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Baldessarini, 2010 Illness Risk Following Rapid Versus Gradual Discontinuation of Antidepressants

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Baldessarini, et al. tapered patients at a "fast" rate (over 1–7 days; N=188) or "gradually" (over 14 days or more) and found those tapered more slowly had a lower rate of "relapse." A year after quitting, about 22% of the "fast" taperers were found to be "stable" in comparison with 42% of the "slow" taperers.

 

Clearly, even a "slow" taper of a few weeks was inadequate, as about 48% of the "slow" taperers experienced "relapse," or, as the authors put it, "recurrence."

 

Undoubtedly, like most antidepressant studies, this study is confounded by mistaking withdrawal syndrome for recurrence. The authors admit:

 

....the phenomenon of posttreatment discontinuation illness risk is very likely to confound the design, conduct, and interpretation of treatment trials based on comparing continued and discontinued treatment, especially in long-term trials that involve transitions from active treatment to placebo and among incompletely recovered patients.

Am J Psychiatry. 2010 May 17.

 

Illness Risk Following Rapid Versus Gradual Discontinuation of Antidepressants.

 

Baldessarini RJ, Tondo L, Ghiani C, Lepri B.

 

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/20478876?dopt=Abstract" Full text here.

 

Objective

Rapid discontinuation of some psychotropic medications is followed by discontinuation symptoms as well as an increased risk of early illness recurrence. Recurrence occurs earlier after rapid than after gradual discontinuation with lithium and antipsychotics. The authors compared illness recurrence after rapid versus gradual discontinuation of antidepressants.

 

Method

The authors compared 398 patients with a DSM-IV diagnosis of recurrent major depressive disorder (N=224), panic disorder (N=75), bipolar II disorder (N=62), or bipolar I disorder (N=37). Two-thirds were women, the mean age was 42 years, and patients were treated with antidepressants for a mean of 8.5 months. Antidepressants were discontinued clinically, either rapidly (over 1-7 days; N=18 or gradually (over 14 days or more; N=210), with a mean follow-up duration of 2.8 years; patients who were ill at discontinuation were excluded from the analysis. The authors compared latency to first new illness episodes using survival analysis and Cox multivariate modeling.

Results

The latency to first illness with rapid discontinuation was 0.4 times that with gradual discontinuation, and the latency after rapid discontinuation was one-fourth the estimated average previous interepisode interval in the same patients. The effect was similar across antidepressant classes and across years; the pace of discontinuation had less effect with drugs of prolonged half-life. The effect also varied by diagnosis (bipolar I >/= panic > bipolar II >/= major depressive disorder) but not by episodes per year, duration of index illness, use of concomitant treatment, or antidepressant dose or duration.

 

Conclusions

The recurrence risk for depression or panic was much shorter after rapid than after gradual discontinuation of antidepressants. These findings have implications for both clinical management and the design and interpretation of clinical trials.

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Altostrata

This study also discussed on About.com http://bipolar.about.com/b/2011/06/20/faster-antidepressant-discontinuation-faster-recurrence-of-symptoms.htm

 

Faster Antidepressant Discontinuation, Faster Recurrence of Symptoms

 

By Marcia Purse, About.com Guide June 20, 2011

 

....

 

About half the patients who took part in the study, entitled Illness Risk Following Rapid Versus Gradual Discontinuation of Antidepressants, stopped taking antidepressants in 1-7 days, while the others took 14 days or more. Following up over almost three years, researchers found that those who had discontinued rapidly became ill again in an average of 3.62 months, while those who stopped more gradually averaged 8.42 months.

 

In response to an inquiry made on my behalf, lead researcher Dr. Ross Baldessarini said: "For me, the main take-home point is that rapid discontinuation is bad news and to be avoided clinically whenever possible." So while quitting an antidepressant quickly may be necessary - for example, if serious side effects are occurring - this study shows one more reason why it's best to stop gradually over time. Not only will it help you minimize withdrawal effects such as SSRI Discontinuation Syndrome, but you are likely to stay stable longer after you stop taking the antidepressant.

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Altostrata

Editorial based on the Baldessarini paper http://ajp.psychiatryonline.org/article.aspx?articleid=102411

 

Note: The Baldessarini paper did not distinguish between withdrawal syndrome and relapse.

 

Abrupt Withdrawal of Antidepressant Treatment
Robert Freedman, M.D.

Am J Psychiatry 2010;167:886-888. 10.1176/appi.ajp.2010.10050783

 

Some studies, while they inform us, nonetheless raise more questions than they answer. In this issue, Baldessarini et al. present provocative information for both clinicians and researchers in their article "Illness Risk Following Rapid Versus Gradual Discontinuation of Antidepressants" (1). The study is not a controlled trial of an intervention, but rather, like much informative clinical research, it is essentially a detailed observation of patients. Patients with mood and anxiety disorders were carefully followed at clinics in Sardinia while they were treated with antidepressants. The study extended from the era of the tricyclic antidepressants to the modern era of selective serotonin reuptake inhibitors. Abrupt discontinuation of medication, usually initiated by patients themselves, was more likely to result in the return of depression within several months, compared to tapering the dosage over several weeks, generally recommended by physicians, which resulted in less likelihood of relapse. All patients included in the study had close to normal mood at the time of medication discontinuation, regardless of who made the decision to stop treatment. Patients whose antidepressants were stopped because of emerging mania were not included in the study. Even when a tapering regimen was used, medications with short half-lives, like paroxetine and venlafaxine, were more likely to produce early relapse than the longer-acting medications, including the tricyclics.

 

As with any observational study, there are uncertainties. It is possible that the patients who decide to stop medications abruptly have particular characteristics of biology, manifest as cyclothymia and rapid relapse, or histories of trauma or personality disorders or socioeconomic disadvantages that make them more vulnerable to relapse into depression. Although baseline characteristics seem similar between the groups of patients in the study, these factors were not specifically checked. Similarly, the apparent advantage of the tricyclics confounds the differences in drug class with differences both in the decades in which the patients were treated and in the longer half-lives of tricyclics compared to the widely used modern drugs with short half-lives (specifically paroxetine and venlafaxine). There may be factors unique to the setting of the study in Sardinia. ....

 

Despite these uncertainties, it is tempting to ponder the meaning of what was observed. Mood disorders are as interesting for their periodic remission and relapse as they are for their symptoms during the acute illness itself. Although there is much evidence that some of the stigmata of mood disorder persist between episodes, it is a common clinical observation that many patients achieve striking remission only to suffer equally striking relapse (3). An illness with such relapsing-remitting properties is difficult to conceptualize as a biological illness, because a biology that could account for a profound change in mood that lasts several months and then remits is unknown, despite the many efforts that have been made to identify the biology of the "switch process" (4). Perhaps Baldessarini et al. have discovered that the switch process is engaged by an abrupt change in serotonergic or noradrenergic neurotransmission, which could be brought about in some instances by traumatic events or developmental crises, but also by abrupt discontinuation of medication, particularly short-acting medications and particularly in illnesses such as bipolar I disorder, which are most likely to cycle. It is interesting that the effect does not occur immediately during drug withdrawal but rather takes several months to manifest itself. While the complexity of interaction between the pharmacological insult and the biological predisposition to illness cannot be fully modeled in laboratory animals, a laboratory study of the longer-term neurobiological changes that follow abrupt withdrawal of a drug like paroxetine might provide new information on biological mechanisms that might underlie remission and relapse in patients. Reviewers suggested that a similar prospective, randomized study could be conducted in patients, but the authors countered that such a study, which would deliberately expose some patients to an apparent harm, would not be ethical.

 

Although clinicians rarely advocate abrupt discontinuation of antidepressants in the absence of the emergence of mania, one clinical situation in which it might seem appropriate is pregnancy. If a woman's mood is under control and she is concerned about the effects of paroxetine on her fetus, she or her physician might consider discontinuing her drug quickly. A comparative risk assessment suggests that the risk of antidepressant drug treatment is not negligible, but depression itself, treated or untreated, appears to be a greater risk factor for pregnancy and the fetus (5). Although the Baldessarini et al. study did not note whether any of the patients were pregnant, the authors point out that the findings of the study suggest that abrupt discontinuation might not be a rational decision, even for an asymptomatic woman who is concerned about effects on the fetus, because depression would be more likely to occur later in the pregnancy or in the postpartum period (6).

 

Accurate record keeping in large populations of patients has led to remarkable insights into the time course of the effects of antidepressants on suicidal behavior in adolescents, effects of antidepressants on diabetes, and now, in this study, the effects of discontinuation pace on relapse (7, 8). Psychiatrists and other physicians are currently being encouraged to transition to the use of electronic medical records. Hopefully, these records can be used constructively to continue long-term observations of the benefits and risks of psychiatric treatments.

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Meimeiquest

You know, we are so playing with fire.

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Altostrata

Exactly.

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westcoast

Here's Baldessarini and some pals 2 years later.

 

“Switching” of Mood From Depression to Mania With Antidepressants

News | November 08, 2013

By Ross J. Baldessarini, MD, Gianni L. Faedda, MD, Emanuela Offidani, PhD, Gustavo H. Vázquez, MD, PhD, Ciro Marangoni, MD, Giulia Serra, MD, and Leonardo Tondo, MD, MSc

 

"Bipolar disorder often presents initially with one or more episodes of major depression, and an episode of mania or hypomania may first occur during treatment with an antidepressant, stimulant, or other agent with mood-elevating effects."

 

It's silly. How about "Endogenous black-eye syndrome typically presents after an accidental blow to the face."

 

They seem confused later on--do they still believe their first sentence? Hard to say--the writing is hard on the brain, but it's forgiveable because they're Italian..

"Of particular concern is that these ambiguous possibilities [that ADs cause a manic reaction in non-bipolars]  leave specifically uncertain the potential lead [us] to question the value of long-term treatment with anti-manic or putative mood-stabilizing agents.

 

Hear, hear!

 

http://www.psychiatrictimes.com/bipolar-disorder/switching-mood-depression-mania-antidepressants.

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Altostrata

Baldessarini has never been a drug cheerleader.

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westcoast

I more or less realized that but it wasn't crystal-clear.

 

 

They seem confused later on--do they still believe their first sentence? Hard to say--the writing is hard on the brain, but it's forgiveable because they're Italian..

"Of particular concern is that these ambiguous possibilities [that ADs cause a manic reaction in non-bipolars]  leave specifically uncertain the potential lead [us] to question the value of long-term treatment with anti-manic or putative mood-stabilizing agents.

 

Hear, hear!

 

Love that "putative."

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