Antidepressants
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Introduction
Antidepressants are most commonly used to treat depression, but also have a role in bipolar disorder, anxiety disorders, and other conditions. Start low, go slow, and don't give up too early. Up to eight weeks are necessary to observe a response.
Choosing an antidepressant
Make sure patient is involved in this decision! Depression, without imminent suicidality, is not an emergency. Take time to plan treatments with the patient to maximize the chances of success.
Similarities
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Differences
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use pictures to get messages across
- warn of side effects (in 2/10)
- benefits over months
- risk of relapse
TO DO: put up drawing of remission/relapse.
Cross-tapering is usually necessary when switching medications. There is little science to this, as long as you go relatively slowly.
Classes of Medications
- SSRI
- SNRI
- NDRI
- TCA
- MAOI
SSRIs (Selective Serotonin Reuptake Inhibitors)
members
- fluoxetine (Prozac)
- fluvoxamine maleate (Luvox)
- paroxetine (Paxil)
- citalopram (Celexa)
- escitalopram (Ciprolex)
- sertraline (Zoloft)
indications
- depression
- anxiety disorders: panic, OCD, PTSD, social phobia
- bulemia
- PMS
- chronic pain
- pediatric complications
- more selective for serotonin
- decreased toxicity compared with TCAs
- less risk of interactions compared with MAOIs
- decreased suicide risk
side effects
- insomnia
- agitation
- headache
- anorexia
- nausea, vomiting, diarrhea
- sexual
- changes in weight
- EPSE/serotonin syndrome - drug interactions maybe
(MAOIs)
- tachcardia
- diaphoresis
- hypertension
- hyperthermia
- may cause suicide in children and adolescents, though effect is minimal
- hyponatremia (SIADH)
- can have anticholinergic effects
- paroxetine: fast-onset withdrawal; discontinuance can be very difficult
- SSRIs inhibit liver CYP 2D6, which is responsible for activation of codeine to morphine
- do not combine with MAOI's or TCA's due to risk of serotonin syndrome
mechanism
- block reuptake in the presynaptic cell, leading to increased serotonin in the synapse
- increased 5-HT signaling on presynaptic autoreceptors is thought to transiently decrease serotonin production; downregulation of autoreceptors then leads to increased production
- may also increase neurogenesis in the hippocampus
SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors)
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- duloxetine
- venlafaxine (Effexor)
- desvenlafaxine (Pristiq)
indications
- depression
- chronic pain
- generalized anxiety disorder
side effects
- elevated blood pressure (at higher doses)
- nausea, vomiting, insomnia, sleepiness
- nightmares (venlafaxine)
- constipation
- dry mouth, tremor, anxiety, agitation, abnormal vision, sexual dysfunction, headache
- interactions with drugs that affect 5-HT, such as SSRIs, St John's Wort, may lead to serotonin syndrome
mechanism
- NE and 5-HT uptake blocker
NDRI (Norepinephrine and Dopamine Reultake Inhibitor)
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- buproprion (Welbutrin, Zyban)
- mirtazepine (Remeron)
indications
- depression
- quitting smoking (continue smoking for first 1-2 weeks, then stop completely)
- improves sexual function
side effects
- seizures
- least impact on sexual dysfunction (buproprion)
- weight gain (mirtazepine)
- insomnia
- dry mouth
contraindications
- seizure disorder
- eating disorder
- MAOI use in past 14 days
mechanism
TCAs (Tri-Cyclic Antidepressants)
TCAs have a narrow therapeutic window.
members:
- amitriptyline
- nortriptyline (less anti-cholinergic side effects)
- imipramine
- clomipramine
indications:
- melancholic depression
- moderate-severe obsessive compulsive disorder (clomipramine)
- bedwetting
- ADD
- antidepressant
- analgesic for chronic pain states, small dose at bedtime
- headache
side effects:
- anti-cholinergic side effects: constipation, urinary hesitation, blurred vision, confusion, dry mouth, sedation
- a month's supply will kill you (arrhythmias)
- orthostatic hypotension
- cardiotoxicity
- confusion: be careful of driving, using tools, etc
- psychosis
- withdrawal symptoms
- weight gain
- increased suicidal tendenencies in the young
- combination with SSRIs or MAOIs can lead to serotonin syndrome
TCA overdose
TCA overdose is rapidly absorbed, with a quick onset. CVS and CNS effects are seen in parallel, and coma in 24-48 hours. Sodium channel blockade is most dangerous effect. ECG can show SVT, with increased QRS >0.1 and right axis deviation.
Treat with best supportive care, charcoal, and sodium bicarbonate. Sodium will assist with restoring CV function. The drug has a large volume of distribution, with a higher concentrations of drug in tissue compared with blood, so it is not dialyzable.
mechanism:
TCAs inhibit NE, 5-HT, and sometimes DA re-uptake. Acting as muscarinic antagonists, they also have various anti-histamine effects.
MAOIs (Monoamine Oxidase Inhibitors)
The clinical effects of MAOIs last for 1-3 weeks after drug has disappeared from blood.
members
- phenelzine
- tranylcypromine
indications
- moderate/severe depression, not responding to SSRI
- atypical depression
- chronic pain
- enuresis
side effects
Hypertensive crisis and serotonin syndrome are the biggest risks.
Some cheeses, red wine, and fermented foods are high in tyramine. Blockade of liver MAO results in high blood levels of tyramine, which can cross the BBB and induce mass release of NE, resulting in hypertensive crisis.
mechanism
MAOIs blocks major interneuronal degradative pathway for amine transmitters NE, DA, 5-HT irreversibly. This induces the accumulation and release of NTs.
Mechanisms of action
Antidepressants all enhance the availability of selected neurotransmitters, leading to increased connectivity between and among neurons.
Immediately after taking a reutake inhibitor, autoreceptors lead to a drop in firing rate. Over time, however, cell firing increases over baseline.
Antidepresants also are protective against future episodes (NNT 4 for 1 year and 3 for 2 years) metaanalysis (Geddes et al, Lancet 2003)
Neurovegetative symptoms begin to change within 1-3 weeks, while the emotional and cognitive symptoms often take 2-6 weeks to begin changing. Accordingly, it is important to be particulary vigilant during the first few weeks, as patients may be at risk of suicide with their increased energy but persistent low mood.
Adverse Effects
Almost half of people have concerns about antidepressant addiction. Side effects are more common in elderly.
common side effects
Common side effects include nausea, vomiting, sleep disturbance, and headache. If possible, encourage use for two weeks, as they are often transient. Sexual dysfunction can be very troubling for patients.
serotonin syndrome
Antidepressants can have potentially fatal interactions, causing hypertensive crisis or serotonin syndrome. MAOIs are particularly worrisome regarding side effects.
Any antidepressant needs to be out of the system (5 half-lives) before going to MAOIs. When switching from a MAOI to another antidepressant, wait 2 weeks to allow irreversibly inhibited MAO to regenerate.
serotonin syndrome
- SSRIs/TCA/SNRI, meperidine, L-tryptophan, L-dopa, epinephrine/norepinephrine, stimulants, hypoglycemic agents, dextromethorphan
suicide
There is at least a theoretical risk of increased suicide ideation, allegedly with SSRIs, especially in young patients. This is a big legal risk, though with proper documentation and warnings to patients, it is very safe.
flipping to mania
Some people will switch from depression to mania. This frequently occurs quickly and is more common in young patients. Stop treatment immediately.
Resources and References
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