on DA
Weight neutral
Contraindicated in patients with seizure and eating disorders = Lowers seizure threshold (at higher doses)
Lacks sexual side effects – add to other antidepressants to txt sexual dysfunction
Other available forms: XR= 24 hours; SR= 12 hours
Less GI distress
Side effects: agitation, jitteriness, mild cog dysfunctions, insomnia
Contraindicated in patients with seizure and eating disorders = Lowers seizure threshold (at higher doses)
A. Tefretol
B. Carbamazepine
C. Buproprion
D. Gabapentin
C. Buproprion
Serotonin Partial Agonist Reuptake Inhibitor (SPARI)
Vilazodone (Vibryd)
In theory, may mitigate some sexual s/e but these still do occur
Other s/e similar to SSRI class
Fairly weight neutral and non-sedating
Serotonin Receptor Antagonist and Agonist
Trazodone (Desyrel)
Acts on the Alpha –adrenergic receptors
Used for MDD, anxiety and insomnia
Main SE: nausea, dizziness, orthostatic hypotension, sedation, Priapism
Low doses for sleep (50mg), higher doses antidepressant effects
Serotonin Receptor Antagonist and Agonist
Nefazodone (Serzone)
BLACKBOX warning for serious liver failure= rarely used
Off the market
Serotonin Receptor Antagonist and Agonist
Mirtazapine (Remeron) 15-45mg
Alpha 2 adrenergic and 5HT2 antagonist =↑ 5HT and NE
Blocks H1 histamine receptors
Sedating and promotes appetite(Used with patients who have weight loss and insomnia as primary symptoms of their depression) E.g. elderly
SE: Sedation, weight gain, dizziness, tremor, dry mouth
Inverse relationship between dose and sedation
Tricyclic Antidepressants (TCAs)
Mechanism of Action: Increases extracellular concentrations of 5HT and NE by inhibiting pre-synaptic reuptake
High affinity to H1, H2 histamine receptors and muscarinic acetylcholine receptors
2nd line treatment for depression
Side Effects
Anticholinergic/Antimuscarinic: dry mouth, blurred vision, constipation, memory problems, urinary retention, narrow angle glaucoma
Antiadrenergic: hypotension, orthostasis; dizziness, reflex tachycardia, arrhythmias, ECG changes – avoid in patients with pre-existing conduction abnormalities or recent MI
Antihistaminic: sedation weight gain
EKG changes and Cardiac dysrhythmias
Seizure risk – related to the dose and serum level
Lethal in overdose (give 1-week prescription especially in high-risk patients); Desipramine is the most lethal
NOTE: 3Cs= Cardiotoxic (arrhythmia), Convulsions, Coma (caution w/ cardiac patients)
Tertiary Amines
Amitriptyline (Elavil)
Used for chronic pain (neuropathy), migraines and insomnia
Tertiary Amines
Imipramine (Tofranil)
IM form available
Used for enuresis and panic disorder
Tertiary Amines
Clomipramine (Anafranil)
Approved for the treatment of OCD
Tertiary Amines
Doxepine (Sinequan)
Used for insomnia
Used as sleep aid in low doses
Tertiary Amines
These are highly anticholinergic/antihistaminergic, antiadrenergic and with greater lethality in overdose.
Secondary Amines
Nortriptyline (Pamelor)
Useful in treating chronic pain
Useful to obtain therapeutic level
Can be safely used in geriatric population
Secondary Amines
Desipramine (Norpramine)
More activating/least sedating
Least anticholinergic
Used off label in ADHD
Secondary Amines
Amoxapine (Asendin)
Metabolite of antipsychotic loxapine
May cause EPS and has similar side effect profile to typical antipsychotics
Secondary Amines
Less anticholinergic/antihistaminic/antiadrenergic
Side effects if TCAs (remember the 3 As)
Indications for Tricyclic antidepressants
TCA overdose= gastric aspiration is helpful, cardiac monitoring is important
NOTE: Desipramine is the most lethal TCA
Monoamine Oxidase Inhibitor (MAOIs)
Mechanism of Action:
Deactivate MOA-A and MOA-B (enzymes needed to deactivate 5HT, DA, tyramine) = increases the number of neurotransmitters in the synapses.
Prevents the inactivation of biogenic amines (NE, 5HT, DA and tyramine)
Selective and reversibleMAO-A inhibitorsare effective in treating major depression.
SelectiveMAO-B inhibitorsare used in the treatment ofParkinson’s DiseaseandAlzheimer’s Disease.
Last resort secondary to dangerous food and drug interactions
Used in refractory cases of depression
Food restriction: Follow Tyramine free diet
SE: Insomnia, weight gain, Anticholinergic, sexual SE, orthostatic hypotension, photophobia, drowsiness, sleep dysfunction
Liver toxicity, seizures and edema (rare)
Require washout period of 5 half-lives when switching
Very dangerous interactions with other antidepressants and opioids, risk of serotonin syndrome
Monoamine Oxidase Inhibitor (MAOIs)
Hypertensive Crisis (Life threatening): When MAOI is taken with tyramine rich foods (inhibits catabolism of dietary amines)
Sudden explosive headaches, high BP, facial flushing, palpitation, diaphoresis, fever, n/v, photophobia, autonomic instability , chest pain, arrhythmia and death
Treatment:
D/C medication
Supportive care
Phentolamine administration (NE antagonist)
Tyramine rich foods: red wine, aged cheese, chicken liver, fava beans, cured meats
Avoid the following: TCA’s Atypical antipsychotics, St. Johns Wort, Asthma meds, SSRI’s, decongestants, opiates (fentanyl, tramadol, meperidine)
Serotonin Syndrome “SHIVERS”: When SSRI’s are taken w/ MAOIs
NOTE: Wait at least 2 weeks before switching from SSRI to MAOI and at least 5-6 weeks with fluoxetine
MAOIs
Phenelzine (Nardil)
Phenelzine has been shown to be more effective than placebo for MDD w/ atypical features, MDD w/ psychotic features and social phobia.
MAOIs
Selegiline (Emsam)
Transdermal Patch
DOES NOT REQUIRE DIETARY RESTRICTION 6mg/24hr or lower
MAOIs should NOT be combined with psychotropic meds.
Newer Antidepressants
Most helpful in patients lacking response to initial SSRIs
Vortioxetine=Trintellix or Brintellix
Approved in 2013
Activates glutamate (excitatory NT) in the frontal cortex
Effective in patients with cognitive deficits associated w/ MDD
Theoretically fewer sexual s/e but clinically/anecdotally not necessarily so
Newer Antidepressants
Most helpful in patients lacking response to initial SSRIs
Vilazodone=Viibryd
Approved in 2011
Take with food to increase absorption and bioavailability
Antidepressant Adverse Effects
Sexual Dysfunction
Highest with SSRI/SNRIs
Impaired sexual motivation, desire, arousal and orgasm affecting men and women
Highest with Venlafaxine and SSRIs
Lowest with Bupropion, trazodone, nefazodone, mirtazapine
Management
First line- switch to bupropion(Wellbutrin)
Use of phosphodiesterase -5 inhibitors such as sildenafil(Viagra) or tadalafil (Cialis)
Antidepressant Adverse Effects
Increased Suicidality
Increased risk of suicidal thoughts and behavior with antidepressants primarily SSRIs
Highest in persons younger than 25
Consider benefits vs. risks – patient education and documentation is critical
SSRIs vs. TCAs and MAOIs
Significantly fewer side effects d/t serotonin selectivity (i.e. not much activity on histamine, adrenergic or muscarinic receptors)
Safer in overdose
Many of the side effects resolve within a few days to weeks (including GI disturbance, insomnia, headache, weight changes)
Antidepressant Withdrawal / Discontinuation Syndrome “FINISH”
F= Flu like symptoms (aches, pains, chills)
I= Insomnia
N= Nausea
I= Imbalance
S= Sensory disturbance (tremors, sensation of electrical shock)
H= Hyperarousal
Gradual taper of medications
Least likely with Fluoxetine and Vortioxetine (Trintellix/Brintellix)
Symptoms usually begin within 5 days of treatment cessation
Consider a 4-week taper (longer with Paxil and Effexor)
Serotonin Syndrome “SHIVERS”
Etiology: Excess. Serotonin in the body (single or multiple serotonergic agents)
S=Shivering
H=Hyperreflexia/Myoclonic jerks
I = Increased Temp (Fever)
V= Vitals Instability ( ↑↓BP; ↑RR; ↑HR)
E= Encephalopathy ( Confusion)
R= Restlessness
S= Sweating ( Diaphoresis)
Progression: Rhabdomyolysis, renal failure, convulsions, coma= DEATH
Txt
Stop medication
Supportive care
Cyproheptadine (5HT antagonist)
ECT in emergencies
Treatment Resistant Depression
NOTE: Each relapse increases symptom severity, decreases treatment response and heightens risk of treatment resistance.
Treatment Resistance: Inadequate response to 2+ antidepressants
Treatment options
Augmentation agents: Lithium, thyroid hormone, buspirone, atypical antipsychotics.
Neurostimulation therapies
Electroconvulsive therapy
Ketamine and Esketamine
Treatment Resistant Depression
Neurostimulation
Repetitive transcranial magnetic stimulation (rTMS)
Nonpharmacologic approach
Approved in 2008
Safe and effective
Electroconvulsive Therapy (ECT)
Effective in severe or refractory depression
ECT generates electrical stimuli for seizure induction through electrodes applied to the scalp
Patient is under general anesthesia and pre-medicated with a muscle relaxant
Full ECT = at least 4-6 sessions over 2-3x/week
S/E: Headaches; muscle soreness, nausea during ECT – transient ; loss of memory recall
Who is eligible for ECT?
First line for severe melancholic
Catatonic
Psychotic or refractory depression
Patients who refuse to eat or drink
High suicide risk or severe distress,
Pregnant women with severe depression
Previous positive ECT response
Ketamine vs. Esketamine
Ketamine
N-methyl D-aspartate receptor (NMDA) antagonist
Standardized subanesthetic dose (0.5mg/kg) IV over 40 minute infusion
Ketamine vs. Esketamine
Esketamine
Ketamine derivative
FDA approved in 2019
Administered via nasal spray given under direct supervision of a provider
Monitor of adverse effects for at least 2 hours following administration
Part of REMS program d/t potential for abuse and misuse
Depression in Children and Adolescents
Goal of treatment
Remission of symptoms
Return to baseline functioning.
Treatment Choice
Pharmacotherapy
Psychotherapy
Combination therapy (pharmacotherapy + psychotherapy)
Depression in Children vs. Adolescents
Depression in Children
- May appear anxious and irritable
- Psychomotor Agitation
Depression in Adolescents
- Hypersomnia
- Hopelessness
- Weight changes
- Illicit drug use
Depression in Children and Adolescents
Factors affecting choice of initial treatment
Illness severity and duration
Presence of agitation, psychosis, suicidal and homicidal ideation, behavior, comorbidity
Patient’s age and functioning
Number of previous depressive episodes, response to and adherence with prior treatment
Adverse effects
Patient and family preference
Clinical preference
Familiarity with treatment options
Cost
Depression in Children and Adolescents
Medication Choices
First line: Fluoxetine
Second line: Sertraline, escitalopram or citalopram; Venlafaxine
Third line: Bupropion or duloxetine
Depression in Children and Adolescents
Pediatric Consideration
Only Fluoxetine (Prozac) is FDA approved for use in treating depression in pediatric patients
OCD in peds: Fluoxetine, Sertraline, Fluvoxamine and clomipramine
Best results in pediatric population: Combination of pharmacotherapy and Cognitive-behavioral therapy (CBT)
Multidisciplinary team approach d/t complexities involved with this population
Monitor for: Agitation, irritability, suicidality, unusual behavior changes during first few months.
Prescribe low dose, small quantities – to reduce the risk of OD.
Depression in Children and Adolescents
Patient Education
Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults when the medicine is first started.
Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
