Antidepressants and Bipolar Depression

The role of antidepressants in treating bipolar depression has been hotly debated in psychiatry for over twenty years. During that time many studies involving bipolar patients have been conducted, thousands of articles written, and hundreds if not thousands of experts in bipolar disorder have expressed their opinion on the matter. The most common view is that antidepressants should be used as little as possible in patients with bipolar disorder, and in those not known to have it but who might have it (based on family history, personal history, response to medications in the past).

The concerns go beyond the possibility of causing a switch from depression into mania. It is commonly stated that antidepressants can cause mixed episodes (a combination of manic and depressive symptoms), cycle acceleration (more episodes in a given period of time than would have occurred without an antidepressant being introduced), treatment resistant depression (a prolonged episode of depression unresponsive to the usual treatment measures), increased risk of suicide, and rapid cycling (four or more distinct episodes of depression or mania in one year). Clinicians have been warned not to use antidepressants, and consequently almost all of us feel bad/guilty to one degree or another because we still use them; they remain the most commonly used treatment in bipolar depression. Their continuing popularity is likely multifactorial. I think part of it is the lack of evidence based alternatives that make intuitive sense. Up until recently the only FDA-approved medications were Symbyax (a combination of olanzapine and fluoxetine that has never caught on in spite of considerable effectiveness and ease of use) and Seroquel (why use a sedating antipsychotic to treat depression?).

Where are we now with over twenty years of study and debate? Which of the many questions about the use of antidepressants in patients with manic-depressive illness can we answer and which guidelines can we confidently follow?

To address this important issue, The International Society for Bipolar Disorders ISBD) Task Force on Antidepressant Use in Bipolar Disorders was convened. These global experts were chosen based upon a search of citations on the specific topic of antidepressant use in bipolar disorder. They represent the big names in bipolar disorder from around the world.

Ten topic areas were researched and the quality of the evidence rated from A (excellent ) to D (poor). Topics covered included the efficacy of antidepressants as monotherapy for bipolar depression, antidepressants used as adjuncts to mood stabilizers such as Lithium and Valproate in bipolar depression, antidepressants  used as part of maintenance treatment and risks of antidepressant use including switches into mania or mixed episodes, cycle acceleration and precipitation of suicidal thoughts and behavior.

The interested reader can study the entire article. It is easy to summarize the findings: We know almost nothing about the use of antidepressants in bipolar disorder in general, and in bipolar depression in particular. Do antidepressants work in bipolar depression? We don’t know. Do antidepressants hurt or cause harm in bipolar disorder? This is unknown. Of the ten questions researched, the data base was rated as poor for seven of them; this is the lowest rating that could be given. Only one out of the ten questions asked had a good data base available for answering the question; none had an excellent data base. The only question that could be answered with some confidence is that Symbyax (the combination of the antidepressant fluoxetine and the second generation antipsychotic olanzapine) works for bipolar depression, and that paroxetine and bupropion in combination with a mood stabilizer probably do not work. It is ironic that experts have for many years stated that bupropion is likely the best antidepressant to use in bipolar depression, and now one of the few things we can say with confidence is that bupropion does not help.

What is the take away message? If we are going to use antidepressants in bipolar disorder, and most of us are (the data is very clear about that), we need to be frank with our patients that we don’t know if they are helpful, or harmful. And that there are alternative treatments, such as quetiapine (Seroquel), fluoxetine/olanzapine (Symbyax), and lurasidone (Latuda) that do have evidence to back up their effectiveness in decreasing symptoms of depression in patients with bipolar disorder. These other medications have more potential side effects, some of which are quite serious, but we know they can work.

The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders

Isabella Pacchiarotti, M.D., Ph.D.; David J. Bond, M.D., Ph.D.; Ross J. Baldessarini, M.D.; Willem A. Nolen, M.D., Ph.D.; Heinz Grunze, M.D.; Rasmus W. Licht, M.D., Ph.D.; Robert M. Post, M.D.; Michael Berk, M.D., Ph.D.; Guy M. Goodwin, F.Med.Sci.; Gary S. Sachs, M.D.; Leonardo Tondo, M.D.; Robert L. Findling, M.D.; Eric A. Youngstrom, Psy.D., Ph.D.; Mauricio Tohen, M.D., Dr.P.H.; Juan Undurraga, M.D.; Ana González-Pinto, M.D., Ph.D.; Joseph F. Goldberg, M.D.; Ayşegül Yildiz, M.D.; Lori L. Altshuler, M.D.; Joseph R. Calabrese, M.D.; Philip B. Mitchell, M.B.B.S., M.D.; Michael E. Thase, M.D.; Athanasios Koukopoulos, M.D.; Francesc Colom, Psy.D., Ph.D.; Mark A. Frye, M.D.; Gin S. Malhi, M.D.; Konstantinos N. Fountoulakis, M.D., Ph.D.; Gustavo Vázquez, M.D., Ph.D.; Roy H. Perlis, M.D.; Terence A. Ketter, M.D.; Frederick Cassidy, M.D.; Hagop Akiskal, M.D.; Jean-Michel Azorin, M.D.; Marc Valentí, M.D., Ph.D.; Diego Hidalgo Mazzei, M.D.; Beny Lafer, M.D.; Tadafumi Kato, M.D., Ph.D.; Lorenzo Mazzarini, M.D.; Anabel Martínez-Aran, Psy.D., Ph.D.; Gordon Parker, M.D., Ph.D.; Daniel Souery, M.D., Ph.D.; Ayşegül Özerdem, M.D., Ph.D.; Susan L. McElroy, M.D.; Paolo Girardi, M.D.; Michael Bauer, M.D., Ph.D.; Lakshmi N. Yatham, M.D.; Carlos A. Zarate, M.D.; Andrew A. Nierenberg, M.D.; Boris Birmaher, M.D.; Shigenobu Kanba, M.D., Ph.D.; Rif S. El-Mallakh, M.D.; Alessandro Serretti, M.D., Ph.D.; Zoltan Rihmer, M.D., Ph.D.; Allan H. Young, M.D., Ph.D.; Georgios D. Kotzalidis, M.D.; Glenda M. MacQueen, M.D., Ph.D.N.; Charles L. Bowden, M.D.; S. Nassir Ghaemi, M.D., M.P.H.; Carlos Lopez-Jaramillo, M.D., Ph.D.; Janusz Rybakowski, M.D., Ph.D.; Kyooseob Ha, M.D.; Giulio Perugi, M.D.; Siegfried Kasper, M.D.; Jay D. Amsterdam, M.D.; Robert M. Hirschfeld, M.D.; Flávio Kapczinski, M.D., Ph.D.; Eduard Vieta, M.D., Ph.D.

Am J Psychiatry 2013;170:1249-1262. doi:10.1176/appi.ajp.2013.13020185


Folic Acid, Vitamin B12 and Negative Symptoms of Schizophrenia

[In Brief: Folic acid and vitamin B12 help a subset of individuals with schizophrenia by decreasing negative symptoms. Side effects are no different than with placebo. Adding folate and vitamin B12 is a low risk strategy for symptoms that are very difficult to treat.]


Negative symptoms play an important role in the disability caused by schizophrenia. Symptoms in schizophrenia are divided into 4 main types: positive, negative, cognitive (impaired concentration, poor planning and problem solving, etc.) and mood. Use of the terms positive and negative has nothing to do with whether the symptoms are good or bad. Positive symptoms refers to hallucinations, delusions and disorganization. Negative symptoms are some of the most disabling, and play a larger role in impaired functioning than positive symptoms. Negative symptoms include loss of interest (apathy), loss of pleasure (anhedonia), decreased motivation (avolition), decreased emotional expression (affective flattening) and decreased speech (alogia). These are sometimes referred to as the 5 A’s.

Negative symptoms are hard to treat. When the newer antipsychotics (Risperdal, Zyprexa, Seroquel, Abilify, and others) became available in the mid-90’s and later, they were promoted as superior to older antipsychotics, in part because of a purported greater ability to decrease negative symptoms. It took quite awhile, but we now know that these second-generation antipsychotics are no better at decreasing negative symptoms than first-generation antipsychotics. It is possible that the older antipsychotics are more likely to increase negative symptoms, particularly when used in high doses.

An article published in the May, 2013 issue of JAMA Psychiatry studied the effect of adding folate and vitamin B12 on negative symptoms, taking into account the role of genetic variation in several genes involved in folate absorption and metabolism. The study was double-blind, placebo controlled and enrolled 140 patients with chronic schizophrenia. Participants were stable but still symptomatic. Doses were 2mg/day of folate and 400micrograms/day of vitamin B12.

The authors were particularly interested in studying folate because of the epidemiological, biochemical and genetic association studies that have identified folate deficiency as a risk factor for schizophrenia. Findings of prior investigations include the following:

* After famines in China and The Netherlands, rates of schizophrenia doubled, presumably as a result of dietary deficiencies.

* Low folate levels in the 3rd trimester of pregnancy are associated with more than a 2 fold increased risk in the development of schizophrenia in offspring.

* Low folate levels have been found in patients with schizophrenia.

* In patients with schizophrenia, low folate levels are associated with more severe negative symptoms, but do not correlate with positive symptoms.

* 2 small studies found that adding a folate supplement benefited patients with schizophrenia, if they had low folate levels.

* In patients with prominent negative symptoms, folate supplements were helpful in the subgroup with a specific genotype.

The author’s hypothesis was that folate and vitamin B12 supplementation would decrease negative symptoms, but only in those patients with hypofunctioning (low functioning) genes involved in the absorption and metabolism of folate. In other words, only some people would have more emotional expression, talk more, and be more motivated, and it would be those with genes that were less effective at absorbing and metabolizing folate.

I should have mentioned earlier that this is a difficult paper. I do not recommend reading the whole thing, unless you like struggling with genotypes, alleles and vague statements, while in search of limited conclusions, of uncertain value.

That being said, the study found (as predicted) that folate and vitamin B12 supplementation did help negative symptoms, but only “modestly”, and only in a subset of patients. Other symptoms of schizophrenia did not benefit. There was no difference in side effects between those taking the vitamins and those taking placebo. When genotype was taken into account, there was a 27% difference in negative symptoms between those receiving folate and B12 and those receiving placebo. Is there any practical significance of this finding?                                                                                                                                                                                                                       

In the authors words:  “Even small effects of folate and vitamin B12 supplementation could be clinically meaningful, though, given the disability associated with negative symptoms, the lack of available treatments,35 and the minimal apparent adverse effects of vitamin supplementation.”

In my slightly optimistic interpretation: negative symptoms interfere with the ability to function, they are hard to treat, these doses of vitamins are safe, and even a small improvement in negative symptoms might mean a lot to the individual and their family. There is little to lose and possibly something small but important to gain.                                                                                                                        I could not find anything in the article that would allow one to estimate the proportion of patients likely to benefit from supplementation.


For those looking for a punishing read, the full article can be found in the May, 2013 issue of JAMA Psychiatry.





Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia


Joshua L. Roffman, MD, MMSc; J. Steven Lamberti, MD; Eric Achtyes, MD, MS; Eric A. Macklin, PhD; Gail C. Galendez, BS; Lisa H. Raeke, MA; Noah J. Silverstein, BA; Jordan W. Smoller, MD, ScD; Michele Hill, MD; Donald C. Goff, MD


JAMA Psychiatry. 2013;70(5):481-489. doi:10.1001/jamapsychiatry.2013.9

Chantix (varenicline) for Smoking Cessation

For any psychiatrist, the following is a very common scenario.

I am seeing Frank, a 45 year old man, who is afflicted with schizophrenia. He has been smoking heavily since he was a teenager. Though Frank has heard many times that smoking is bad for him, in all kinds of ways, he has never given much thought to quitting, until now. It might be his recent health changes, the death of a relative, the high cost of a pack of cigarettes, the hassles of finding a place where he can smoke in peace, or some combination of these. Whatever the cause, he is willing to discuss smoking cessation, and smoking cessation aids, for the first time. We talk about the options (one of my favorite words): going cold turkey (commonly done, not very effective for most people), bupropion, nicotine replacement in all it’s forms (gum, patches, lozenges, inhaler, nasal spray), and Chantix. As we go over the pros and cons, I point out that Chantix is the most effective at helping people quit (I use the brand name rather than the generic name varenicline since most people know it as Chantix and it is not yet available as a generic). He is clearly interested in going with the most effective medication, and his case manager and I are excited at his intent to give it a try. But wait, doesn’t Chantix cause people to get depressed, even become suicidal and to try and kill themselves, or to hear voices? Isn’t it contraindicated for people with mental illness?

Soon after Chantix was released it became clear that it was very effective for some individuals, and was generally superior to the medications already being used. Nausea was the biggest problem.

However, not long after it’s release there were reports that it might cause depression, suicidal thoughts, suicide attempts, psychosis and other neuropsychiatric side effects. That  presented smokers and their clinicians with a dilemma.  Smoking kills and disables very large numbers of people. Chantix was the most effective treatment available. Most people do not succeed with their first, second or even third attempt at quitting. It is hard to quit and many people get discouraged.  How dangerous is Chantix? Do the benefits outweigh the risks? Is it dangerous for everybody, or just some people?

These questions generated considerable interest and study, and not just from the makers of Chantix (who have such a strong vested interest that they cannot be trusted to study the issues objectively). We have learned, among other things, that smokers as a group are more prone to depression, and are more likely to attempt and commit suicide than non-smokers. Also, that the act of quitting smoking puts a person at risk of developing depression and suicidal thoughts. The question is not is Chantix dangerous, but is taking Chantix to quit smoking more dangerous for your mental health than other ways of quitting, such as cold turkey, or with nicotine replacement therapy, or with bupropion. And we now have evidence to answer that question, and I think the answer is good news for smokers.

In a study published online on Sept. 13, 2013 in AJP in Advance, researchers from the University of Chicago and at Columbia University performed the largest analyses to date, by combining data from a number of studies that in total included more than 40,000 smokers.

The data showed that varenicline was highly associated with inducing nausea among patients, but not suicide events, depression, or aggression. Current or past psychiatric illness increased the risk of neuropsychiatric events equally among the varenicline and placebo groups. In the drug-comparison studies, the rate of neuropsychiatric events in the varenicline cohort was significantly less than in those receiving nicotine-replacement therapy. Overall, varenicline was more successful in achieving smoking abstinence than placebo or nicotine-replacement therapy.”

In plain language: Chantix was more effective than nicotine replacement and bupropion, and it was no more likely than placebo to be associated with depression, suicidal thoughts, and other neuropsychiatric effects such as hallucinations.

Getting back to the questions asked earlier: Chantix is not contra-indicated in those with a current or past history of mental illness. The evidence at this point, and there is now good data to guide treatment decisions, is that Chantix is more effective than nicotine replacement and bupropion, and possibly even safer. And, it is no more dangerous than taking no medication when trying to quit smoking and a lot more effective than going cold turkey.

Varenicline, Smoking Cessation, and Neuropsychiatric Adverse Events  Robert D. Gibbons, Ph.D.; J. John Mann, M.D.                Am J Psychiatry 2013;:. doi:10.1176/appi.ajp.2013.12121599

Declaration of interest: I have no financial interest in Chantix or an other product used in helping people quit smoking.

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.


Group Psychoeducation for Bipolar Disorder

Medication is only 1 way to decrease the likelihood of  having another episode for people with bipolar disorder. In a study of 120 patients with bipolar disorder who were currently euthymic (back to baseline), the addition of group psychoeducation significantly reduced the chances of having another episode compared to participating in a support group.

The psycho-education group emphasized

1) early detection of symptoms of an impending mood episode

2) sticking with treatment (such as taking medication regularly, attending appointments, etc.)

3) lifestyle regularity (having a routine or schedule for physical activity, bedtime, social activity)

Though more people in the support group completed the study, those in the psycho-education group

1) fewer mood episodes

2) fewer days hospitalized

3) a longer time to the next episode

Though this is not a new study, being published 10 years ago, subsequent studies have backed up it’s central finding: there are ways to decrease the chances of having another episode in bipolar disorder in addition to taking medication.

The take away message is that learning about bipolar disorder, sticking with the treatment plan and leading a regular lifestyle can help to stay better.

A Randomized Trial on the Efficacy of Group Psychoeducation in the Prophylaxis of Recurrences in Bipolar Patients Whose Disease Is in Remission 

Francesco Colom, PhD; et. al.
Arch Gen Psychiatry. 2003;60(4):402-407. doi:10.1001/archpsyc.60.4.402.

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

PTSD: Overview

Much of the following is based on a lecture by Bruce P. Capehart, M.D. given on 5/10/2012, as part of the Massachusetts General Hospital Psychiatric Academy series From the War Zone to the Home Front: Supporting the Mental Health of Veterans and Their Families.

What helps in the treatment of PTSD

1) Evidence Based Psychotherapy (Cognitive Behavioral, EMDR, Cognitive Processing Therapy)

2) The right medication

3) Treating insomnia

4) Avoiding alcohol and drugs

5) Treating chronic pain

I will briefly cover medications.

In general it is not a good idea to rely too heavily in medication. Psychotherapy has proven to be more effective in a larger number of patients. There are only 2 medications approved for PTSD, sertraline and paroxetine.  However, there is good evidence for venlafaxine and fluoxetine as well and these 4 medications are the first-line pharmacological treatments for PTSD. Higher doses and longer durations are often needed to get a response.

Nefasadone is a very useful second-line med, and would probably be considered a first-line treatment if not for rare liver toxicity. It’s sedating properties can help with insomnia.

Mirtazapine is useful, particularly as an augmentation to a first-line med. It’s sedative properties can help with sleep.

Prazosin has been useful for nightmares and a recent article in the American Journal of Psychiatry confirmed it’s benefits for nightmares and found that it improved overall symptom levels.

Medications that can be useful as add-ons but for which good evidence is lacking include buspirone, trazodone, bupropion, tricyclic antidepressants, and second-generation anti-psychotics (studies using risperidone have not found it to be helpful0.

There is general agreement that benzodiazepines should not be used alone, and if used for a co-morbid condition it is best to use them for short periods of time.

Anti-epileptic medications (with the possible exception of topirimate) and guanfacine have not been helpful.