Results tagged “Antidepressant” from Ψ Dare To Dream...

This is a topic that gets scant attention leaving the consuming public largely in the dark. Even though I work in the field, I've not hear this information except from my own reading. Fortunately, SSRIs are not as susceptible to problems crossing from brands to generics or between generics. But buproprion in other forms may not be as good as Wellbutrin.

Medical News

"Antidepressant and antipsychotic drugs have become blockbusters for the firms that developed them, making them hot markets for generic competition. Moreover, the effectiveness of these drugs is measured in the same way as anticonvulsants -- either they work or they don't.

Consequently, psychiatry is another specialty that has had to think about how to handle the variability in potency among generics.

Michael Thase, MD, of the University of Pennsylvania in Philadelphia, said that when problems do arise, it's usually when patients switch between different generic versions of a drug.

"There are multiple generics," Thase said, noting that broad bioavailability confidence intervals allow for substantial variation between different generics.

"If the pharmacy changes generics frequently, which often they do because it's a highly competitive business ... you might have some series of 40% fluctuations," he said. "Every few months there might be such a large fluctuation."

But for antidepressants, clinical problems resulting from these fluctuations are not that common, he said.

The dose-response relationships with SSRIs are not rigid, and, therefore, patients generally don't see big changes in drug effects, he said.

"You might have an increase in side effects with the change, or you might feel you've lost a bit of the therapeutic effect."

But some non-SSRI antidepressants aren't so forgiving, said Jeffrey Lieberman, MD, a psychiatrist at Columbia University in New York City.

He mentioned the tricyclic drug nortriptyline and bupropion (Wellbutrin) as more susceptible than most antidepressants to dosage variations.

In the case of bupropion, he said, seizure risk is relatively sensitive to dosage.

Thase acknowledged that cases do occur when patients suffer serious problems following switches to or between generics. But he said those cases tend to have an outsized influence on perceptions.

"You don't hear about all the times [problems] don't happen," he pointed out. "We may think it's a bigger problem than it is."

Lieberman said the common antipsychotics generally posed few problems with generics.

He said anecdotal reports of problems tended to focus on clozapine. "[It] seems to be a particular compound that suffers from this kind of experience," Lieberman said.

But he cautioned that these reports may result from "the kind of selective memory Michael [Thase] was talking about."

Lieberman noted that it was hard to pin down the potential for problems because -- as is the case with the antiepileptics -- systematic, controlled trials to compare different generic formulations and the branded original are generally lacking."

Related articles by Zemanta

• Predicting Antidepressant Response with EEG (neuroskeptic.blogspot.com)
• Antidepressants: Benefit of SNRI is proven (scienceblog.com)
• Cognitive Therapy Generally As Effective As Medication (dare-to-dream.us)
• Serotonin and Depression: A Disconnect (dare-to-dream.us)
• Assessing Risk of Suicide (dare-to-dream.us)
• Suicide Rates for Oldest and Youngest Dropping (dare-to-dream.us)

Not surprisingly,the biochemical theory regarding "chemical imbalance" is under attack again. The theory has always been an oversimplification of actual research data. All the research has said is that (1) anti-depressants have worked on average slightly better than placebo and (2) anti-depressants and therapy works slightly better than one or the other alone.

Key to understanding what this means are the words "on average", "placebo" and "slightly better". On average, some people did not benefit from anti-depressants, and some did. Some experienced more benefit than others. Anti-depressants, I believe, are over prescribed mainly because clients don't want to invest the time and emotional energy in therapy. People don't want to see themselves as, in part, responsible for their own depression. They'd rather take a pill.

The other part of the confusion is about what is a "placebo". Use of a placebo is a research technique designed to separate the effects of the anti-depressants from all other effects. In anti-depressant research, all the effects of a pleasent psychiatrist, and all of the things a client can do themselves to improve their mood is part of the "placebo". As you can see, a lot of what we all think of as treatment is part of the "placebo". So it is not surprising that there is only a slight improvement in effectiveness of an anti-depressant over "placebo".

Psych Central News

"The chemical imbalance theory, which was formulated in the 1960s, was based on the observation that mood could be artificially altered with drugs, rather than direct observation of any chemical imbalances," Leo said. "Since then there has been no direct evidence to confirm the theory and a significant number of findings cast doubt on the theory."

The researchers said the popularity of the theory is in large part based on the presumed efficacy of the SSRIs, but they say that several large studies now cast doubt on this efficacy.

A review of a full set of trial data published in the journal PLoS (Public Library of Science) Medicine last month concluded that much of the perceived efficacy of several of the most common SSRIs was due to the placebo effect.

Other studies indicate that for every 10 people who take an SSRI, only one to two people are truly receiving benefit from the medication, according to Lacasse and Leo.

Still, the National Center for Health Statistics found that antidepressants are the most prescribed drugs in the United States, with doctors writing more than 31 million prescriptions in 2005.

Both Lacasse and Leo emphasized the importance of patients being given factual information so they can make informed decisions about medications and the role of other potentially useful interventions, such as psychotherapy, exercise or self-help strategies.

"Patients might make different choices about the use of medications and possibly use alternative approaches to their distress if they were fully informed," Lacasse said.

"We believe the media can play a positive role by ensuring that their mental health reporting is congruent with scientific literature.""

This research simply says that anti-depressant have, in general, been over prescribed. They can't possibly justify such high use when other viable alternatives, like psychotherapy, are available.

The Wild Moods explains well how the concept of cause and effect is way too simplistic.

"In my experience, depression is several pieces of rope, tied up together such that tugging just one tends to tighten the others. Addressing the biochemical is very important, whether through SSRIs or food or amino acid therapy, but it's just one thread, and doesn't in and of itself totally stabilize chronic depression. And in my experience, it certainly does not pull up the roots of the depression, which is more like crab grass than something with a single tap root."

There is some major progress in the treatment of persons with Bipolar DO - Mixed episodes. Bipolar DO-Mixed is characterized by less serious manic symptoms, or hypomania, and significant depressive symptoms occuring at the same time. As you might expect, having a high energy level, little impulse control, impaired judgment and significant depression is a miserable condition, prone to substance abuse, suicide ideation and serious attempts. Persons with BPDO-Mixed are more prevalent in my practice than any other subtype of the disorder. That fact could be an artifact of primary finding of the following studies.

Anti-depressants, when combined with mood stabilizers such as Lithium or Depakote, or atypical anti-psychotic medications like Abilify or Seroquel have been found to provide no more symptomatic relief for the depressive symptoms and a significant risk of increasing manic symptoms. The contradicts standard psychiatric practice which calls for treating mania with mood stabilizers or atypical anti-psychotic medications and the depression with anti-depressants.

Intensive psychotherapy has been found to be modestly helpful with persons with Bipolar DO-Mixed. These findings affirms my recent clinical findings that persons with Bipolar DO-Mixed can experience significant symptomatic relief and, perhaps more importantly, a budding sense of recovery based on personal responsibility and enhanced skills in managing moods.

Excerpts from a review of the research follow:

Anyone taking or contemplating anti-depressants for treatment of depression have been concerned about the blackbox warnings from the FDA. The FDA has issued blanket warnings to anyone considering or taking anti-depressants that they may actually induce suicidal thinking.

The truth is that there is still very little and conflicting information about the risks. Highlighting the risks in the way the FDA did by issuing a blackbox warning has been controversial. The problem is that the risks have been assessed in only a few studies and it is not clear what is happening. The other problem is that anti-depressants also treat and prevent suicidal behavior. Not taking an anti-depressant when you need one can also be a grave risk.

There is concern within the psychiatric and advocate community that the FDA is driven more by politics than science these days. A coalition of psychiatry and advocate organizations has issued an open letter to the FDA pointing to the life and death consequences of their actions.

Psychiatry News

The coalition's "Open Letter on Antidepressants" was released at the coalition's lunch briefing on the same December day that the FDA's Psychopharmacologic Drugs Advisory Committee (PDAC) held a public hearing to discuss the report.

"As advocates for people living with depression and other mental illnesses," the letter began, "we strongly urge the FDA to carefully consider the potential impact of the agency's public statements on the risks and benefits of antidepressants. Access to effective treatments for depression is pivotal in improving the lives of the 19 million Americans that face this devastating illness each year."

The coalition's efforts were led at the December 13 briefing by David Shern, Ph.D., president and CEO of Mental Health America (MHA). He noted that "without treatment, this disorder can be fatal--15 percent of people who live with untreated depression take their own lives.

"Any knee-jerk or pressure-based actions by the FDA may put an untold number of Americans at risk of the tragedy the agency aims to avoid--suicide," Shern stressed. "The risk associated with not treating depression is far greater than any potential risk of adverse effects of medication," he added, echoing his testimony before the PDAC during the public-comment section of the panel's hearing.

As more data emerges about the risk of suicide in the early stages of taking anti-depressants, there appears to be a trend that narrows concern to the very youngest of those prescribed. It also gives a relative sense of the risk by stating incidents as events in a thousand people treated by anti-depressants.

Psychiatr News

FDA's Stone, during his presentation to the panel that morning, emphasized, "The observed relationship between suicidality, age, and antidepressant treatment appears not only in [subjects with] major depressive disorder, but in all subjects with psychiatric diagnoses." One could interpret this finding, he added, as indicating that "[t]here is nothing different in the psychopharmacology of suicide versus the psychopharmacology of depression or another illness--the suicide factor is independent of actual diagnosis."

[...]Risk difference, he explained, "is simply asking the question: How many additional patients--out of 1,000--would you expect to see experience suicidal behavior and/or ideation as a result of taking antidepressant medication?"

From the pediatric data, Levenson said, the answer is 14 out of 1,000 patients under age 18; for those aged 18 to 24, it's 4; and for those aged 25 to 30, it's none-- that is, patients in this age group taking an antidepressant are no more likely to experience suicidal thoughts or behaviors than those not taking such medications.

For patients aged 31 to 64, two fewer patients would likely experience suicidal thoughts/behaviors. For those aged 65 and over, he concluded, "taking an antidepressant prevented 6 patients out of 1,000 from experiencing suicidal thoughts or behaviors."

The risk is clearly focused on the youngest prescribed, those under 18. The risk is sufficient to warrant increased caution for those under 18, but hardly to rule out the use. I think, as with every mental health issue, treat depression starting with therapy. If there is no change in six sessions, then consider adding a medication. If sleep disturbance persists, then a medication review is warranted much earlier. If suicidal behavior is present, an anti-depressant with close monitoring and therapy may be necessary from the beginnings of treatment. Partial hospitalization may be an appropriate alternative for rapid intervention for those who don't present an imminent risk of suicide. Hospitals are not healthy places for people until there is an imminent risk of death or grievous harm to self or others.

Sunday I found a disturbing article in a blog that has a good reputation. Dr. Peter Breggin at The Huffington Post wrote about the FDA decision to require a "black box" warning on the anti-depressant medication Paxil because of the risk of suicide in the beginning of treatment. Dr. Breggin is the author of the book Talking Back to Prozac which is highly critical of the anti-depressant medication Prozac. In his post at Huffington's, Dr. Breggin makes statements that appeared designed to attract attention at the expense of misleading the reader. I've written about the problem with reading articles about mental health in the press. Essentially, reader beware, what you read many be misinforming you. Sometimes misinformation occurs in the interest of selling a publication. Science has it's own issue with chasing the money. Research is expensive and finding the means to fund it can be difficult. It's also a necessary process to advance a science. Psychotropic medications are extremely expensive to develop and submit to the FDA for approval. The FDA makes the decision to approve a medication based on research completed by the pharmaceutical companies who have a vested interest in the outcome. It's pretty clear that this procedure invites significant inappropriate salesmanship into the research process, but the alternative is likely even more expensive. The only alternative I can imagine would require a large government bureaucracy to manage a process that may be no less fraught with potential for corruption due to the millions of dollars at stake. I can't criticize a system when I can't imagine a working alternative.

Meanwhile, a comprehensive review of all studies of anti-depressant drugs submitted for approval to the FDA showed that when the studies are taken as a whole, anti-depressants don't work.

To support this statement, he sites only two sources when there are literally thousands of articles out there that have different conclusions. Antonuccio et al (2002) makes some quite critical statements about the FDA approval process and questions the magnitude of efficacy of anti-depressant medications. His second source is his own book, Talking Back to Prozac. Antonuccio et al (2002) is not a research study. It is a commentary about a review of the literature in the same publication: Kirsch et al (2002). That particular volume of Prevention and Treatment is full of supporting and detracting articles about the Kirsch et al (2002) study. It's results are universally described as important, but they range in characterization from exaggerated and politically and financially motivated to underestimated. Most of the articles in Prevention and Treatment Volume 5 note that anti-depressant medications ARE shown effective in the Kirsch et al (2002) study. Even Kirsch et al (2002) conclude anti-depressants are effective, just not as much as one would like to see. One has to keep in mind that drugs affect individuals differently. While on average across large numbers of persons in the study, the magnitude of the drug effect may be relatively small, a sizable proportion of the individuals could have substantial benefit from medication. Dr. Breggin next makes a statement that implies taking prescribed anti-depressant medications have a following because it gives users a high like recreational drugs.

Of course, many people feel helped by antidepressants, as well as many other psychiatric and even recreational drugs. The placebo effect is enormous. In addition, the artificial euphoria or emotional flattening produced at times by antidepressants may provide temporary relief at the cost of rationality and effective dealing with life.

The uninformed reader very likely would be discouraged from using anti-depressant medications and misinformed that they make a person "high". Not only does this statement misinform and confuse, it adds to the stigma of mental illness by equating anti-depressants to recreational drugs. Next Dr. Breggin takes the argument to unsubstantiated scare tactics.

It's time to say again what I've been saying for too many years on end. The antidepressants aren't antidepressants. They are more likely to make a person worse than better. More tragically, these toxic agents push many people over the brink into suicide and violence.

He cites no evidence that anti-depressants are "more likely" to make a person feel worse. Even the article he cites says otherwise.

Meanwhile, the antidepressants are very difficult to stop taking. Withdrawal from antidepressants can lead to "crashing," with agitation, violence and suicide. Withdrawal from these noxious drugs should be done slowly with experienced clinical supervision. These drugs are not only unsafe to start--they are dangerous to stop. The best approach to antidepressants: Don't start taking them.

Now Dr. Breggin implies anti-depressants are effectively an addictive drug with a characteristic withdrawal syndrome. There is no evidence of this cited. I've not seen any literature that supports this assertion. In fact, one of the key requirements of an addictive drug is that a person develops a tolerance for the medication requiring an periodic increased dose. My clinical experience has not born this out. Instead, what I've seen across many patients, a life time course of medications requiring occasional adjustments, both up and down or a change to a different drug, typically attributed by the prescribing psychiatrists to changing body chemistry over time and age. That is not even close to the typical abuse pattern of patients addicted to, for example, benzodiazopines where they gradually increase their dose over a relatively short period of time supplementing the prescribed supply with illegally obtained prescription drugs, street drugs and alcohol. The increased incidence of suicide attempts during the medication trials is of concern. However, what this might be attributed to is unclear. I know from my clinical experience, many people report uncomfortable side effects, including flu-like symptoms and increased anxiety that have been known to make some patients worry about "going crazy". These side-effects may well be enough to induce a suicide attempt in someone who is already depressed and hopeless with suicide ideation. As I have stated before, medications are an important part of treating depression. But they should not always be the first attempt to intervene. Research has shown repeatedly that psychotherapy and medication used together has consistently the best outcomes. I suggested on April 1,

that the indications for anti-depressants be limited to (1) those people who show neuro-vegetative signs of depression, especially significant sleep deprivation due to insomnia or sleep disturbances and a significant loss of weight due to loss of appetite, (2) a moderate or high risk of suicide as indicated by a lethal and available plan, and (3) after a course of psychotherapy of say six sessions produced insufficient improvement in functional impairments in relationships, productivity at work, keeping up with chores, etc, that the therapist refers the patient to their physician for a medication evaluation.

It appears that the literature agrees with me. In a companion article by Irving Kirsch and Alan Scoboria (2002), the authors offer much the same advice:

In the meantime, what are the alternatives for treating patients? Imagine having a choice between four treatments. Treatment A produces a large therapeutic response but also a large number of adverse effects, including diarrhea, nausea, anorexia, sweating, forgetfulness, bleeding, seizures, anxiety, mania, sleep disruption, and sexual dysfunction. Treatments B and C produce therapeutic responses that are almost as great as those produced by treatment A, but without the adverse effects. In fact, the side effects produced by Treatment B are beneficial (e.g., better general physical health). However, the therapeutic effects of Treatments B and C have been evaluated in relatively few studies. Treatment D has been assessed in many comparative studies, in which it has been found to be as effective as Treatment A in the short term and more effective in the long term. It does not produce adverse effects. Given a choice between these alternatives, which would you choose?

Of course, these alternatives are not merely hypothetical. Treatment A corresponds to SSRIs, and the list of side effects is drawn from those that have been shown to be produced by these medications. Treatment B is physical exercise, which has been reported to have lasting therapeutic benefits in the treatment of major depression. It may be nothing more than a placebo, but if so, it is one with desirable rather than adverse side effects. Treatment C is bibliotherapy, another low-cost treatment with demonstrated effectiveness and little danger of side effects. Treatment D is psychotherapy. As noted by Antonuccio et al (2002), "psychotherapy (particularly cognitive therapy, behavioral activation, and interpersonal therapy) compares favorably with medications in the short term, even when the depression is severe, and appears superior to medications in long-term comparative studies. Given these data, antidepressant medication might best be considered a last resort, restricted to patients who refuse or fail to respond to other treatments.

Part of the problem here is that treatment of depression in a clinical setting contains many components only one of which is medication. To test the effectiveness of a medication, a treatment group receives the medication and a control group receives a sugar pill. Both the treatment group and the control group receive the sort of care that is an integral part of a clinical setting. The part of the treatment that is not mediation is called "placebo". Rehm (2002) describes this placebo. The author lists life events, social support, hopeful expectations, and biochemical changes that accompany treatment and enhance immune function and biochemical balances that facilitate recovery from depression. Rehm also lists spontaneous remission and regression or random fluctuation in the measured factors of depression attributable to the instruments measuring them. These final two factors are essentially improvement that can't be attributed to anything else. While I understand the argument that without a placebo control, one can never hope to measure the effect of treatment attributable to medication alone. However, imagine if a patient picked up his medication from a grumpy, shaming pharmacist, do you think the medication would be as effective? I think not. The placebo effect is as integral a part of treatment as the medication. It's effects on treatment are not well known. The other problem is that the typical medication trial used for justifying the approval to the FDA is 6-8 weeks, mainly to contain the costs of research. Anti-depressant medications just come up to therapeutic levels in the blood in the fourth week. From my clinical experience, those four weeks of waiting for the therapeutic levels are quite uncomfortable for the sufferer. The client is waiting for relief from a miserable condition made even more so by the well known side effects of starting and ending anti-depressant treatment. By the end of the fourth week, the clients sense of equilibrium at best is improved but tenuous. Recovery continues over the next few weeks in a stutter-step fashion: one step forward, two steps back, two steps forward, one back. To measure effectiveness in the 6th to 8th week is not likely to show anything more than the beginings of therapeutic effect. Finally, as demonstrated convincingly in the recently released mega-study of anti-depressants called STAR*D2:

These results highlight the need for longer treatment duration and more vigorous medication dosing than is current practice in order to achieve optimal remission rates. Informed triage or critical decision points (i.e., the discontinuation of patients who experience minimal benefit after 6-9 weeks of treatment) allow for extended dosing for those who are benefiting, while curtailing extended treatment for those who experience minimal benefit after a substantial treatment period. The measurement-based care methods used in this study were easily implemented in actual practice. Controlled trials of this approach in practice are recommended.

And from my previous post on STAR*D2:

The important finding in the STAR*D Part 2 study was that persistence in seeking a combination or a change in medication increased remission rates. If one counts each medication trial as 6-8 weeks and add to this 12 to 16 weeks or more for psychotherapy to address complicating factors like anxiety, a history of mistreatment, abuse or trauma or substance abuse, it's reasonable to expect at least 16 weeks of concerted, persistent and painful effort to make progress with a resistant depression. Many sufferers are tempted to give up after the first attempt at treatment.

There is no reason to discourage use of anti-depressants. There is however reason to be concerned. I think the concern is sufficient to require frequent monitoring by the prescribing physician and consultation by a psychiatrist whenever there is suicide ideation. I complained to Huffington Post about this article. I encourage you to join me in encouraging Huffington Post to reconsider the content of this article by emailing them here.

Kirsch, I., Moore, T.J., Scorboria, A., Nicholls, S.S. (2002). The emperor's new drugs: An analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment, 5 (1)