Antidepressants (Linger) Flashcards
SSRIs
drug list
Citalopram (Celexa) Escitalopram (Lexapro) Fluoxetine (Prozac) Fluvoxamine* Paroxetine (Paxil) Sertraline (Zoloft)
SNRIs
drug list
Duloxetine
Venlafaxine
have actions at > serotonin and norepinephrine transporters
Tetracyclics and Unicyclics
(atypical antidepressants) drug list
Bupropion
Mirtazapine (common for seniors due to depression and weight loss issues)
have potent action at NE transporters
5-HT Modulators
drug list
Trazodone - can cause priapism (erection)
TCAs drug list (tricyclic)
Amitriptyline
Desipramine
Imipramine
Nortriptyline
not first line anymore
MAOIs drug list
Selegiline
Biological Basis of Depression
Several hypotheses have been proposed
- Monoamine Hypothesis
- Receptor Hypothesis
- Neurotrophic Factor Hypothesis
- Neuroendocrine Factor Hypothesis
These hypotheses are not mutually exclusive
MDD is a complex disease likely to involve aspects of all these ideas
Mood is regulated by 3 systems
dopamine (attention, motivation, pleasure, reward)
norepinephrine (alertness, energy)
Serotonin (obsessions and compulsions)
Major Classes of Antidepressants
First-line agents:
- Selective Serotonin Reuptake Inhibitors (SSRIs)
- Serontonin-Norepinephrine Reuptake Inhibitors (SNRIs)
- (Some) Tetracyclics and Unicyclics (catch-all class)
Second- and third-line agents:
- Tricyclic Antidepressants (TCAs)
- Monoamine Oxidase Inhibitors (MAOIs)
Infrequently used agents:
- 5-HT2 Antagonists
Efficacy of Antidepressants
30-40% of patients achieve remission within a single trial of 8-12 weeks
70-80% of patients achieve remission by switching to another agent or augmentation by addition of another drug
* Antidepressant drugs are roughly equivalent in terms of efficacy
Antidepressants are more effective when combined with psychotherapy
Choosing an Antidepressant
The choice of an antidepressant depends first on the indication; not all indications are equally responsive to all antidepressants
In the treatment of MDD, safety and side effects are usually primary considerations in deciding which drug will be tried first in a depressed patient
Although antidepressant drugs are roughly equivalent in terms of efficacy, individual patients may fare better on one drug than on another for unknown reasons
Often finding the right drug for a patient must be done by trial and error
Selective Serotonin Reuptake Inhibitors (SSRIs)
Newest generation of antidepressants
Fewer side effects than older agents due to minimal affinity for muscarinic, adrenergic, and histamine receptors
Relatively safe in overdose unless combined with other drugs, including alcohol
Fluoxetine (Prozac®) Sertraline (Zoloft®) Paroxetine (Paxil®) Citalopram (Celexa®) Escitalopram (Lexapro®) Fluvoxamine* (Luvox®)
- Labeled only for obsessive-compulsive disorder
SSRIs: Mechanism of Action
Allosteric inhibition of the serotonin transporter (SERT)
Effectively increases the concentration of serotonin in the synaptic cleft
~80% of SERT activity is blocked at therapeutic doses
Downregulation of postsynaptic 5-HT2A receptor density has been proposed as an adaptive process provoked by chronic administration of SSRIs
SNRIs & TCAs: Mechanism of Action
Inhibit SERT and NET, the norepinephrine reuptake transporter
Effectively increases the concentration of both 5-HT and NE in the synaptic cleft
Most SNRIs tends to exhibit greater affinity for SERT than for NET
Different TCAs have different relative affinities for either NET or SERT
MAOIs: Mechanism of Action
MAOs are mitochondrial enzymes that metabolizes monoamines
MAOIs cause accumulation of NE, 5-HT, and/or DA in vesicular storage in nerve endings and enhances neurotransmitter concentrations in the synaptic cleft
5-HT2 Antagonists: Mechanism of Action
5-HT2A receptor inhibition is associated with substantial antianxiety, antipsychotic, and antidepressant effects
Deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients, suggesting that postsynaptic 5-HT2A overdensity is involved in the pathogenesis of depression
Trazodone: rare ADR = priapism
SSRIs: Common Side Effects
Sexual dysfunction occurs in 30-40% of patients
GI disturbances
Initial agitation and insomnia
Sedation – usually less frequent than seen with TCAs
Discontinuation syndrome, causing dizziness and parethesia (feeling of “pins and needles”), can occur after sudden discontinuation of agents with short half-lives (e.g., paroxetine and sertraline)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Duloxetine (Cymbalta®)
- Nausea is a significant side effect
- Taper up and down slowly to avoid side effects
Most SNRIs exhibit the same side effects as SSRIs (e.g., sexual side effects) as well as noradrenergic effects
Venlafaxine (Effexor®)
- Low sedative and antimuscarinic effects
- Dose-related, sustained increase in blood pressure
- – Particularly problematic in overdose (cardiac toxicity)
- – Potentially dangerous with abrupt discontinuation
Bupropion: A Unicyclic Agent
CNS activating properties - occasionally associated with agitation, insomnia, and anorexia; lowers seizure threshold
Little or no sexual dysfunction
Mechanism of action incompletely understood
- Selective inhibitor of the dopamine transporter (DAT) and stimulates presynaptic release of NE and DA
- Virtually no direct effect on serotonin reuptake or receptors
Also used in smoking cessation
- Inhibitor of neuronal nicotinic receptors
- Marked under different trade name (Zyban)
Tricyclic Antidepressants (TCAs)
Were the dominant class of antidepressants until the introduction of SSRIs
Highly effective, but exhibit numerous side effects due to high affinity for muscarinic receptors, H1 histamine receptors, and α-adrenergic receptors
Amitriptyline (Elavil®)
- Has the most sedative and strongest antimuscarinic and cardiac side effects of all the TCAs
TCAs: Dangerous in Overdose!
A patient may overdose on as little as a 4 day supply of TCAs (depressed patients are at risk for suicide)
The three Cs: coma, cardiotoxicity, and convulsions
Can be fatal
The pharmacokinetics of TCAs hinder treatment of overdose (large volume of distribution and high plasma protein binding make dialysis ineffective in removing ingested drug)
- MAOIs are also potentially lethal in overdose producing autonomic instability, hyperadrenergic symptoms, psychotic symptoms, confusion, delirium, fever, and seizures
MAOIs: Serotonin Syndrome
Life-threatening interaction of MAOIs with serotonergic agents including SSRIs, SNRIs, most TCAs, and some analgesics
Thought to be caused by overstimulation of 5-HT receptors
Symptoms range from mild to lethal: sweating, rigidity, hyperthermia, autonomic instability, seizures
Discontinue for two weeks before switching drug classes
Monoamine Oxidase Inhibitors (MAOIs)
First used about the time of the TCAs (mid 1950’s)
Generally as effective as other antidepressants
Rarely used because of the risk of interactions with many foods (those high in tyramine) and drugs (sympathomimetic agents)
Isocarboxazid Phenelzine Selegiline Tranylcypromine Side effects Orthostatic hypotension and weight gain Highest rates of sexual side effects of all the antidepressants
MAOIs: Tyramine Interactions
Tyramine is a naturally occurring monoamine compound that stimulates catecholamine release
In foods, it is often produced by decarboxylation of tyrosine during fermentation or decay
Tyramine is normally metabolized by MAO
When MAOIs reduce tyramine metabolism, hypertensive crisis can occur – dramatic (and potentially fatal) rise in heart rate and blood pressure
Foods to avoid: Pickled, aged, or smoked meats and fish Chocolate Beer and wine Aged cheeses Fava beans Dried sausages Yeast extract And others
