Stop Antidepressants Slowly

People commonly decide to stop taking an antidepressant. Does it matter how this is done? If a patient is pregnant, isn’t it best to stop the medication immediately? If you or your patient is taking one of the antidepressants that is rarely associated with the SSRI withdrawal syndrome, it doesn’t matter whether the medication is stopped quickly or slowly, does it? What about the patient who has been stable for a year, or two years; if they are asymptomatic, happy, and at a good place in their life, surely it doesn’t matter if they stop citalopram 20mg without tapering.

An article published in the American Journal of Psychiatry in 2010 indicates it does matter. Though this article is three years old, its significance leads me to write about it now. It is my impression that many clinicians are unaware of the risk of not tapering antidepressants, or neglect to educate their patients about the importance of going off medication gradually in almost all situations.

It is well known in psychiatry that rapid cessation of mood stabilizers increases the risk of a mood episode. In fact, previous studies of maintenance treatment have been criticized for including a treatment arm randomizing patients to abruptly stopping their medication. This is because it is widely understood that by stopping the drug suddenly, the group randomized to placebo is going to have an increased rate of relapse. This unnecessarily puts patients at higher risk for an episode of their illness and makes the drug being studied look more effective at preventing relapse than it really is. It is no longer considered ethical or valid to stop medication suddenly in trials involving bipolar disorder.

Ross Baldessarini and his colleagues have been publishing studies for many years involving the inhabitants of the island of Sardinia. They have previously documented the risks of rapidly stopping mood stabilizers and antipsychotics. The Sardinian studies have focused on mood, anxiety and psychotic disorders, particularly the longitudinal course of these illnesses, using a naturalistic design.  In the current study they looked at the consequences of the abrupt withdrawal of antidepressants in patients with major depression, bipolar 1 and bipolar 2 disorder, and panic disorder.

One of the strengths of this study, and of the other studies from this group, is the comprehensive nature and duration of follow up. Meticulous records have been kept for over forty years. There may not be a comparable database of such a large number of individuals, followed so closely and for so long, anywhere else in the world. The studies published have been of great interest and usefulness to psychiatry.

The principal finding of this study was that “the abrupt or rapid discontinuation of clinically effective antidepressant treatment was associated with a significantly shorter time to a first new episode of major depression or panic.” The patients were clinically well at the time the medication was stopped, without even mild degrees of depression or panic. In other words, there was no evidence that these patients were experiencing a relapse or recurrence prior to going off medication. The decision to stop medication rapidly was made by the patient in a large majority of cases. The increased risk of recurrence was found with both newer and older antidepressants, though the benefits of a slow taper of the medication was more pronounced with older medications.

Based on the findings, the authors made the following recommendations:

1) Gradual dose tapering should be done in all situations unless a patient is experiencing a severe adverse medical effect or a severe manic reaction.

2) Patients should be warned that abrupt discontinuation of an antidepressant can lead to early withdrawal reactions and, over a period of several months, a return of the illness being treated.

3) Primary care clinicians, who prescribe most of the antidepressants in the US, should be aware that it is the rate of dose tapering and discontinuation that plays an important role in determining the risk of stopping medication.

Though they do not say this unequivocally, the authors imply that even in the case of pregnancy the risks of stopping antidepressant medication outweigh any potential benefits. Based on the current data available to clinicians, I agree. There is a very high risk of recurrence of illness if a woman stops medication for schizophrenia, bipolar disorder or depression while pregnant. The evidence does not indicate any benefit from suddenly or abruptly stopping medication during pregnancy. The fetus has already been exposed to the medication, and rapidly discontinuing it puts the woman and her baby at the added risk of an episode of the illness she suffers from. The more appropriate course of action is to get an expert in mental illness and an obstetrician involved, so that the risks and benefits of continuing or stopping pharmacological treatment can be examined and discussed with the patient. The knee jerk reaction of stopping the antidepressant right away can create a much more severe situation and cause more harm.

Summing up: Stopping antidepressants suddenly increases the risk that symptoms will return. This applies to depression (both in unipolar and bipolar disorders) and panic disorder. Slowly tapering medication rather than stopping it rapidly is almost always the right thing to do. If treating patients with antidepressants, educate them about this. Many of them will choose to stop medication on their own in the future, and it will decrease the risk of recurrence if they do so slowly.

Illness Risk Following Rapid Versus Gradual Discontinuation of Antidepressants                                                                 Ross J. Baldessarini, M.D.; Leonardo Tondo, M.D., M.S.; Carmen Ghiani, M.D.; Beatrice Lepri, Psy.D.                           Am J Psychiatry 2010;167:934-941. 

Do antidepressants have any role in treating mild depression?

In recent years there has been a lot of attention given to the question: “Do antidepressants really work”? There is general agreement that in cases of severe depression, the evidence supports their efficacy. However, there is ongoing debate about the usefulness and role of pharmacotherapy for milder depressions.

There have been at least two meta-analyses of antidepressant trials that found no benefit from taking an antidepressant when an individual has mild to moderate depression. I am not an expert on statistical methods, and am not qualified to judge the merits of these meta-analyses (in fact, about all I can say about a meta-analysis is that it involves lumping the results of a number of studies together, giving some more weight than others depending on the size and quality of the study, and then running statistical tests on the combined results). There are many critiques of these two studies by other experts in psychiatry and statistics, pointing out the various ways in which the studies chosen to be included in the meta-analyses, and the statistical methods used to analyze them, lead to erroneous conclusions. Also, there are other analyses, using a larger database, that find that antidepressants are effective in treating mild depression.

There are points on which I am in complete agreement with the medication skeptics. Psychotherapy is underused, is often undervalued, and sometimes has more lasting benefits. Insurance coverage for psychotherapy should be equal to that of coverage for treatment with an antidepressant. Medication has been over-utilized and relied on to do things which it is unable to accomplish. Pharmaceutical companies have had much too great an influence on training and education of physicians, and have proven to be unethical on so many occasions that almost anything that comes from them is suspect. Even diagnostic categories have been influenced by them. Their impact has been so great that I wonder if much of the research done over the past couple of decades is reliable, even some not directly supported by drug company funding.

As an example, during the late 1990’s and into the 2000’s, there was an enormous push to get clinicians to suspect bipolar disorder under every rock or bush on the clinical landscape, with warnings of the dire consequences that comes from using an antidepressant rather than a mood stabilizer, preferably a second-generation antipsychotic. Much, probably most, of the research done, studies published, conferences held and speakers paid to talk about this were funded by pharmaceutical companies with a financial incentive for clinicians to prescribe a newer antipsychotic (such as Zyprexa, Seroquel, Risperdal, Abilify, Geodon). The list of soft signs of bipolar disorder, and clues from the history, that supposedly supported a diagnosis of bipolar disorder became quite extensive. One of the consequences of Big Pharma money was an explosion in the rates of diagnosis of bipolar disorder, which continues today.There are good reasons to screen for bipolar disorder when a patient presents with depression, in particular the facts that antidepressants don’t work very well for bipolar depression and that some patients can be harmed by them. The exact role of antidepressants in bipolar depression continues to be debated, in part because we still don’t have enough information from good studies.

Getting back to the main issue I wanted to address: are antidepressants ever helpful for chronic mild depression, or recurring forms of mild-moderate depression? Putting aside the research, which can be interpreted either way depending on what you want to believe, my experience leads me to say yes, most definitely. But not always, and not for everyone. Both professionally and in my private life, I have observed them help some individuals, and do nothing for others. Most convincing to me is the antidepressant effect they have produced, of many years duration, for people I know well. Without an antidepressant, they would have been forced to endure years of depression. And psychotherapy had been engaged in, sometimes for long periods of time. If clinicians were to follow the current trend in some circles and not prescribe for mild or moderate depression, it would consign some people to experience unnecessary suffering, impaired functioning and a lower quality of life. And of course, the impact on family can be severe.

I am not arguing that every depression should be treated with medication. I believe that medication should be one of a number of treatment options, and that clinicians should not be the ones to decide what is the right treatment. Rather, they should educate their patients and be guided by their patients’ preferences. Psychotherapy can be effective for depression, but it does not work for everyone, and some people don’t want psychotherapy. Also, most psychotherapy studies used well-trained therapists following a manualized treatment approach, such as Interpersonal Psychotherapy or Cognitive Behavior Therapy. In the real world, therapists tend not to follow evidence-based therapy guidelines, opting for an “eclectic” approach, which has little or no evidence to support its effectiveness. Having personal experience with both traditional psycho-analysis and a humanistic/eclectic approach, I know that psychotherapy can work and be very helpful. However, I also know from professional and personal experience that psychotherapy can be a waste of time and money; it can turn people off to getting help of any kind if they have the misfortune of seeing an incompetent therapist, and it occasionally makes some people more ill or worse off than before they engaged in therapy. Harm from psychotherapy may not be common, but it is incorrect to assume that only medication has the potential to have adverse effects.

Antidepressants are one of a number of treatment options that should be offered to someone with depression, even if it is mild. Exercise, behavioral activation, cognitive therapy, dynamic therapies and medication are some of the evidence-based treatments to be discussed with patients, so that they can make an informed decision.

Can Antipsychotics help Depression?

[Short take: Not first-line for most people with depression. Newer antipsychotics help 1 out of 10 takers achieve remission. They have a number of potentially serious side effects.]

Major depression affects between 10% and 20% of people in the US at some point in their lifetime. Though there are many antidepressants available, from a number of different classes of medication, the majority of people that take an antidepressant do not get a complete response to the first, or even second medication they take. As each new treatment is tried, and fails, the likelihood of a good response decreases. As a result, many with depression are left with no response or only a partial response  and are unsure what to do next. Psychotherapy, particularly the evidence based forms (such s Cognitive Behavior Therapy (CBT), Commitment and Acceptance Therapy (ACT), Interpersonal Therapy (IPT), and probably mindfulness based therapies founded on CBT), are successful as first-line treatments and good alternatives to medication. They should also be tried in treatment resistant depression. Finding a well-trained therapist can sometimes be difficult, though perhaps no more difficult than finding someone up to date in psycho-pharmacology. Both medications and psychotherapies have benefits and risks.

In recent years, in an effort to expand the market for their medications, pharmaceutical companies have funded a number of large, well-done studies to assess the usefulness of adding the newer antipsychotics to antidepressants for treating major depression. The FDA has approved 2 of these medications, quetiapine and aripiprazole, for major depression that is not responding adequately to antidepressants (olanzapine has been approved in a fixed-dose combination with fluoxetine, but not as an add-on to any antidepressant). Unlike T3 and Lithium, which have been studied primarily with older antidepressants, the second generation* antipsychotics have been studied as an add-on to SSRI’s (sertaline, fluoxetine, paroxetine, citalopram, escitalopram) and SNRI’s (venlafaxine, duloxetine).

Do the atypical* anti-psychotics help decrease symptoms of depression when added to an antidepressant? Given the size of the studies and their statistical power, it is clear that they do help. When compared to adding a placebo, quetiapine and aripiprazole help more people respond (meaning that the symptoms decrease by at least 50%) and achieve remission. And the experts all agree, remission is what counts. When a person is in remission from depression they are back to normal, or at least almost completely back to their non-depressed baseline. And this is very important, since even mild residual symptoms of depression increase the risk of depression coming back, and each episode of depression increases the risk of another episode and the risk of entering a state of chronic depression.

How well do they work? Simply put, not very well, particularly given the potential side effect burden associated with them. The NNT (number needed to treat) is 10. This means that compared to placebo, the addition of an SGA to an antidepressant will help 1 in 10 people achieve remission. NNT is one of simplest ways of looking at the clinical meaningfulness of a treatment. Studies frequently report results that are statistically significant, but statistically significant is not the same as clinically meaningful. A large study may have a very strong finding in a statistical sense, but the treatment may not help very many people, or not help them very much. An NNT of 2 or 3 indicates a very useful treatment. NNT’s of 4-7 are helpful.

Partial or non-response to antidepressants is a big problem, and reasonable and effective treatment options are badly needed. The SGA’s are effective, but helping only 1 in 10 is on the borderline of usefulness. An NNT of 10 is considered marginal, and though a completely benign treatment might be looked at favorably, these medications are not free of side effects.

What are the side effects of the atypical antipsychotics? The side effects vary somewhat between medications, but can be substantial. Aripiprazole (Abilify) is less likely to cause sedation, weight gain, increased triglycerides and increased blood sugar than quetiapine (Seroquel XR), but more likely to cause restlessness and inability to stay still (akathisia). Long-term side effects have not been systematically studied for either of them, and it is unclear how much risk of tardive dyskinesia (abnormal muscle movements that can be permanent) is associated with their use. Since these medications can cause increased weight, blood sugar and lipids, they likely put people at risk of developing diabetes and cardiovascular disease.

Should SGA’s be used in treating depression? Yes, they definitely have a role. Following the recommendations of Connolly and Thase as stated in Management Of Treatment-Resistant Major Psychiatric Disorders, SGA’s should be considered as first-line add-on options when the antidepressant is well-tolerated enough to be continued, and there is some urgency in decreasing symptoms. The evidence supports them as having a fairly rapid effect, with some improvement seen within 1-2 weeks. The other situation in which they are first-line and clearly indicated is when psychotic symptoms are present along with depression.

To sum up: Lack of a complete response to an antidepressant is the norm. There are many options, but not a lot of information to guide the selection of treatments, or the best sequence to use them in. If a person has taken just one antidepressant and not had a good response, and the situation is not urgent, then adding an antipsychotic is not likely to be the next step. On the other hand, if someone has had several antidepressants, and their depression is not getting better, then an antipsychotic could be a very helpful option. Unanswered is the question of how long the antipsychotic should be taken, and monitoring of side effects is important, particularly weight gain, metabolic and muscular ones.

* Several terms are used in referring to a group of medications that were initially used in treating schizophrenia, and which now are commonly used in treating Bipolar Disorder, Major Depression, and other conditions; these include atypical antipsychotics, second-generation antipsychotics (SGA’s), and newer antipsychotics. This is to distinguish them from the older, or typical, antipsychotics such as Thorazine, Haldol, Stelazine and Prolixin. Though the SGA’s all block dopamine, and hence share the ability to decrease psychotic symptoms, there is a lot of variability among them, and antipsychotic may not be a very good term for them. They are effective at treating manic episodes, preventing recurrence of manic episodes and decreasing depressive symptoms, among other things.

References for Treatment Resistant Depression

1) Connolly,K.R., Thase,M.E. (2012) Systematic Approach to Treatment-Resistant Depression: Psychopharmacology and Psychotherapy. In C.B.Nemereoff, Management Of Treatment-Resistant Major Psychiatric Disorders(pp. 23-48). New York: Oxford University Press.

2)Phillip,S.P.,Pharmacologic Approaches to Treatment Resistant Depression:A re-examination for the Modern Era. Expert Opin Pharmacother. 2010 April;11(5):709-722. doi:1517/1465651003614781.

Thyroid hormone and Depression

This is a brief note about the use of T3 (the active from of thyroid hormone in the body) in the treatment of depression. Thyroid augmentation, though usually well tolerated, has the potential for serious side effects and should only be done in conjunction with a professional licensed to prescribe it.

Low levels of thyroid hormone are associated with depression, and many clinicians check a TSH level (a very sensitive screening test for low thyroid, known as hypothyroidism) as part of the assessment of symptoms of depression.

It is less widely known that even if a person has normal levels of thyroid, they may benefit from taking T3 as a supplement or augmentation agent along with their antidepressant.

T3 has primarily been studied in combination with tricyclic antidepressants (such as imipramine, doxepin and nortriptyline). However, it has also been combined with an SSRI (selective serotonin reuptake inhibitor), such as in the STAR-D studies. In one of the STAR-D studies, when citalopram (a SSRI) was ineffective on it’s own for major depression, either T3 or Lithium was added to citalopram. T3 and lithium were equally effective as an add-on agent for decreasing symptoms of depression; however, T3 was better tolerated.

In general it appears to be more helpful for women than men, and very well tolerated. In my experience it works quickly, but in the STAR-D study the mean time to becoming well took 6 weeks, and for some this did not occur until week 14. So be patient with it.

The usual starting dose is 25 micrograms (not milligrams, the typical unit of dosing in psychiatry), though sometimes it is better to start with just 12.5 mcg. This dose is usually continued for about 2 weeks before assessing benefits and side effects. The maximum dose is 50 mcg/d. Don’t be surprised if you find that it helps and you start wondering if an even higher dose would work better. Don’t increase it on your own. After a month a TSH level should be checked to make sure that you are not getting too much T3.

T3 is generally quite safe and easy to tolerate, but too much is associated with atrial fibrillation and osteoporosis. Symptoms of hyperthyroidism, a condition in which the body is making too much thyroid hormone (or is taking too much) include sweating, loose stools, anxiety, rapid heart rate and heat intolerance.

T should be taken on an empty stomach to improve absorption. Antacids, zinc and iron supplements can decrease absorption.

I have frequently discussed using T3 as an augmentation agent. Both I and my patients have been struck by it’s lack of side effects and the improvement in energy and mood that they experienced. One of it’s most attractive features as an add-on agent is it’s ability to improve energy, and for some people, to decrease appetite, or at least not increase appetite (which is a side effect of many augmentation agents). It has sometimes been hard to put the brakes on over enthusiastic patients who have suffered from depression, decreased motivation, lack of enthusiasm and no pleasure for a long time. It is easy to understand the reasoning: “if 50mcgs helps, 75 or a 100 would be fantastic”. Don’t do it. Check a TSH level, and respect that though T3 can help, it is a potent substance and must be used appropriately.

For more information refer to the following articles:

1. Augmenting antidepressants with triiodothyronine: An underutilized strategy:T3 augmentation can improve depressive symptoms in patients without subclinical hypothyroidism

Current Psychiatry Vol. 10, No. 07 / July 2011 Daniel Gih, MD

2. T3 Augmentation in Major Depressive Disorder: Safety Considerations

Lisa J. Rosenthal, M.D., Whitney S. Goldner, M.D., John P. O’Reardon, M.D.


Omega-3 Fatty Acids and Depression

Bottom line: Taking 1-4 grams per day of O3FA can decrease symptoms of depression, when the EPA component of the supplement is at least 60% of the total fatty acid content. DHA, another omega-3, should not be used by itself or make up more than 40% of the total fatty acid content.

Background: Many studies have been published looking at the usefulness of omega-3 fatty acids in the treatment of depression, bipolar disorder, schizophrenia and other conditions. The results have been conflicting and confusing. Recent articles in the Journal of Clinical Psychiatry (Dec. 2011) and Current Psychiatry (Sept. 2012) help to make sense of the data. Meta-analyses of fatty acid studies in the treatment of depression have found that when used alone the omega-3 fatty acids are not effective in decreasing depressive symptoms. DHA, one of the major omega-3’s, is not helpful for depression. EPA, another omega-3, is effective. However, the benefit from from EPA is most apparent when

* the depression is on the severe end of the spectrum

* the patient is on antidepressant treatment (the fatty acid is not used alone)

* EPA makes up at least 60% of the fatty acid content of the supplement

The amount of omega-3 that works best has not been determined. It is recommended that at least 1 gram be taken each day, with a maximum dose of perhaps 4 grams. Higher doses have been associated with less benefit.

Example: If you are taking an antidepressant, say sertraline 150 mg/d or venlafaxine 225 mg/d, and you are still suffering from significant symptoms of depression, and do not want to increase the dose (a reasonable option in both cases), adding 1-2 grams/d of omega-3 fatty acid (with EPA at least 60% of the total) made by a reputable company may be a good choice. There is no evidence whether it is more or less likely to help continuing symptoms of depression than any of the many other options, at least so far. Side effects are pretty minimal, unless you get the fishy tasting burps. Also, the omega-3s are not recommended for someone with a bleeding disorder. Eating fish 2-3 times a week(at least those high in omega-3s, such as salmon, sardines, herring and halibut) will get you plenty of omega-3.

1) Morreale, M Omega-3 Fatty Acids for psychiatric Illness. Current Psychiatry Vol. 11, No. 09 / September 2012

2) Sublette,M et al Meta-Analysis of the Effects of EPS in Clinical Trials of Depression. Journal of Clinical Psychiatry2012;72(12):1577

Folate and Depression

Folate, which is involved in making neurotransmitters such as serotonin and dopamine, has been found to be low in some individuals with depression. And low levels appear to be associated with a decreased response to antidepressants.

In an article from the December, 2012 issue of the American Journal of Psychiatry, Papakostas and colleagues found that L-methylfolate (folate is converted into L-methylfolate prior to it’s role in making neurotransmitters) increased the number of responders when it was added to an SSRI-type antidepressant. These patients had been taking an SSRI (a category which includes fluoxetine, sertraline, citalopram, paroxetine and others) for 8 weeks without responding to the SSRI alone. 32% responded to L-methylfolate plus SSRI, versus 14% taking placebo and SSRI.

The number needed to treat (NNT, one of the better measures of the practical usefulness of a treatment) was 6, which means it is a clinically useful strategy.

l-Methylfolate was well tolerated when added to an SSRI, with rates of side effects no different from those reported with placebo plu an SSRI.

An important unanswered question is whether it is necessary to use L-methylfolate (marketed as Deplin at about $90-$95 dollars a month), or if over the counter, very inexpensive, folic acid would be just as effective. Another question is what dose of folic acid should be used if added as an augmentation agent in the treatment of depression.

l-Methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parallel-Sequential Trials

George I. Papakostas, M.D., et. al.

The Evolving Story of Folate in Depression and the Therapeutic Potential of l-Methylfolate

J. Craig Nelson, M.D.

Creatine and Depression

In an article published in the American J of Psychiatry in 2012, the addition of creatine to escitalopram (an SSRI, marketed under the brand name Lexapro) led to a more rapid decrease in symptoms and a greater remission rate (the most important outcome parameter when assessing a treatment for depression) in women with major depression. Escitalopram was given at 10mg/d for 1 week, then 20mg/d. Creatine was given at 3 grams a day for 1 week, then 5 grams a day. There was no difference between placebo and creatine in the type of side effects experienced. No serious side effects occurred. Side effects reported included tension headaches, nausea, vomiting and sleep difficulties.

The number needed to treat (NNT) for remission, one of the best measures of the practical usefulness of a treatment, was 4. 52% of patients taking creating with escitalopram went into remission, versus 25% of those taking placebo plus escitalopram.

A Randomized, Double-Blind Placebo-Controlled Trial of Oral Creatine Monohydrate Augmentation for Enhanced Response to a Selective Serotonin Reuptake Inhibitor in Women With Major Depressive Disorder

In Kyoon Lyoo, M.D., Ph.D., Sujung Yoon, M.D., Ph.D., Tae-Suk Kim, M.D., Ph.D., Jaeuk Hwang, M.D., Ph.D., Jieun E. Kim, M.D., Ph.D., Wangyoun Won, M.D., Sujin Bae, Ph.D., Perry F. Renshaw, M.D., Ph.D.

American Journal of Psychiatry, Sep 2012; 169 (9); 937-945. doi: 10.1176/appi.ajp.2012.12010009