Antidepressants: SSRI, SNRI & Tricyclics

Antidepressant Mechanism:

One hypothesis for the pathophysiology of depression is that it is due to low levels of monoamine neurotransmitters (mainly serotonin, norepinephrine and dopamine). That is why antidepressants aim to increase the levels of these neurotransmitters in the synaptic cleft. They do this by slowing the reuptake of the neurotransmitters so that they stay in the cleft longer and interact with post synaptic receptors more often. The first drugs in this group were non-specific and increased all of the monoamines, which lead to lots of side effects and safety issues related to toxicity. Newer antidepressants are more selective and mostly only effect 1 or 2 monoamines.

General Principles:

Unfortunately, antidepressants take at least a month to start working. Good patient education about the delayed onset of effect and close monitoring of the patient during this initial period is extremely important. Patients can become hopeless if they expect the drug to start working right away. This may be one reason why antidepressants are associated with suicide, especially in patients 25 years old and younger. Another proposed mechanism is that a depressed person may have the energy to carry out their suicide once the medications start to work. There is now a black box warning for suicide on antidepressants. Some psychiatrists argue that they don’t actually see this association with suicide in clinical practice, and that the thing that really increases the risk for suicide is not treating a depressed person with the proper medications. However, it is still standard practice to have a close follow up with patients you are starting on antidepressants. Usually this will involve a follow up visit about 2 weeks after the medication is started. At this visit the drug will not have started working yet so you can’t evaluate efficacy, but you can monitor for side effects like suicidality. Another serious side effect you have to be on the lookout for soon after initiating treatment is mania. If a bipolar individual is incorrectly diagnosed as having depression, an antidepressant may induce a manic episode.


Another very serious side effect that has to be considered for antidepressants is Serotonin Syndrome. This usually occurs when you combined multiple antidepressants at the same time or combine an antidepressant with another medication that increases serotonin such as dextromethorphan or an opioid.  It presents with tremor, diaphoresis, tachycardia, flushing and hypertension. If not corrected it can progress to delirium, AMS and death. Treatment includes medication cessation and the use of Cyproheptadine (a serotonin antagonist). In order to prevent this from happening you should have about a month “Wash Out” period when you are switching between antidepressants. So you taper the 1st medication down and then stop it, give the patient at least a month with no antidepressant and then start adding the new medication slowly.


Most side effects begin immediately after starting the medication, but diminish over the course of a month. This is another reason why patient compliance is poor with these meds. It makes them sick and the drug doesn’t work during the first few weeks. However, if they can stick with it the medications will likely start working and the side effects will diminish over time. A principle that applies to all of the antidepressants is “start low and go slow.” This means that you start with a lower dose and slowly increase it in order to decrease side effects and increase patient compliance. The dose you start the patient on may not even be at a therapeutic level, but every month or so you can increase the dose a bit.


Everyone reacts differently to antidepressants. Some will inevitably be partial responders or non-responders to certain drugs that you prescribe. Oddly, patients may react differently even to drugs within the same class. For example, one SSRI may work great for a patient while another SSRI does nothing for them. This is why treating depression is sometimes a trial and error process.  Since there is a delayed onset of effect you usually work your way up to the max dose and wait for about 6 weeks before switching to another medication.

About half of people who have their first depressive episode will eventually relapse and have another episode of depression. Therefore, treatment is usually continued for at least a year after their first episode of depression. After 2-3 episodes of depression the odds of having another depressive episode are so high that most docs would treat with antidepressants for life.


Most antidepressants can have a withdrawal effect if they are discontinued abruptly. It can presents with a wide variety of symptoms including insomnia, flu like symptoms and changes in mood. Antidepressants with short half-lives like Paroxetine more commonly have withdrawal effects. To prevent withdrawal most antidepressants should be tapered before discontinuation.


Tricyclic Antidepressants (TCAs) block reuptake of norepinephrine and to a lesser extent serotonin. They are more selective than the very old MAOIs, but not as selective as SSRIs/SNRIs. This is why they have largely been replaced by SSRIs/SNRIs as first line depression treatments. They are still used to treat depression resistant to other antidepressants as well as off label use for a number of other conditions including fibromyalgia, chronic pain/neuropathic pain, and enuresis (loss of control of urination such as bedwetting). If a patient has depression and something like a chronic pain syndrome than it should be your first choice.


TCAs: [most end in -iptyline & -ipramine]

  • Amitriptyline
  • Nortriptyline
  • Imipramine
  • Clomipramine
  • Doxepin


Side effects limit the use of TCA. The most common side effects fall under the category of anticholinergic. Depending on the specific side effect you may be able to more specifically describe these at anti-muscainic, antihistamine or anti-adrenergic effects. They include dry mouth, blurry vision, urinary retention, constipation, sedation, orthostatic hypotension, and cognitive impairment. These symptoms are not nearly as common in newer antidepressants. Like SSRIs insomnia, weight gain and sexual dysfunction are also common side effects. There are also rare but very serious cardiac adverse reactions. TCAs can cause QT interval prolongation, which is why they are contraindicated in those with underlying conduction abnormalities and recent MI. An EKG should be done before starting a patient on TCAs. TCAs are fatal in overdose due to arrhythmias. This is very risky considering that antidepressants are given to a group of individuals who may be suicidal. TCAs are correlated with seizures and coma while also interacting with many different drugs via their metabolism via cytochrome P450.


Selective-Serotonin Reuptake Inhibitors (SSRIs) increase serotonin in the synaptic cleft by decreasing their reuptake. They are “selective” because they have less effect on the reuptake of other monoamines like norepinephrine and dopamine. They are first line treatment options for depression, OCD, social phobia, PTSD, Generalized Anxiety, Eating Disorders and other psychiatric conditions. They are used for so many different things that if you are stuck on a psych med question and don’t know the answer just selecting the SSRI is probably the safest bet.



  • Paroxetine (Paxil)
  • Fluoxetine (Prozac)
  • Sertraline (Zoloft)
  • Citalopram (Celexa)
  • Escitalopram (Lexapro)

They have become the first line medication for depression as they have a better safety profile and fewer side effects than TCAs. Unlikely TCAs, SSRIs are usually not fatal in overdose. That is obviously a big advantage when you are treating depressed patients that may be suicidal. SSRIs can also have GI problems (Nausea, diarrhea etc.), headache and insomnia as side effects. These adverse reactions will usually diminish overtime, but if insomnia persists Trazadone is sometimes added to an SSRI to lessen the insomnia side effect. The most common side effect is sexual dysfunction which can include anorgasmia, diminished libido and erectile dysfunction. Thankfully this side effect can largely be eliminated by combining an SSRI with Bupropion. The sexual side effects can also be a plus for some patients as SSRIs are sometimes abused or used off label to treat premature ejaculation. SSRIs are also associated with bleeding as they can interact with anticoagulants like Warfarin.


Serotonin-Norepinepherine Reuptake Inhibitors have a similar mechanism to SSRIs but they block the reuptake of serotonin and norepinephrine. Other than that SNRIs have very similar indications, efficacy and side effects as SSRIs so I will not spend much time specifically on SNRIs.



  • Duloxetine (Cymbalta)
  • Venlafaxine (Effexor)
  • Desvenlafaxine (Pristiq)

Atypical Antidepressants

“Atypical Antidepressants”:

  • Bupropion (Wellbutrin)
  • Trazodone (Desyrel)
  • Mirtazapine (Remeron)


Bupropion (or Wellbutrin) does not have sexual side effects and may actually increase sexual function. This is why Bupropion is often added to SSRIs, because it counteracts the sexual dysfunction of SSRIs. Another important thing to know is that Bupropion can be used off label for smoking cessation. So if you have a patient who is depressed and wants to quit smoking this is the clear choice. A downside to this drug is that it lowers the seizure threshold, especially in those that are bulimic. So this medication is contraindicated in people with a history of eating disorders and epilepsy.


Trazadone is almost never used purely as an antidepressant anymore, because the side effect of sedation is so strong. However, Trazadone is commonly used off label as a sleep aid or in conjunction with an SSRI if they are having insomnia. The rare but dangerous side effect of this drug to remember is Priapism. This is a prolonged erection that does not return to flaccid state and can lead to impotence if not treated. Some people remember this side effect by the mnemonic “Traza-BONE”.


The only high yield thing to remember for Mirtazapine (Remeron) is that it commonly has weight gain.  This may actually be a positive thing if you are treating depression in somebody (like a frail elderly patient) that needs to gain weight.


Pictures Used:

  • “SynapseSchematic” by Thomas Splettstoesser available at via Creative Commons 4.0 Attribution-Share Alike
  • “Zoloft Bottles” by Ragesoss available at via Public Domain

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