See introduction
ANTIDEPRESSANTS
SSRI’s, or Selective Serotonin Reuptake Inhibitors, modulate the serotonin system. They keep serotonin in the synapses between cells longer, which increases serotonin activity. This happens within 12 hours and some conditions like Premenstrual Dysphoric Disorder and premature ejaculation respond very quickly to these medications. It takes 2-3 weeks for SSRI’s to start helping anxiety and depression. This is because it’s not the direct effect of serotonin but how it effects the receiving cells and the sending cells. I call SSRI’s modulators because they increase serotonin activity if it’s too low (as in depression) and decrease it if it’s too high (as in anxiety). Sometimes serotonin is high in some brain areas and low in others.
SSRI’s started with Prozac in 1987 and now include Zoloft, Paxil, Luvox, Celexa, and Lexapro. I include Effexor XR 37.5 to 75mg in this group because at these doses its primary effect is on serotonin. At higher doses (150-225mg) it is an SNRI. SSRI’s, including low doses of Effexor XR are better for anxiety disorders than depression. All SSRI’s have potential side-effect issues in the short term and long term.
The biggest problem with the SSRI’s is in the long term. This is what matters the most to patients because they usually need these medications long term. Over several weeks to months there is frequently a “poop out” effect associated with some decrease in energy/motivation. Sexual dysfunction, especially loss of libido, and weight gain are common. Sometimes these can be improved by lowering the dose or adding another medication (like Wellbutrin XL), or in the case of Effexor XR, either increasing or decreasing the dose. But sometimes patients prefer to stop the medication or change to something else.
Protein binding is an important factor with the SSRI’s because it’s only the percentage of the medication that is free (not protein bound) that interacts with the receptors on the cells. Medications are like keys, and receptors are like locks. Medication can either turn on the receptors or plug them up and prevent them from being turned on.
BEST SSRI’s

1. EFFEXOR XR
Effexor XR is my first choice for an SSRI mainly because it is the one that in my experience patients are most likely to be happy with long term. It is the quickest to work probably because it has the lowest protein binding (27%). I expect some benefit for anxiety/depression by 7 days. Effexor XR doesn’t have any significant drug-drug interactions. It has the flexibility of being increased to higher doses if/when needed, so that it becomes also a norepinephrine reuptake inhibitor. (see SNRI’s below) Effexor XR comes in capsules that can be opened and sprinkled on food to take partial doses or for people who have trouble swallowing.
Of the SSRI’s it is one of the least likely to have drug-drug interactions. It is well tolerated. Occasionally it causes initial jitteriness or nausea, but these side effects go away quickly. In general, long term side effects are the lowest of this group, except for delayed orgasm – sometimes a benefit for men. If it occurs in women, taking it after sex sometimes solves the problem.
Because Effexor XR clears the system in 3 days, it can cause rebound symptoms if stopped abruptly. It needs to be gradually tapered. On the other hand, for women who may get pregnant unexpectedly they can stop taking it and have it out of the system before maternal blood mixes with the embryo. Also, when used for Premenstrual Dysphoric Disorder, it is out of the system more quickly once stopped. With this type of very short term use, there are no rebound concerns.
2. LEXAPRO
Lexapro is my 2nd choice in this category. It has the most pure effect on serotonin, and this is an advantage for patients who don’t tolerate any norepinephrine effect. (see SNRI’s below) Because it is 56% protein bound, it is fairly rapid in onset of benefit – I expect improvement beginning in 10 days.
It has flexible dosing since it comes in tablets that can be cut. Like Effexor XR, it has minimal drug-drug interactions. Rebound is not a significant issue at least in adults.
CELEXAis 1/2 Lexapro and 1/2 relatively inactive. It acts much in the same way as Lexapro.
PROZAC
Prozac (fluoxetine) is my 3rd choice because of my long term success with many patients, especially with Obsessive Compulsive Disorder. It may be the safest in kids and young teenagers, probably because it has such a long duration of action. It takes 6 weeks to clear the body, and therefore, rebound symptoms are not an issue. Weight gain and sexual dysfunction aren’t as bad as with some of the other SSRI’s. It has 96% protein binding so onset of action usually takes at least 2 weeks.
A major problem with Prozac is that it blocks a certain enzyme system that will increase other medications. These include tricyclics, Risperdal, Dextromorphan, Strattera, and others, and decreased benefit of pain medications.

PAXIL CR
Paxil CR is a controlled release form of Paxil. 25mg of CR is equal to 20mg of the regular Paxil. It is the only SSRI that has a formal approval for all five anxiety disorders. It may be the most effective SSRI for Social Anxiety Disorder possibly because it has blocking action on the parasympathetic nervous system – which is frequently overactive with social anxiety. This blocking effect may also contribute to a sedative effect that it sometimes has – which may help with sleep even when first starting it. But the blocking effect may also contribute to side effects like constipation and sexual dysfunction.
In my experience Paxil has the worst rebound symptoms if stopped suddenly or doses are missed. It may also be more likely to cause agitation in kids and young teens. It is probably the worst SSRI for weight gain and sexual dysfunction. It also is the strongest blocker of one of the liver enzyme systems – blocking benefit from pain pills related to codeine or hydrocodone and also increasing levels of other meds like TCA’s, Strattera, Risperdal, and others. This can potentially cause toxic levels of these other meds. Because of the side effects and drug-drug interactions, I only prescribe it when other medications have not worked well. I do have many patients who have done well on it especially for Social Anxiety Disorder.
ZOLOFT
Zoloft was the 2nd SSRI available, so I had a lot of experience with it early on. It was also one of the first to be formally approved for many of the anxiety disorders. It has some effects on dopamine, and one study showed that at doses of 150mg, it had comparable benefits to Effexor. Unfortunately the dopamine effect may cause anxiety or restlessness that is sometimes severe. One 10 year old girl I had on it described her side effects as there was something inside of her that she wanted cut out because she couldn’t stand it (severe inner restlessness). It is the least likely to cause drowsiness or sluggishness and drug-drug interactions are mild (except at higher doses).
Mainly, I rank it low because over the years in my experience the percent of people who do real well on it long term is very low.
LUVOX
Luvox is now only in generic and is only formally approved for OCD but is not necessarily better for OCD than any other SSRI (several are also formally approved for OCD). I have a couple of patients on it – mostly because they were on it when I first saw them, and it seems to work o.k. So “if it ain’t broke, don’t fix it”.
The reason I rank it last is that it has a lot of side effects and the most drug-drug interactions. It’s the most likely to cause drowsiness and the most likely to cause insomnia. It prolongs the effect of caffeine by several hours, which may also contribute to a feeling of anxiousness. For these reasons I rank it last.
One indication may be for people who take Zyprexa – especially if they smoke. Luvox will decrease their daily dose requirement – which could save several hundred dollars per month. How esoteric is that?
SNRI’s
Serotonin Norepinephrine Reuptake Inhibitors are serotonin modulators (SSRI’s), and norephinephrine modulators (NRI’s).
By blocking the reuptake of norepinephrine SNRI’s modulate this system just as SSRI’s modulate serotonin. Adding the norepinephrine effect increases benefit for generalized anxiety and especially increases the benefit for depression. In multiple studies antidepressants that modulate both serotonin and norepinephrine consistently help more patients reach full remission.
Chronic major depression is associated with low serotonin and low norepinephrine levels and this results not only in increased pain from all causes, but multiple other physical/medical problems such as urinary and sexual dysfunction.
It also seems that the norepinephrine effect reduces “poop out” seen so frequently with SSRI’s. It may also help with ADHD.
1. EFFEXOR XR 150-225mg
I rank Effexor XR as my #1 choice in this category. As the dose of Effexor XR goes up, the effect on serotonin levels off and the effect on norepinephrine increases. Effexor XR has the flexibility of being an SSRI at lower doses and an SNRI at higher doses. It works quicker (probably due to low protein binding), has no significant drug-drug interactions, and has a proven record for the full range of anxiety disorders and depression. In my experience over the long haul, it has the greatest benefit and the best tolerability of any antidepressant, and I therefore rank it my #1 antidepressant.
2. CYMBALTA
I rank Cymbalta as my #2 choice in this category, partly because it has been on the market for less than a year, so we don’t have a lot of experience with it. It works well for depression, and it may help all the anxiety disorders. But the studies haven’t been done. It may not be tolerated by panic patients. There are more controlled studies with Cymbalta showing benefit for all kinds of pain than any other antidepressant. It is especially helpful for back pain.
Some patients don’t tolerate it very well, and the dosing isn’t as flexible because it’s in capsules that can’t be sprinkled. There are issues with drug-drug interactions – it shouldn’t be mixed with Paxil or Prozac. It will weaken the effect of pain medications. 7% of Caucasians are genetically slow metabolizers and may have a significant increase in blood levels of Cymbalta and may show more side effects. Cymbalta will increase Strattera, Risperdal, Dextromorphan, and others. Having drug-drug interactions increases the complexity of prescribing any medication.
Because of its proven track record, I start with Effexor. But for those that don’t do well on Effexor for whatever reason, I have had some success with Cymbalta, especially for depression associated with chronic pain.

Other Antidepressants
WELLBUTRIN XL
Wellbutrin XL is a totally different type of antidepressant. It is not a reuptake inhibitor, so it is not a modulator like the SSRI’s and SNRI’s. Its mechanism of action is not as well understood but we know it increases norepinephrine and to a lesser degree increases dopamine. Wellbutrin’s main benefit is to increase motivation, energy and interest and to restore the capacity for pleasure and enjoyment that is often lost when someone is clinically depressed.
Sexual dysfunction, (reduced libido, arousal, orgasmic delay or absence) can be a part of clinical depression or a side effect of SSRI’s or SNRI’s. Wellbutrin frequently improves sexual functioning either given alone or with other antidepressants.
Wellbutrin may help some of the symptoms of ADHD, but like Provigil, Tenex, or Strattera it doesn’t have the level of effectiveness that the stimulants (Adderall XR, Concerta, etc.) have.
Wellbutrin is the most effective medicine currently on the U.S. market to decrease craving for smoking and to make it easier to quit or at least cut back. It was marketed for smoking cessation under a different name, Zyban, which I thought was silly and causes a lot of confusion.
The best thing about Wellbutrin is that it doesn’t cause weight gain or sexual dysfunction short term or long term. It may cause nervousness, irritability, insomnia or constipation.
Wellbutrin is not a broad spectrum antidepressant like Effexor XR or Cymbalta. It is not useful for premenstrual dysphoric disorder, anxiety disorders or the cognitive symptoms of depression. It is not as good for sadness and guilt. But overall it is probably the best tolerated antidepressant long term, and many of my patients take it.
The XL form is better tolerated than the SR (now in generic) and especially better than the short acting tablets which are much more likely to cause side effects and lower seizure threshold. Caution still is necessary even with the XL in someone with an elevated risk of seizure either because of a previous seizure or severe head injury. It is also not safe in actively purging bulimics. In over 15 years of using Wellbutrin, the only seizures I have seen have been associated with abruptly stopping Xanax – usually with excess levels of shorter acting Wellbutrin. For most patients it is a non-issue.
Wellbutrin XL is very good for motivation, interest, and pleasure, but because it doesn’t do well with the whole range of depressive symptoms nor with anxiety disorders, I rank it 2nd overall of the antidepressants.

REMERON
Now available in Sol tabs that dissolve immediately for those who have trouble swallowing like the elderly and young children. The regular tabs are now available in generic.
Remeron is a broad spectrum antidepressant that is sometimes used to immediately enhance sleep and appetite. I tell patients you’ll sleep the first night and you’ll gain weight in your sleep. For people who have lost a lot of weight due to depression or for the elderly who have no appetite with or without depression this is very helpful. It is also sometimes used to treat stimulant side effects – especially in preadolescent boys who are usually not interested in losing any weight.
I use Remeron most often to enhance other antidepressants, especially Effexor XR. In addition to helping with sleep and appetite, it accelerates the antidepressant effect of Effexor XR and blocks side effects so that I can push the dose of Effexor rapidly – this is especially important with severe melancholic depression.
I usually start at 7.5mg or less because a.m. sedation/grogginess is so common. Starting with a higher dose may be less likely to cause a.m. sedation but may actually be worse, so I prefer to start low. This effect improves in a few days.
Remeron is usually not a good long term treatment because of the carbohydrate craving and weight gain. One lady told me, “Doctor you don’t understand. I got up during the night, drove to an all night grocery store and bought a cake. Then I went home and ate the whole cake.”
Because of daytime drowsiness that is so common and major league weight gain my overall ranking for Remeron is low. But for certain situations or for short term use it is very effective, and it’s in generic so reasonably priced.

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