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Terms in this set (92)
Mood disorder in which feelings of sadness, loss, anger, or frustration interfere with everyday life for weeks or more.
Major depressive disorder (MDD)
Depressed mood most of the time for at least 2 weeks; primary indication for antidepressant agents; at least one recurrence in a lifetime; may progress to more serious, chronic, and treatment-resistant episodes.
Major depressive disorder morbidities
Coronary artery disease, diabetes, and stroke
Most clinically useful antidepressant drugs
Potentiate the actions of 5-HT and/or NE in the brain.
Monoamine hypothesis of depression
Depression is due to a deficiency in the amount or function of cortical and limbic 5-HT, NE and DA; fails to explain the pharmacological effects of any of the antidepressant drugs on neurotransmission, which occur immediately
The time course for a therapeutic response
Occurs over several weeks
Antidepressants indications (FDA approved)
Panic disorder, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD).
Antidepressants indications (common uses)
Pain disorders such as neuropathic pain and the pain associated with fibromyalgia; premenstrual dysphoric disorder (PMDD), mitigating the vasomotor symptoms of menopause, and treating stress urinary incontinence
Specifically inhibit serotonin reuptake; little blocking activity at muscarinic, α-adrenergic, and histaminic H1 receptors (less side effects than TCA); Relatively safe (overdose is not fatal); drug of choice in treating depression
GAD, PTSD, OCD, panic disorder, social anxiety disorder, PMDD, sleep disturbances and bulimia.
Fluoxetine (the prototypic drug), citalopram, escitalopram (pure S-enantiomer of citalopram), fluvoxamine, paroxetine, and sertraline.
Highly lipophilic; half-lives range between 16-36 hours; extensive metabolism by cytochrome P450
Much longer half-life (50 hours) and the half-life of its active metabolite S-Norfluoxetine averages 10 days; only drug approved for bulimia; lowest risk of discontinuation syndrome; serum levels of TCA agents tend to be substantially influenced their concurrent administration; should be discontinued at least 6 weeks before a MAOI is initiated
Fluoxetine and paroxetine
Potent inhibitors of CYP2D6 responsible for the elimination of TCAs, antipsychotic drugs, some antiarrhythmic and b-adrenergic antagonist drugs. Administration of a 2D6 substrates (TCAs, antipsychotic drugs, some antiarrhythmic and beta adrenergic antagonist drugs) lead to unpredictable elevations in drug concentration
Dosages of the SSRIs should be reduced
Allosterically inhibit SERT, leading to increased concentrations of the neurotransmitter in the synaptic cleft; modest effects on other neurotransmitters; typically take at least 2 weeks to produce significant improvement in mood, and maximum benefit may require up to 12 weeks or more
Paroxetine and fluvoxamine
Useful in patients who have difficulty sleeping (More sedating than activating )
Fluoxetine or sertraline
Use in patients who are fatigued or complaining of excessive somnolence
Caution when SSRI's are used in children and teenagers
Suicidal ideation; pediatric patients should be observed for worsening depression and suicidal thinking with initiation or dosage change of any antidepressant
Fluoxetine, sertraline, and fluvoxamine
Approved for use in children to treat obsessive-compulsive disorder (OCD)
Fluoxetine and escitalopram
Approved to treat childhood depression.
SSRI's adverse effects
Considered to have fewer and less severe adverse effects than the TCAs and MAOIs; enhance serotonergic tone; gastrointestinal adverse effects (associated with nausea, gastrointestinal upset and diarrhea); diminished sexual function and interest; associated with hyponatremia, especially in the elderly and patients who are volume depleted or taking diuretics
Bupropion or mirtazapine
Fewer sexual side effects antidepressants
Weight gain is common; cardiac septal defects in first trimester exposures
Paroxetine and Sertraline
Associated with a discontinuation syndrome (headache, malaise, and flu-like symptoms, agitation and irritability, nervousness, and changes in sleep pattern beginning 1 or 2 days after stopping the drug)
Overdose with SSRIs
Does not usually cause cardiac arrhythmias, with the exception of Citalopram; seizures are a possibility because all antidepressants lower the seizure threshold; potential to cause serotonin syndrome, especially when used in the presence of a MAOI or other highly serotonergic drug (symptoms of hyperthermia, muscle rigidity, sweating, myoclonus, clonic muscle twitching), and changes in mental status and vital signs.
May cause QT prolongation; cause cardiac arrhythmias
Inhibit reuptake of both serotonin and norepinephrine; effective in treating depression in patients in whom SSRIs are ineffective; little activity at α-adrenergic, muscarinic, or histamine receptors
SNRIs and the TCAs
Effective in relieving pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and low back pain; used in the treatment of generalized anxiety, stress urinary incontinence, and vasomotor symptoms of menopause.
Venlafaxine, desvenlafaxine, levomilnacipran , milnacipran and duloxetine.
Potent inhibitor of serotonin reuptake and, at medium to higher doses, is an inhibitor of norepinephrine reuptake; weak inhibitor of NET; minimal inhibition of the CYP450 isoenzymes and is a substrate of the CYP2D6 isoenzyme
Desvenlafaxine, duloxetine, milnacipran, and
Balanced inhibitors of both SERT and NET.
Inhibits serotonin and norepinephrine reuptake at all doses; metabolized in the liver to inactive metabolite; should be avoided in patients with liver dysfunction; inhibitor of CYP2D6 isoenzymes and may increase concentrations of drugs metabolized by this pathway, such as antipsychotics; hepatic toxicity in patients with a history of liver damage; approved for the treatment of chronic joint and muscle pain.
Active enantiomer of milnacipran
Approved for the treatment of fibromyalgia in the USA.
SNRI's adverse effects
Same serotonergic adverse effects associated with SSRIs; noradrenergic effects, including increased blood pressure and heart rate, and CNS activation, such as insomnia, anxiety, and agitation; dose-related increase in blood pressure; discontinuation syndrome resembling that seen with SSRI discontinuation.
Combination with MAOI's
Imipramine (the prototype drug), amitriptyline, clomipramine, doxepin and trimipramine, desipramine (metabolite of imipramine), nortriptyline (metabolite of amitriptyline) and protriptyline
Maprotiline and amoxapine
"Tetracyclic" agents; beneficial in patients who do not respond to TCA's
Potent inhibitors of the neuronal reuptake of norepinephrine and serotonin. Also block serotonergic, α- adrenergic, histaminic, and muscarinic receptors; vary in their affinity for SERT versus NET.
Potent inhibitor of the neuronal reuptake of norepinephrine and serotonin; blocks 5-HT2 and dopamine D2 receptors
Maprotiline, nortriptyline and desipramine
Relatively selective inhibitors of norepinephrine reuptake (NET)
Lipophilic; penetrate into the CNS; variable first-pass metabolism in the liver results in low and inconsistent bioavailability; substrates of the CYP2D6 system, narrow therapeutic index
Elevate mood, improve mental alertness, increase physical activity, and reduce morbid preoccupation in individuals with major depression; onset of the mood elevation is slow, requiring 2 weeks or longer; necessitates slow withdrawal to minimize discontinuation syndromes and cholinergic rebound effects
More serotonin effect initially; desipramine balances this effect with more NET inhibition; used to control bed-wetting (enuresis) in children older than 6 years of age; most likely to cause orthostatic hypotension
Little affinity for NET but potently binds SERT; benefits in the treatment of OCD; sexual adverse effects are common;
Therapeutic applications of TCA's
Effective in treating moderate to severe depression; panic disorders
Used to help prevent migraine headache and treat chronic pain syndromes (neuropathic pain).
Used to treat insomnia and pruritus because of their antihistamine properties.
TCA's adverse effects
Anticholinergic effects are the most common (dry mouth, constipation, urinary retention, blurred vision, and confusion); potent α-blocking property often results in orthostatic hypotension; H1 antagonism is associated with weight gain and sedation; sexual; prominent discontinuation syndrome characterized by cholinergic rebound and flulike symptoms
Least likely to cause orthostatic hypotension
Affected cardiac conduction and may precipitate life-threatening
Cautions with TCA
Should be used with caution in patients with bipolar disorder (May cause a switch from depressed state to manic behavior)
Benign prostatic hyperplasia, epilepsy, and preexisting arrhythmias.
TCA + anticholinergic or antihistamine
Antihypertensive drugs + TCA
May exacerbate the orthostatic hypotension
CYP2D6 inhibitors + TCA
Elevated levels of drug
Monoamine oxidase Inhibitors (MAOIs)
Inactivate the enzyme MAO allowing NE, DA and 5-HT to accumulate in the synapse; limited by dietary restrictions required while taking these agents
Phenelzine, tranylcypromine, isocarboxazid, and selegiline
Form stable complexes with the enzyme, causing irreversible inactivation; Increases stores of NE, 5-HT and DA within the neuron and subsequent diffusion of excess neurotransmitter into the synapse.
Well absorbed; enzyme regeneration usually occurs several weeks after termination of the drug; minimum of 2 weeks of delay must be allowed after termination of MAOIs therapy and the initiation of another antidepressant from any other class; extensive first-pass effects that may substantially decrease bioavailability.
Selegiline transdermal patch
Less inhibition of gut and hepatic MAO at low doses because it avoids first-pass metabolism; only antidepressant available in a transdermal delivery system.
Selegiline and tranylcypromine
Amphetamine-like stimulant effect that may produce agitation or insomnia.
MAOI's therapeutic uses
Depressed patients who are unresponsive or allergic to TCAs and SSRIs or who experience strong anxiety; atypical depression
Treatment of Parkinson's disease; adjunct to levodopa decreases the required dose, reducing motor complications; at low doses selectively inhibits MAO B which metabolizes dopamine, but does not inhibit MAO A which metabolizes NE and 5HT
MAOI's adverse effects
Severe and often unpredictable; drug-food (tyramine) and drug-drug interactions, limit their widespread; orthostatic hypotension and weight gain; anorgasmia is fairly common; sudden discontinuation syndrome manifested in a delirium-like presentation with psychosis, excitement, and confusion
Causes the release of large amounts of stored catecholamines resulting in a hypertensive crisis, tachycardia, cardiac arrhythmias, seizures and stroke
Due to the risk of serotonin syndrome, the use with other antidepressants; OTC cold preparations containing pseudoephedrine and phenylpropanolamine
MAOI's; risk for drug-drug and drug-food interactions.
Both SSRIs and MAOIs
Require a washout period of over 2 weeks before the other
type is administered
Irreversible nonselective MAOIs
Associated with the highest rates of sexual effects of all the antidepressants.
SSRIs, SNRIs, TCAs and some
analgesic agents (meperidine) + MAOI's
Life-threatening serotonin syndrome (overstimulation of 5-HT receptors)
Tyramine in the diet or sympathomimetic substrates of MAO + MAOI's
Prevents the breakdown of tyramine in the gut, resulting in peripheral noradrenergic effects,including raising blood pressure dramatically; Malignant hypertension and subsequently a stroke or myocardial infarction.
Inhibition of this receptor is associated with substantial antianxiety, antipsychotic, and antidepressant effects
Most common use in current practice is as an unlabeled
hypnotic; associated with priapism
Black box warning for hepatotoxicity, including lethal cases of hepatic failure; potent inhibitor of the CYP3A4
Nefazodone + simvastatin
20-fold increase in plasma levels of simvastatin
Serotonin reuptake inhibitor and a 5-HT1A partial agonist; risk for
Serotonin reuptake inhibition, 5-HT1A agonism, and 5-HT3 and 5-HT7 antagonism; common adverse effects include nausea, vomiting, and constipation, which may be expected due to its serotonergic mechanisms
Antagonist of the α2-AR (enhances the release of both norepinephrine and 5-HT), of 5-HT2 and 5-HT3 receptors
and potent H1 antagonist; no antimuscarinic side effects of the TCAs, or interference with sexual function; increased appetite and weight gain; treatment of major depression, as a hypnotic and as an adjunctive treatment to more activating antidepressants.
Sedating effects of mirtazapine
Additive with other CNS depressants such as alcohol and benzodiazepines.
Weak dopamine and norepinephrine reuptake inhibitor that is used to alleviate the symptoms of depression; decreasing cravings and attenuating withdrawal symptoms of nicotine in patients trying to quit smoking; inhibit CYP2D6; major depression, including seasonal (winter) depression; not effective in the treatment of anxiety disorders and may be poorly tolerated in anxious patients; commonly combined with other antidepressants to augment
therapeutic response; non-sedating, produces weight loss and has low incidence of sexual dysfunction
Bupropion adverse effects
Dry mouth, sweating, nervousness, tremor, and a dose dependent increased risk for seizures
Bupropion use cautions
Patients at risk for seizures or those who have eating disorders such as bulimia; patients taking MAOIs
Choice of Antidepressant
Depends first on the indication; not all conditions are equally responsive to all antidepressants.
Choice of Antidepressant: MDD
Primarily on practical considerations such as cost, availability, adverse effects, potential drug interactions, the patient's history of response or lack thereof, patient's age, gender, and medical status
First-line agents in the treatment of both MDD and anxiety disorders; first-line treatment for PTSD
SNRIs, bupropion, and mirtazapine
Reasonable first-line agents for the treatment of MDD.
Bupropion, mirtazapine, and nefazodone
Antidepressants with the least association with sexual side effects and are often prescribed for this reason.
TCAs and SNRIs
Used in the treatment of pain conditions
Bupropion or mirtazapine + SSRIs or SNRI
Augment antidepressant benefit if monotherapy is unsuccessful
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