Tuesday, August 31, 2010

SSRI Tales

In 23 years of clinical experience prescribing them since they first made the scene, I have found that the type of antidepressant medications called Selective Serotonin Inhibitors (SSRI’s) are, for the majority of patients (with some important exceptions described in the next paragraph), relatively side effect free. Especially when combined with a long acting benzodiazepine tranquilizer such as Clonazepam, they are also highly effective for many patients who have major depression, panic attacks, obsessive compulsive disorder, PTSD, or the extreme emotional hyper-reactivity characteristic of borderline personality disorder.

Just so I don’t have to keep answering the same question, YES, some people do indeed have nasty side effects from them. YES, the drugs can increase suicidal ideation for some patients under some circumstances. YES, they often wreck havoc on sexual functioning. YES, they can have nasty withdrawal symptoms if stopped cold turkey, especially Paxil. YES, they do not work for everyone. But NO, there is not a shred of clinical or experimental evidence to back up Robert Whitaker’s assertion that patients who get better with the meds in the short run are made worse by them in the long run

In my new book I talk about how first benzodiazepines and now antidepressants are being demonized by the drug companies ever since most of the drugs in each class became available (or were about to) as cheaper generic medications. The only antidepressant that is really different that is not available as a generic is Cymbalta, which is technically not an SSRI. (Lexapro and Prestiq are just old drugs in new packages, as per my blog post of June 14).

Cymbalta has been trying to position itself as the drug best for people with chronic pain – but the old antidepressants like Elavil work just as well for that – and for the wastebasket diagnosis of fibromyalgia. (Another disclaimer: just because fibromyalgia is a made-up disease does NOT mean that “neurogenic” pain is not very very real and significant, so please, no nasty missives on that subject).

Back in January, the headline "Antidepressants May Only Be Effective in Treatment of the Severest Depression" was seen in newspapers around the country and even made the network newscasts. It was based on a meta-analysis, which means that the results of several different individual studies were combined.

The headline was sort of true in some ways but was extremely misleading. It is true that a milder type of depression called dysthymia is less likely to respond to drugs than a more severe variety of depression called major depression. Dysthymia tends to involve the thinking parts of the brain more and is usually more amenable to psychotherapy; major depression tends to involve a more primitive part of the brain called the limbic system more and tends to respond better to drugs. Of course there is considerable overlap between the two syndromes because all parts of the brain are highly interconnected, so diagnosis can at times be an issue.

The news stories did not mention psychotherapy at all and left the vague impression that current drugs should not be used much. Maybe doctors should be adding Abilify, just as the commercials say. NOT!

Only six studies were used in this meta-analysis. All of them did a poor job of distinguishing major depression from dysthymia. All six studies compared anti-depressants to placebo (sugar pill) and only tested one drug. Clinically, that is not the way the drugs are used by psychiatrists. Patients who do not respond to one of the antidepressants often will respond to another. Sometimes we have to try three or four before meeting success. There are diminishing returns with each switch, but the total response rate to antidepressants is the sum of the response rate to drug one plus the response rate to drug two, and so on. The type of study I am criticizing makes the drugs look way less effective than they actually are.

Not only that, but in at least one of the studies, the antidepressant was severely under-dosed! Do you think the authors were trying to make it look bad or something?

In my book, I also tear apart an article in the usually well-respected New England Journal of Medicine that purported to show that antidepressants do not work in depressive episodes seen in bipolar disorder. That paper was dishonest as the day is long.

Now comes a brand new attack on  something called the STAR*D study.  The STAR*D study attempted to study antidepressants in the way that clinicians actually use them, rather than the way they are used in studies. It did indeed show that if one antidepressant does not work after the required amount of time, then another should be tried and so on, and if this is done then the total response rate to antidepressants is actually fairly high in properly diagnosed patients with major depression.

The authors of the attack (Psychother Psychosom. 2010;79:267-279) pointed out that “the effectiveness of antidepressant therapies was probably even lower than the modest one reported…with an apparent progressively increasing dropout rate across each study phase."

“We found that out of the 4041 patients initially started on the SSRI [selective serotonin reuptake inhibitor] citalopram in the STAR*D study, and after 4 trials, only 108 patients had a remission and did not either have a relapse and/or dropped out by the end of 12 months of continuing care,” lead study author Ed Pigott, PhD, a psychologist with NeuroAdvantage LLC in Clarksville, Maryland, told Medscape Medical News.

In truth, if a study has a lot of dropouts, then it can just as easily underestimate as overestimate drug effectiveness. This is especially true for antidepressants because they must be continued for a few months after remission is achieved, and patients will often quit taking them prematurely precisely because they feel better. They then relapse. It is disingenuous to the utmost to count drop outs as non-responders!

I agree that the Star-D study was poorly designed to determine sustained efficacy, because that was not its main purpose. The initial good results on the patients who did not drop out are pretty much identical to what is seen clinically.

It is important to follow depressed patients very closely and have a therapeutic relationship with them to emphasize the need to stay on the medication for a while. Some patients have also significant psychosocial stressors that they do not tell the doctor about either because no one asked, or because of shame. A doctor has no hope of sorting out antidepressant response from other variables - often difficult under the best of circumstances - if he or she does not know about the psychosocial context in which symptoms are seen. The type of relationship in which such information becomes readily available to the doctor just does not happen in studies.

In general, drop outs in almost all studies are not tracked, so we have no way of knowing how many might relapse.

Two of the authors of the attack paper, H. Edmund Pigott, PhD, and Gregory S. Alter, PhD., are founders of NeuroAdvantage, LLC, a for-profit "neurotherapy" company. This is a company that has products that one can reasonably assume are competition for antidepressants. The company “offers a number of light & sound neurotherapy (LSN) programs designed to decrease symptoms of depression and anxiety as part of an overall treatment plan. Numerous clinical researchers have found that LSN is a robust treatment effective in facilitating profound relaxation and meditative states.” (From their website).

The first SSRI that was FDA approved was Prozac. As mentioned earlier, that was 23 years ago in 1987. Paxil, Zoloft, and Luvox followed soon thereafter. Isn’t it amazing, after all that time, that a whole bunch negative “new “information about SSRI’s is coming out just as they are all going generic?

Of course, I cannot prove that Big Pharma or alternative medicine is behind this.

Certainly, Big Pharma does want as many depressed patients as possible to be put atypical antipsychotics like Abilify while they still have the patents. More frightening potential evidence is that the drug company giant GlaxoSmithKline sat on data that showed that Paxil caused a huge number of birth defects in pregnant rats (teratogenesis) that they had known about since the drug first came out. Now, after twenty years and like magic, this data suddenly has seen the light of day!

Coincidence? You be the judge.


  1. You may be technically correct that there is not a shred of evidence (I'm assuming you are referring to double blind studies), but who is actually doing these long run studies? Isn't this part of the problem? Loads of short term studies, no long term studies? According to studies, people stay on their antipsychotics an average of 18 month before switching or dropping. That would imply that their short term experience with these drugs is not a good one. I don't know of any studies that are interested in the outcomes of people on psych meds long term.

    But NO, there is not a shred of clinical or experimental evidence to back up Robert Whitaker’s assertion that patients who get better with the meds in the short run are made worse by them in the long run

  2. Rossa - I was talking about SSRI's in this particular post, and I was talking about long term clinical experience as well as the few and usually inadequate long term double blind studies.

    The situation with anti-psychotics is more complicated, but people stop taking them for all kinds of reasons besides lack of effectiveness. Also, sometimes symptoms break through because of non-compliance, substance abuse, or family discord. Psychiatrists these days don't spend enough time with patients to find out about these extraneous factors, and jump to the false conclusion that the medication is no longer working. So they change it - often again and again and again. Bad psychiatry!

    Clinically, we see a lot of patients with severe schizophrenia who have been stable on the same meds for decades. The downside of that is that those are the patients who often develop tardive dyskinesia.

  3. Dr. Allen, I have corresponded with you before on the issue of Robert Whitaker and the thesis he carefully presents in his book and you admitted then you hadn't read it and from the way you are summarizing what you call his "assertion" here it's quite clear you still haven't read it. His argument has more to do with long term outcomes of people taking medications vs. people who don't and he presents a great deal of evidence in the form of published studies as well as case examples. I think the person doing the "asserting" here is yourself, not Robert Whitaker.

    You clearly believe strongly in the clinical experience you have had with SSRI antidepressants. It's true I really don't know how to explain it because all the people I know who have been on SSRIs long term are either doing poorly or like delicate time bombs waiting to implode either physically or mentally. They are almost all reliant not just on their SSRI but a whole host of other drugs -- benzos, hypnotics, antipyschotics. It's scary that these people are walking around, driving cars, trying to hold jobs. They are very fragile, yet also kind of zombie like. I am greatly saddened because I don't think many of them deserved to have their lives impacted in this way.

  4. Hi Sara,

    Thanks for your comment. It's good to hear from you again.

    You just said the magic words: "They are almost all reliant not just on their SSRI but a whole host of other drugs -- benzos, hypnotics, antipyschotics."

    At least some of the damage to people that you are seeing is from people who are on what we call polypharmacy, often with no good rationale. One post on an anti-SSRI website I looked at mentioned that the person posting had also been put an Adderall - an amphetamine. Speed kills!

    I believe from my clinical experience that the damage of which you speak, and it is certainly real, is usually not caused by the proper prescribing of SSRI's but from improper prescribing of multiple meds. My residents and I have to get new patients off of these horrible stews of medication all the time.

    I go into detail about the misdiagnoses that these people get labeled with in my new book, and the misuse of antipsychotics and amphetamines as well.

  5. Dr. Allen,

    Have you seen the articles by Gustava (sp?) Fava who suggests that long term treatment of antidepressant drugs worsen the outcome of depression?

    It sounds like he is suggesting that just being on ADs long term can do what Robert Whitaker has suggested.



  6. Hi AA,

    Thanks for your comment.

    I did a literature search on Fava, whose first name is actually Giovanni. In a review article of his in 2003 he explored the possibility later discussed by Whitaker, but said in the conclusion of the article (Journal of Clinical Psychiatry. 64(2):123-33, 2003 Feb) "At present we have no sound data to support the view that antidepressant drugs may worsen the course of depression, and, if they do, whether the problem is generalized or very limited....There is only a high degree of suspicion if we examine various clinical phenomena reported in the literature."

    In the body of the article he discusses some of the same diagnostic issues (dysthymia vs. major depression) and methodological problems with current studies that I discuss in this post and in some previous posts.

    He also says in the conclusion that with severe major depression, "There are no feasible alternatives to treating major depressive episodes with antidepressant drugs..."

  7. I've already read some reliable studies about this subject and it shows that some of the SSRIs has really caused birth defects to some babies after their mothers has been taking anti-depressant drugs during her pregnancy.
    Some of those affected parties even filed a birth defect lawsuit to get compensated from the damages that they have suffered. I think this is more than just a tale.

    1. Yes, you are right. Please the paragraph about paxil near the end of the post. I was not implying that the drug company made up this data to demonize their product; they were clearly hiding it until the drug was no longer a big profit center for them.

      A lot of drugs of all sorts, not just psych meds, can cause birth defects in a baby if the mother takes them during pregnancy. ALL meds should be avoided, especially during the first trimester, if at all possible.

      Since doing experiments on humans to see if a given drug causes birth defects would be unethical, for a lot of meds, the answer is "we just don't know," so err on the side of caution.

  8. I have taken SSRI ( Seroxat ) chemical name is Paroxetine for about 2 to 3 years and now I am very well without it. If anyone need help how to get off it I will help you for free. Just contact me