PHAR 752 Antidepressant Drugs Flashcards
Symptoms of Depression
Thoughts:
- Gloomy, hopeless, helpless
- Worry, dread, doom
- Worthlessness and guilt
- Inability to concentrate and slowed thinking
- Suicidal ideation (10-15% will attempt suicide)
Emotions and Pain (pain, sadness, anxiety, irritability, anger and anhedonia apathy)
Behaviors (loss of appetite and libido, disturbanecs in diurnal rhythm, insomnia, inability to act, social withdrawal)
Unipolar vs Bipolar depression
Bipolar characterized by manic phase (antidepressants can precipitate this phase)
Mood stabilizers often used for bipolar phase
Unipolar/Major Depression
5-15% of US adult population impacted
Major economic burden
2-3 times more common in women
Episodes can last 4-12 months with an average onset age of 30 years | usually recurrent
40% have a genetic disposition and 80% respond to treatment
Depression subcategories
Mild, moderate and severe (medication works best for moderate to severe)
Reactive depression (normal response to circumstances)
Agitated or atypical depression (fear, insomnia, extreme irritability, and restlessness)
Dysthymia (low level, long term melancholy - usually over 2 years)
Premenstrual dysphoric disorder (hormone driven?)
Post-partum depression (can occur up to 6 months following delivery)
Psychotic depression (perception of reality becomes altered)
Seasonal affective disorder
Treatment options for depression
Talk therapy Light therapy Antidepressants Exercise (reduces relapse) Electroconvulsive Therapy (ECT)
Electroconvulsive Therapy Pros/Cons
Effective in resistant depression
Rapidly effective
Disadvantage is confusion and memory loss
Antidepressant Effects
2-6 weeks latency
Improve mood, affect, appetite and sleep
Effective in 70-80% of patients
Taken prophylactically
Also used to treat neuropathic pain
Natural herbal remedy for depression
St. John’s Wort
Antidepressants biogenic amine hypothesis
Antidepressants work by extending duration of action of biogenic amines (norepinephrine, serotonin and dopamine) through blockade of reuptake or inhibition of metabolism.
This leads to an elevation in mood.
Norepinephrine deficit depression symptoms
Attention deficit, poor working memory, reduced alertness, low energy and social withdrawal
5-HT deficit depression symptoms
Agitation, appetite disturbance, sleep disturbance, anxiety
Describe antidepressant affects on biogenic amine synthesis
NE or 5HT levels increase within 2-3 hours but effects do not manifest for 2-3 weeks due to receptor and transporter modification in the brain
The integrated hypothesis of antidepressant action
Increases in 5HT or NE transmission will decrease some presynaptic receptors, increasing neurotransmitter release.
Transporter levels also decrease long-term, increasing levels of neurotransmitter in synaptic cleft.
Long-term increases in NE or 5HT transmission will cause changes in the brain (neurogenesis, increased number of synapses, glutamate signaling and improved mood)
Drugs that only target ________ reuptake are not good antidepressants. There must be some inhibition of _________ reuptake.
Norepinephrine | Serotonin
Inhibition of degradation in antidepressants (as opposed to block of reuptake) differs in that..
The transporter is not lost
Potential ultimate effects of antidepressants
Increase brain derived neurotropic factor (BDNF) and neuronal sprouting, primarily in the hippocampus
Cocaine and ketamine
Cocaine is a terrible antidepressant
Ketamine (via infusion) has a lasting antidepressant effect but often causes hallucinations
Tricyclic antidepressants
Block NE and 5HT transporters
Was the standard therapy prior to 1990
Drugs include Imipramine (Tofranil), Amitriptyline (Elavil), Desipramine (Norpramin), Doxepin (Sinequan) and Maprotiline (Ludiomil)
Used for neuropathic pain
MANY SIDE EFFECTS
Side effects of TCAs
CV effects:
- a1 adrenergic receptor antagonism (increased HR)
- Antagonism of muscarinic cholinergic receptors (increased HR) –> least with doxepin, most with amitriptyline
- NE activation of cardiac b-adrenergic receptors
Other side effects:
- histamine H1 receptor antagonism (sleepiness; worst with amitriptyline and doxepin)
- weight gain
- decreased seizure threshold
- sexual side effects related to 5HT alterations including loss of libido and impotence
TCAs and overdose
Lethal in overdose
Toxic sedative effects when combined with alcohol, benzos and barbiturates
Toxic cardiac effects
CNS anticholinergic psychosis (similar to scopolamine)
MAOIs
Block NE and 5HT breakdown
Irreversible and very long lasting
Includes Phenelzine (Nardil), Tranylcypromine (Parnate) and Isocarboxazid (Marplan)
Used only in cases of treatment resistant or atypical depression (e.g. high anxiety, phobias, hypersomnia, hyperphagia)
Useful in narcolepsy
Watch tyramine intake (wine and cheese)
MAOIs adverse effects
Insomnia followed by daytime sleepiness
Dry mouth
Impotence and loss of libido
Hepatotoxicity associated with phenelzine
Long washout period
Overdose toxicities include hyperthermia (too much serotonin) as well as hypertension, tachycardia and muscular agitation (all from too much NE)
_________ is given in hyperthermia as a result of MAOI
Dantrolene (as seen in co-administration of succinyl-choline with inhaled anasthetic)
MAOI toxic drug interactions
Can dangerously prolong half-lives of oxidatively deaminated drugs
Sympathetic crisis with sympathetic amines
Serotonin syndrome (similar to neuroleptic malignant syndrome): hyperthermia, muscle rigidity, myoclonus, mental disorientation, dose dependent and treated with dantrolene -->problematic with any drugs increasing serotonergic transmission, including triptans, SSRIs, meperidine (opioid) or dextromethorphan
MAOI toxic food interactions
Aged cheese, aged meats, spoiled meats and fish, sauerkraut, soy sauce, fava beans, banana peels, beers on tap
Have red or white win in moderation (4 oz or less)
Have bottled or canned beers in moderation
MAO-B Inhibitor Antidepressant
Selegiline (Eldepryl or Emsam)
More commonly used with Parkinson’s disease
Mechanism: Interferes with dopamine metabolism and may affect serotonin receptors (even though MAO-A is selective for NE and 5HT, MAO-B may still play a role)
Reversible MAO-A Inhibitors as Antidepressants
Some approved outside of US but none currently in the US
SSRIs
First line agents
Block 5HT reuptake
Same therapeutic effects and latency of action as TCAs but much better side effect profile (no affinity for alpha adrenergic, muscarinic, histamine or dopamine receptors)
Fluoxetine, Sertraline, Paroxetine, Fluvoxamine, Citalopram, and Escitalopram
Fluoxetine
Prozac
First of SSRIs to be marketed and the best characterized
Most stimulating of SSRIs
Hyponatremia in older patients (as serotonin regulated secretion of vasopressin)
Sertraline and Paroxetine
SSRIs
Zoloft; Paxil
Better for anxiety with depression
Questionable efficacy teens, therefore, don’t usually start teens on these two
Fluvoxamine
SSRI
Luvox
Shorter half life so less time is needed for wash out
Citalopram and Escitalopram
SSRIs
Celexa; Lexapro
Largest selectivity for SERT over NET of all SSRIs (doesn’t really alter efficacy)
QT prolongation limits dosing for Citalopram (usually half of the dose of Escitalopram)
Fewer histamine side effects with Escitalopram
Adverse effects of SSRIs
Nausea, headaches, nervousness and insomnia
Sexual dysfunction in men and women
Hyponatremia from elevated vasopressin
Hypomania/mania
Serotonin syndrome
Suicidal ideation (seems to be tied to age - teens are most at risk, elderly actually have decreased suicidal ideation)
SSRI discontinuation syndrome
Nightmares, insomnia, confusion and vertigo
Irritability, agitation
Electrical sensations (brain zaps, brain shivers, or cranial zings)
Taper dose, symptoms usually resolved after several weeks
SSRI overdose toxicity
Extremely rare
Seizures, leading to death, in combination with other drugs only
Multimodal SSRIs
AKA Serotonin modulators and stimulators
Have affinities for various 5HT receptor subtypes in addition to blocking SERT (e.g. 5HT1A, 5HT2, 5HT3, 5HT7)
Vilazodone and Vortioxetine (few sexual side effects)
Trazodone
Trazodone
Multimodal SSRI
Desyrel
Weaker SSRI but given in higher doses to block SERT
Off label use as a sleep aid
Additionally an H1 histamine and a1 antagonist (sleepiness | orthostatic hypotension and tachycardia)
Has more predictable side effects than others
Off label use in OCD (**belemia)
SNRIs
Venlafaxine (Effexor), Duloxetine (Cymbalta), Desvenlafaxine (Pristiq), Levomilnacipran (Fetzima)
All have affinity for SERT and NET
No affinity for adrenergic or muscarinic receptors
Adverse effects similar to SSRIs (additional side effects from increased NE including mild hypertension, dry mouth, increased HR and dilated pupils)
Atypical antidepressants
Buproprion and Mirtazapine
Do not appear to block SERT
Same efficacy and delayed onset of action as SSRIs
Bupropion
Wellbutrin for depression (causes weight loss in 25% of patients )
Zyban for smoking cessation
MOA is elusive (inhibition of central nicotinic receptors, weak inhibition of NE and dopamine reuptake)
–>theory is that depression is an OCD, and that OCD is a dysfunction of the reward mechanism
Stimulating
Not anticholinergic, antihistamine or sexual side effects reported
Safer for bipolar depression
Mirtazapine
Remeron
Good for anxiety with depression
H1 antagonist
Useful for treatment of resistant depression
MOA not well understood:
- may potentiate NE and 5HT release by blocking autoreceptors
- weak NET blocker
- No anticholinergic or sexual side effects
St. John’s Wart
Herbal supplement from Hypericum perforatum
MOA unknown
Active ingredient unknown (standardized to levels of hyperforin; extracts also contain polycyclic phenols, hypericin, flavonoids, kampferol and biapigenin)
Meta analysis suggests St Johns Wort is superior to placebo and has similar efficacy to SSRIs in treating depression
*do not use at same time as other antidepressants, especially SSRIs due to serotonin syndrome\
**still takes 6 weeks for action, may be less withdrawal but should still be tapered
Adverse effects of St. John’s Wart
Dry mouth, dizziness, sleepiness and some confusion
Photophobia, nausea, and/or diarrhea
Can induce manic episodes in bipolar patients
Mild form of serotonin syndrome may ensue in combination with SSRIs
Induces cytochrome P450 (decreases bioavailability of digoxin, theophylline, cyclosporin, phenprocoumon and other drugs…including oral contraceptives)
Natural remedies are not necessarily any safer than synthetic drugs
