Are All Anti-Depressants Equal?: The Answer is Yes and No

As a mathematics major (admittedly some time ago) majoring in probability and statistics, I can heartily agree with the old Mark Twain phrase: “There are three kinds of lies: lies, damned lies, and statistics.” In this regard, it is irrefutable that all anti-depressants currently on the market are equally effective (roughly speaking in the 60-80% range). However, it is also true that there are important provisos to this statement which render it less true than it appears. Let us then examine the case:

It would be more wholistic to make the statement that all anti-depressants are equally effective so long as in a given population a therapeutic dose is achieved.  When looked on in this manner, then, it is clear that all anti-depressants are not equally effective.  For instance, the old-time anti-depressant trazadone (brand name Desyrel), in order to effectively treat depression, has listed (by the manufacturer in the book the Physician’s Desk Reference [PDR]) or website Rxlist.com) as a recommended starting dose of 150 milligrams (mg) per day which they advise may then be increased by 50 mg per day every 3 to 4 days up to a maximum dose of 400 mg per day for an outpatient or 600 mg per day for a psychiatrically hospitalized inpatient. Contrast this situation with Trazadone’s utility as a sleep aid, which has been endorsed by the American Academy of Sleep Medicine as an-off label (or non-FDA approved) indication.* Here the drug is often prescribed as a non-addicting sleep aid usually at doses anywhere from 25 mg up to 100 and rarely as high as 200 mg. Thus, common sense dictates that trazadone makes people quite drowsy at doses that are markedly less (in fact 50 % or less) than its therapeutic dose for depression. Another way of saying this is that it is difficult (if not impossible) to get Trazadone to a high enough dose in a given individual where it would be effective as an anti-depressant without the person first falling asleep!   So yes, strictly speaking it is true, that in those select few people who can tolerate a very large dose of trazadone, they may expect to have a good-antidepressant effect equal to the newer antidepressants.

Not to pick on trazadone, then, as this statement is true of Remeron (generic mirtazapine), Sinequan (doxepin), Pamelor (nortriptyline) and Elavil (amitriptyline), all of which are highly sedating in many individuals to the point where they are useful off-label as sleep aides but would not be useful in most patients with depression as they could never tolerate a high enough therapeutic dose.
So if all anti-depressants are equally efficacious for depression, then how does one go about picking an antidepressant for a given patient? The answer in most cases, which we have already alluded to, is quite simply, based on the side-effects profile. And what determines medications side-effects? Without a doubt, the category it is in based on its mechanism of action. So taking a look at the anti-depressants category-wise:

Since we have already dealt with the older tricyclic-type anti-depressants above in referring to their sedative properties, let us move on to the newer categories of antidepressants (see chart below) all of which are termed “neurotransmitter reuptake inhibiters.” Therefore, these drugs create a greater amount of neurotransmitter (serotonin, dopamine or norepinephrine) in the cleft or space between two nerve cells, by blocking their re-uptake or storage by the original nerve cell which released them (see diagram below). This in turn causes changes in the way the neurotransmitter and receptor interact resulting in a change in firing rate by the nerve cells.  This ultimately leads to changes in a person’s behavior, cognitions (thoughts), or feelings and emotions (see diagram below).
Most antidepressants are found in a particular category based on the main neurotransmitter which they influence: Thus we have the selective serotonin reuptake inhibiters (SSRI’s) or norepinephrine/dopamine re-uptake inhibiters and finally the dual re-uptake inhibiters which influence both.

Of the SSRI’s the forerunner which came on the market in 1987 was Prozac (fluoxetine), swiftly followed by the now “golden-oldies” Paxil (paroxetine), Zoloft (sertraline), Celexa (citalopram) and Lexapro (escitalopram) .  Since there are serotonin receptors in the gut (sometimes referred to as the “gut brain) the major side-effects these agents cause are gastrointestinal (GI) including nausea, vomiting, constipation and diarrhea.  These drugs have some propensity for causing drowsiness as well, so that I usually recommend that they be started in the morning (in case there are bad side-effects they are usually easier to handle during the day than at night). However, if drowsiness is an issue they can be given as effectively at night. Viibryd (vilazodone) and Brintellix (vortioxetine) are the newest SSRI’s. Their main claim to fame again is not in their efficacy per se, but in improved side-effects profile so they are better tolerated especially in the realm of weight gain and sexual side-effects.  Thus, as opposed to the older SSRI’s which have a significant probability of sexual side-effects (in the 5-15% range) and weight gain (1-2 %) these drugs are purported to have side-effects comparable to placebo and similarly be weight neutral.

On the other side of the spectrum in terms of mechanism of action is the category of dopamine/norepinephrine reuptake inhibiter of which there is one drug on the market in the United States commonly known as Wellbutrin (bupropion) and bupropion derivatives thereof.  In terms of side-effects, bupropion has the virtue of being body weight neutral. Furthermore, not only does it not tend to cause sexual side-effects on a statistical base, it can actually be used as “an antidote” to the SSRI’s when they impair libido or orgasm.  The analogy here is like a see-saw, so that the greater or heavier the dose of SSRI the more likely is the chance of sexual side-effects, and conversely the larger the dose of Wellbutrin the less likely these sexual side-effects are to occur. Furthermore, in terms of clinical effects, whereas the SSRI’s (and the dual re-uptake inhibiters described below)  tend to be more calming and indeed are FDA approved for a variety of anxiety disorders (including obsessive-compulsive disorder or OCD, panic disorder, social phobia, generalized anxiety disorder  and posttraumatic stress disorder or PTSD) , bupropion derivatives tend to cause anxiety and agitation at a rate significantly higher than placebo which may not infrequently lead to discontinuation.  The most common side effect of Wellbutrin or bupropion is actually dry mouth, but most people get used to this so that they do not have to stop taking the drug.

The last group of anti-depressants with this mechanism of action as a re-uptake inhibiter is the “dual re-uptake inhibiters” of both serotonin and norepinephrine/dopamine including Effexor (venlafaxine), Cymbalta (duloxetine) and the newer agent Fetzima (levomilnacipran). Similar to the SSRI’s, the major side effects probability-wise fall into the GI category most notably nausea.  Fetzima as the new kid on the block has as a claim to fame weight neutrality and relatively low sexual side effects. Like the SSRI’s these drugs are approved for various indications in the anxiety spectrum and tend to be calming, although in rare instances they can actually make the patient more nervous.

For the sake of completeness, there is an older group of anti-depressants which for whatever reason (chalk it up to “regional differences”) has historically been more popular in England and the rest of Europe termed “MAO-I’s” which stands for monoamine oxidase inhibiters which is their mechanism of action.  Thus, these medications inhibit the enzyme monoamine oxidase which helps to break down or metabolize neurotransmitters.  And since a minus multiplied by a minus is a positive, voila, again (as with the re-uptake inhibiter type anti-depressants) the result is more neurotransmitter between the nerve cells altering firing rate and thus mood and other behavioral and cognitive capacities.

Aside from the “classical” anti-depressants documented above, other medications used to treat depression along with or to “boost” anti-depressants are termed the “augmenting” agents.  Approved by the FDA for the use are the “second-generation” or new antipsychotics: Abilify (aripiprazole), Seroquel (quetiapine) XR or extended release, and Zyprexa (olanzapine), the latter only when given in conjunction with Prozac (fluoxetine). As may be gleaned from this list which does not include other of the newer antipsychotics (like Risperdal [risperidone] and Geodon (ziprasidone)], some of these FDA approvals may be attributed more to an artifact of the testing procedures for approval than to the medication efficacy itself.  That is, some of the drug companies were smart enough to subject their respective medications to clinical trials in order to get their drug “approved,” while others for whatever reason were not as rigorous in their testing procedures and thus did not gain official FDA approval as “augmenters.”

Other medications in various miscellaneous categories have historically been utilized as augmentation agents including Lithium, T3 or triiodothyronine (thyroid hormone) and Buspar (buspirone).  Stimulant medications (like Adderall [(dextro-) amphetamine], Ritalin (methylphenidate, etc.) have been utilized successfully as augmentation agents. Lastly, although not strictly speaking an “augmentation” strategy, the use of two anti-depressants in conjunction oftentimes proves the aphorism that “two is better than one.”  In this regard, an SSRI (e.g., Lexapro or Viibryd) along with a DA/NE reuptake inhibiter (e.g., Wellbutrin) can oftentimes be safely used together.

With all of these various possibilities how does one go about choosing an anti-depressant?  One obvious answer is in terms of drug interactions so that for instance, an anti-depressant may be metabolized by a common enzyme which breaks down a medication the person is already being prescribed perhaps for non-psychiatric purposes. When 2 medications share a common enzyme due to their “competition” they each may be broken down less quickly than usual resting in a potential high blood level or drug toxicity situation.  Therefore, in this instance, it would be prudent to choose an anti-depressant that does not have a potential drug interaction side-effect. Also, obviously, if the patient has been on various anti-depressants in the past which have not worked or worn off it may be advisable to avoid these medications or medication from that particular drug class.  On the other side of the coin, patient may have had family members who benefitted from a particular medication in which case the odds of that person themselves responding may be increased so quite naturally it may be wise to gravitate towards that one.

*Most medications in the United States are prescribed off-label meaning it is up to the Dr’s discretion as to which medications to use for what indication. The fact that the Food and Drug Administration (FDA) has approved an indication also means that the drug in question must have been “proven” to work statistically in a clinical trial.  Once a drug goes generic, it makes it much less likely that the drug company will pay to have it studied, so that FDA approved indications are somewhat of an artifact of this “political”-type process.
Examples of effective medications commonly prescribed for depression or depression-related problems are listed in the chart below.
 
Drug Name
Type of Medication
Potential Side Effects

• Anafranil
  
• Adapin
  
• Aventyl
  
• Elavil
• Endep
  
• Norpramin
  
• Pamelor
  
• Pertofrane
  
• Sinequan
  
• Surmontil
  
• Tofranil
  
• Vivactil
• Zonalon

These medicines are tricyclic antidepressants (TCAs) which work by increasing the available amount of serotonin and/or norepinephrine in the brain. Dry mouth, blurred vision, increased fatigue and sleepiness, weight gain, muscle twitching (tremors), constipation, bladder problems such as urine retention, dizziness, daytime drowsiness, increased heart rate, sexual problems.

• Emsam
• Eldepryl
• Nardil
  
• Marplan
• Parnate
• Zelapar
  

Monoamine oxidase inhibitors (MAOIs) increase the amount of norepinephrine and serotonin in the brain
Must avoid certain foods and medications to avoid dangerous interactions.*
Serious side effects may include: headache, heart racing, chest pain, neck stiffness, nausea and vomiting. If you experience any of these symptoms, seek medical care immediately.

• Celexa
  
• Lexapro
  
• Luvox
  
• Paxil
• Pexeva
  
• Prozac
• Sarafem
  
• Zoloft

Selective serotonin reuptake inhibitors, or SSRIs, work by increasing the functioning of serotonin, a neurotransmitter found in the brain.
Sexual problems including low sex drive or inability to have an orgasm are common but reversible, dizziness, headaches, nausea right after a dose, insomnia, feeling jittery.

• Aplenzin
• Budeprion
• Buproban Forfivo
• Wellbutrin

These contain bupropion, which may increase the amounts of the neurotransmitters norepinephrine and dopamine in the brain.
Weight loss, decreased appetite, restlessness, insomnia, anxiety, tremor, constipation, dry mouth, diarrhea, dizziness, seizures.

• Cymbalta
• Effexor
• Fetzima
• Khedezla
• Pristiq

These drugs increase the levels of the neurotransmitters serotonin and norepinephrine in the brain.
Drowsiness, blurred vision, lightheadedness, strange dreams, constipation, fever/chills, headache, increased or decreased appetite, tremor, dry mouth, nausea.
Remeron can be sedating and cause weight gain. Cymbalta may increase sweating and blood pressure and also cause fatigue and reduced energy.

• Desyrel Ludiomil
• Oleptro

These drugs block various neurotransmitter chemicals including serotonin or dopamine.
Desyrel and Oleptro may cause drowsiness, fatigue, tremor, headache, dry mouth, nausea, and vomiting.
Ludiomil may cause headache, dizziness, dry mouth, fatigue, daytime sleepiness, and sweating.

• Brintellix

This drug works to block the serotonin reuptake pump much like an SSRI does, but in addition affects a number of other serotonin receptors. Brintellix may cause nausea, constipation, vomiting, dizziness, decreased interest in sex, and changes in sexual ability.





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