How Antidepressants Should be Prescribed

 

As psychiatrists are pressured by various business interests to see more and more patients in less and less time, more and more shortcuts have come into practice. Not a good thing. Especially when it comes to anti-depressant prescribing practices. The drugs have become way over-prescribed, and antipsychotic medications are added to them for "augmentation" far more often than necessary. I’ve spoken about the use of symptom checklists, which are screening tests and not diagnostic tests, being used to make diagnoses.

Another recent development has been companies that offer various “genetic testing” to try to predict which medications might work best in a given patient, or what side effects they are likely to get. For example, GeneSight Psychotropic offers a “pharmacogenomic” test which means that it analyzes how your genes may affect medication outcomes. They say: “The GeneSight test analyzes clinically important genetic variations in your DNA. Results can inform your healthcare provider about how you may break down or respond to certain medications commonly prescribed to treat depression, anxiety, ADHD, and other psychiatric conditions.”  

The problem with these tests is that their predictive validity is actually quite poor – even the company admits that “It is important to note that not all patients who received a GeneSight Psychotropic test experienced improved outcomes.”  According to two docs at the NYU School of Medicine, "The tools were developed using small sample sizes, focusing on specific patient populations...and were not tested in real world settings different from the one in which they were developed."

The tests are IMO a waste of money.

Because people are so complicated biologically, psychologically, and socially, I think a far better way for docs to decide which meds to use is to use pattern recognition: Doing a wide-ranging diagnostic evaluation and looking at what factors suggest certain courses of action.

Let’s start with the diagnosis of major depressive disorder. That diagnosis has to be based on a variety of considerations. Symptoms must be pervasive (almost all day every single day, even if you suddenly win the lottery. I exaggerate, but only slightly) and persistent (at least two straight weeks), and the patient’s functioning and stress responses must be significantly different that their norm. (Antidepressants do not work on chronic unhappiness). All symptoms must take place at the same time – having no appetite on Monday and poor sleep on Thursday does not cut it.

If it’s a patient’s first episode, another big issue is that there is no way for the doc to be absolutely certain that it is not a first episode of bipolar disorder rather than a unipolar depression. This is important because if the doc prescribes an antidepressant to a bipolar patient, it can trigger a manic episode – with disastrous consequences. So what is a doctor to do to make sure that doesn’t happen?

Family history is important, since bipolar disorder usually runs in families. If a patient has a family history, the doctor has to be more careful. The problem is of course that the patient might not know if he or she even has a relative who had a manic episode. So what does a good doctor do? In addition to asking about family history, the doc should carefully review the patient’s history for any symptoms suggestive of the disorder. These symptoms should not have occurred only when the patient was high on cocaine, or during a rage reaction upon having found out that the their spouse and best friend were having an affair!

Next, the doc warns the patient about the bipolar issue, and informs patients that in the event of suddenly feeling revved up, they need to STOP the antidepressant and call the office immediately. This instruction can be given at the same time as the doctor describes all possible major side effects with instructions on what to do should they occur. Then, the doctor needs to have the patient comeback for a scheduled follow up visit, preferably within two weeks.

Now, about picking an antidepressant with which to initiate treatment. As I mention, genetic testing is not particularly valuable. It’s always a bit of a crap shoot because a patient’s presentation may be somewhat atypical, but if the doc takes a complete history, it can suggest which agent to try first. If the patient has some obsessive-compulsive qualities, an SSRI like fluoxetine  or escitalopram is a good first choice. If in addition to that there is a lot of anxiety, the SSRI paroxetine is usually the best choice. If the patient has chronic pain, then duloxetine is usually a good starting point. If sexual side effects are a big concern, buproprion is usually the place to start.

Next, the doctor raises the dose of the medication every three to four weeks until there is a response, or it reaches the maximum dose, or until side effects become too big a problem. At this juncture, the doctor should NOT add another, different class of medicine to “augment” the antidepressant, as is suggested by a lot of Pharma commercials. If there has not been a good response to the first drug, the anti-depressant should be stopped, and a trial of a second antidepressant should come next. And again, if no response, a third one. There are diminishing returns here but eventually most patients will have a decent response. If they do not, then than and only then should an augmentation strategy be instituted. Or the diagnosis may need to be re-evaluated.

Close follow up. Close follow up. Close follow up.

Latuda and Bipolar Depression

Have you seen them? The brand new, direct to consumer (DTC), ads touting the drug Latuda for bipolar depression? The drug company just received the indication for this purpose from the FDA a very short time ago, but the drug company, Sunovion Pharmaceuticals Inc., was ready to roll.

Latuda is a dopamine blocking drug, which makes it an antipsychotic medication and not an antidepressant.  We have known since the 1950’s that all antipsychotic medications have some effectiveness in bipolar disorder, although primarily for the prevention of the manic phase of the illness. We have known that they also may augment an antidepressant for those who only get a partial response to the antidepressant in both unipolar and bipolar depression. A colleague of mine routinely used the antipsychotic Navane to augment the old tricyclic antidepressants in the 1970's.

Only two other antipsychotic medications have official FDA indications for bipolar depression, probably because the other drug companies did not spend the money to get it.  If doctors know one member of a class works, they’ll know that the others probably will too, so why bother?  One of these two drugs that has the bipolar indication is actually a combination drug containing an antipsychotic medication (Olanzepine [Zyprexa]) AND the antidepressant Prozac. The other is Quetiapine [Seroquel].

The main problem with using an antipsychotic instead of an antidepressant in this condition – aside from the unequivocal fact that antidepressants are way more effective – is that antipsychotics have much more potential toxicity. Latuda is probably one of the safer ones in this regard, having a low incidence of the two biggest concerns, metabolic syndrome (weight gain, higher cholesterol, diabetes - horrible and very common problems with Zyprexa and Seroquel) and the long-term neurological side effect, tardive dyskinesia.  Interestingly, the FDA won’t let Sunovion make that claim despite the fact that it’s true!  Go figure.

Almost simultaneously with the start of Latuda's DTC ad campaign, two research studies of the drug’s use in bipolar depression were published in the February 2014 issue of the flagship psychiatry journal, the American Journal of Psychiatry (AJP). The studies showed that the drug was effective by itself for the disorder, and also effective as an adjunct treatment when combined with either of the two major anti-manic drugs, lithium and valproate.  Weirdly, the  “effect size” of the improvement in patients, a measure of how much better patients got, was less (0.34) with combination therapy than it was in the case of the drug by itself (0.51). Both of these effect sizes are moderate at best, btw.

That difference is particularly odd in the case of valproate, since there is zero evidence that it is effective for the depressed stage of bipolar disorder (lithium sometimes is, but not usually). Does valproate somehow make Latuda less effective than it would be otherwise?

There is a big issue here:  the question of whether antidepressants alone are the better choice for treatment of bipolar depression.

The last author of the first AJP Latuda  study is Gary Sachs, someone I have discussed previously in this blog [ 10/31/11].  He is the author of a major study that claimed to show that antidepressants were completely ineffective – worse than placebo – in the treatment of the depressed phase of bipolar disorder.  

He conveniently neglected to point out in the earlier paper that the sample of patients he used in this study had already proved to be resistant to antidepressant medication in the first place, and continued to dissemble about this omission when I had the opportunity to confront him about it. Some subjects of his had even failed a trial of a combined antidepressant and antipsychotic. The conclusion of the study as presented in the study was bogus as hell.

A defender of Dr. Sachs made this point: Dr Sachs and colleagues in the abstract did not say that they had proven that antidepressants were ineffective in bipolar depression. They reported their finding and immediately called for additional long-term well designed studies - what I have called plausible deniability.

The more recent Latuda article which Sachs co-authored did in fact state the following: “There is limited evidence of the use of standard antidepressants for the treatment of bipolar depression.”  I guess that isn’t exactly the same as saying they don’t work, is it?  Might as well be, though! It's not what you say, it's what people hear.

Furthermore, I learned from the article that Dr. Sachs is a paid consultant for Sunovion pharmaceuticals!  

The article’s reference for the statement about antidepressants not being effective was one study that was a meta-analysis of existing studies of antidepressants in bipolar depression (a study which combines the statistics from several other studies). In an editorial in the same AJP issue publishing the Latuda studies, one R.H. Belmaker restates the opinion that “the evidence that antidepressants can be useful seems less and less convincing.”  

His reference for this statement? It is an editorial he himself wrote in the same journal as the original bogus Sachs article appeared [New England Journal of Medicine 356 (17), 4/26/07 (NEJM)]!  I went and got a copy of it.  These folks seem to all run in the same circles, as well as in the same circular reasoning.

In that editorial, he mentions the same meta-analysis that was mentioned in the AJP Sachs article.  But he also mentions that there are two other meta-analytic studies, both totally ignored in the AJP Latuda articles, that showed that antidepressants could be “highly beneficial” in bipolar depression.

There is fairly subtle obfuscation of the evidence going on here, since the other two meta-analyses never seem to be mentioned in articles touting antipsychotics for bipolar depression any more.  I wonder why that is?

In Belmaker’s original NEJM editorial, he opines that maybe the condition is heterogeneous and that subjects in studies outside of the United States may be different than they are here. The two positive metastudies were by authors from outside the USA.

Aside from the fact that there is absolutely no clinical evidence for that whatsoever, Belmaker neglects to mention that at least one of the two meta-analyses showing that antidepressants were effective did not limit itself to studies done overseas, but included studies done in the States! (I could not get a hold of the second, but this is probably also true of that one as well).

Of course, the issue of antidepressants causing bipolar patients to switch into mania is also brought up again and again ad nauseum all over the place, even though everyone agrees – even the original Sachs article in NEJM - that the anti-manic drugs like lithium and divalproate prevent this.  Since true bipolar patients should be on one of those drugs to begin with, this is a superfluous issue.

I also have my doubts that all of the subjects in the Latuda studies were even diagnosed correctly, since one of the diagnostic tools used was the Bipolarity Index, which includes the items, “Episodes with characteristic symptoms of hypomania, but symptoms, duration or intensity are subthreshold for hypomania or cyclothymia” and “baseline hyperthymic personality when not manic or depressed. " 

For a discussion of the significance of that nonsense, see my posts about treatment resistant depression and bipolar disease mongering.

These folks are doing nothing but trying to sell expensive and potentially toxic drugs to both doctors and the public when more effective and safer alternatives already exist.

Antidepressant Medication and Bipolar Disorder: The Lies and Confusion Continue

The continuing stoow-ry of psychiatric research that has gone to the dogs

In my last book, How Dysfunctional Families Spur Mental Disorders, I discussed my theory that the drug companies of Big Pharma seem to go out of their way to demonize entire classes of drugs once they are mostly available as generics, so that practitioners will use their new brand named drugs instead - regardless of whether or not they are as effective or more dangerous. This happened with benzodiazepines, which now seem to be referred to absurdly as the most addictive and dangerous substances on the planet and full of "side effects" - which don’t actually occur in the real world in the vast, vast majority of patients who take them.

(BTW. demonizing generics does not just occur in psychiatry. One patient told me that a relative was given an anticoagulant that was more dangerous than generic Coumadin because, according to the doctor, “That’s what the drug companies want us to do”).

I wrote that I suspected that the same strategy is now being applied to antidepressants. Most of them have gone generic. (The ones that haven’t yet are Viibryd, Cymbalta, and Prestique.  Although no more effective that the generics, it amazes me how many doctors seem to use them as first line drugs). All of sudden we are being deluged by both news and journal articles questioning whether the drugs are effective. I have written in previous posts on this blog that placebo response rates for antidepressants have gone up significantly every decade, indicating that the patient population being used in the studies is changing. 

Specifically, so-called contract research organizations are being given financial incentives for finding patients that they can diagnose with major depression, and potential patients are given financial incentives for exaggerating their symptoms so they can get paid for being research subjects. So the studies are using patients that don’t really have the diagnosis they are supposedly being treated for. No wonder they have a high placebo response rate. This higher rate makes the advantage of the drug over placebo in these studies seem highly questionable.

A similar process is happening in doctors’ offices all over the country. Diagnostic interviews are getting sloppier and more slipshod all the time. A new study published by Psychotherapy and Psychosomatics, according to the June 2013 issue of the newspaper Clinical Psychiatric News, seems to be highly consistent with this idea. The authors ascertained whether patients who were identified by their doctors as depressed actually met DSM criteria for major depressive disorder. Results with 5639 participants showed that only 38.4% of these patients actually met the criteria!

This phenomenon has led to a couple of ironic developments. First, the rabidly anti-psychiatry zealots point to the bad studies as “proof” that psychiatric meds are a hoax, while of course completely ignoring all the earlier studies that show that antidepressants are highly effective. The more severe the depression, the more likely a patient is to respond to them.

Second, people both inside and outside of the psychiatric profession unfairly rail against the diagnostic manual, the DSM, for not having valid criteria, when the real problem is in many cases that many doctors are not applying the criteria to the patients in making "diagnoses!"

Then there is the matter of the use of antidepressants in the depressed phase of bipolar disorder.  Of course, as I have said many times, the duration and pervasiveness criteria for bipolar episodes, either manic or depressed, are more and more often ignored, which calls into question whether the diagnoses in studies are even correct.

Anyway, in my book I brought up a study by Sachs and others in the New England Journal of Medicine, the most prestigious journal in all of medicine, that purported to show that antidepressants work worse than placebo in this population. I showed how the authors of the study used a sample of patients that were especially treatment resistant, having already failed a trial of at least one previous antidepressant, but did not acknowledge this fact in the paper at all. I was even able to question the author through a third party, since my e-mails directly to Sachs were ignored, and he steadfastly refused to answer the question, “What percentage of your sample had failed a previous antidepressant?”

Now comes another bogus study that purports to show the same thing as the Sachs study. According to an article in Medscape on May 20, 2013, “Investigators at Brown University in Providence, Rhode Island, found there was no difference in hospital readmission rates among patients who received antidepressants and those who did not." Since the authors are strongly implying that the patients had to be readmitted because their antidepressant was not working, this is taken to mean that antidepressants don’t work in bipolar depression.

That antidepressants do not work in bipolar depression is a flat out lie. Psychiatrists like myself have been using antidepressants successfully in bipolar patients for thirty five years. Of course, true bipolar  patients need to be on a mood-stabilizer first, preferably lithium, so they don't switch from depression into mania.

So what’s wrong with this study? Well, just about everything. First of all, we do not know if these patients were correctly diagnosed for the reasons discussed above. Another huge problem: all over the country, hospitalized patients with borderline personality disorder are being misdiagnosed with bipolar disorder because of the “everything is bipolar" craze, coupled with the fact that insurance companies will often not pay for hospital stays if the patients are given the correct, "lesser" diagnosis! 

The subjects in this survey were undoubtedly a very mixed lot. The study did not address whether the patients even took their medication after they were discharged. Non-compliance rates for all medications are very high according to every available study that has looked at this issue. Also, we do not know what percentage of these patients may have fallen into the “treatment resistant” category described above. Most depressed patients are treated as outpatients, not inpatients, so the ones that are hospitalized have often failed a trial of outpatient medication.

Adding to this is the fact that antidepressants do not work for at least a couple of weeks, while managed care insurance companies will not pay for that length of stay. Therefore, patients on antidepressants are often discharged before the doctor knows whether a particular antidepressant even worked. Often patients do not respond to one antidepressant but do respond to a different one. 

Hence, discharge and re-hospitalization rates tell us pretty much nothing about the effectiveness of antidepressants in the depressed phase of bipolar disorder.

The International Society for Bipolar Disorders (ISBD) Task Force recently released its long-anticipated recommendations on antidepressant use in bipolar disorders. "The take-home message is that antidepressants have a questionable benefit-risk and should only be used in certain cases in bipolar disorder," said Dr. Eduard Vieta, who presented the recommendations on behalf of the ISBD Task Force, in an interview.

Eduard Vieta

"First, they shouldn't be used in mania or in mixed episodes, they should only be used in bipolar depression in patients with a history of a good response in the past to antidepressants and no history of rapid cycling or switches into mania right away," he said.

“Further, antidepressants should not be used in patients with bipolar disease with mixed features during a depressive episode or some manic symptoms during depression.” 

The recommendations said that antidepressants should not be used as monotherapy for bipolar depression, or in rapid cycling. 

I have a few reactions to this.  

1. Duh! We've known about the risks of using antidepressants alone in Bipolar I patients since the sixties. We've also known that they are perfectly safe and highly effective if a bipolar patient in a depressive episode is on an effective mood stabilizer, preferably Lithium.  

The way that the recommendation is made, however, is highly misleading. Antidepressants indeed should not be used as "monotherapy," but not because they are ineffective for depression. It may sound to some doctors that this is what is being said. The real reason is because patients need to be on a second drug to prevent switching into mania.

2. What are they defining as "rapid cycling?" A majority of patients who get this diagnosis nowadays are not bipolar at all, but have anxiety disorders, mixed anxiety and dysthymia, and/or personality disorders - otherwise known as 'crappy childhood syndrome." A lot of drugs can cause these folks more harm than good if improperly used!  Why single out antidepressants?

3.  How are we supposed to know if a patient will respond to an antidepressant in cases of patients who have never taken one, if we are not supposed to use them unless the patient already has a history of responding to them? That would be quite a trick! Additionally, a history of a switch into mania is not a contraindication for antidepressants unless this history took place when the patient had been adequately medicated with a mood stabilizer. If they switched when not taking one, that fact would be completely irrelevant. Even the Sachs study showed patients on a mood stabilizer don’t switch into mania with antidepressants.

4. As for so-called mixed episodes, they are in reality manic episodes, with the difference being that the patient feels really uncomfortable instead of the more typical euphoria. Since they are in a manic state and not a depressed one, of course antidepressants should not be used!