1. Q. What was the goal of the STEP-BD depression psychosocial treatment trial and how did it fit into STEP-BD?

A. The study reported in the April 2007 issue of the Archives of General Psychiatry describes the results of a clinical trial examining the effectiveness of four psychosocial interventions for people with bipolar disorder who are experiencing a depressive episode. The clinical trial was part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) research program, the largest, federally funded treatment trial ever conducted for bipolar disorder. STEP-BD enabled researchers to explore a range of treatment options related to bipolar disorder, including mood-stabilizing medications, antidepressants, atypical antipsychotic medications, and psychosocial interventions (talk therapies).

Once enrolled in the STEP-BD program, participants aged 15 or older received individualized care from their STEP-BD treatment provider that included the best available treatment options. This approach was called the Best Practice Pathway. Participants in the Best Practice Pathway who were age 18 or older and whose depression did not improve or who experienced a new depressive episode, could enter the randomized clinical trial that examined the effectiveness of different combinations of medication and psychosocial therapy for the depressive phase of bipolar disorder.

In this one-year randomized clinical trial, the goal of the psychosocial study was to determine if receiving intensive (and long-term) treatment with any one of the three psychosocial therapies offered in STEP-BD was more effective in relieving bipolar depression than receiving treatment with a brief, short-term talk therapy intervention.

2. Q. Why is the psychosocial treatment trial important?

A. Although various treatments currently are available for treating bipolar disorder, including medications and talk therapies, it is not known if psychosocial interventions, when received alongside medication, can help relieve bipolar-related depression and keep patients well in typical, real-world clinical settings. In addition, most previous clinical trials were conducted in single academic centers and included carefully selected groups of research participants who may be different from the people seeking care in everyday practice settings.

In this regard, the psychosocial treatment study in STEP-BD is unique because it included “real world” patients experiencing the early phases of a depressive episode, who were already receiving care for their bipolar disorder as part of STEP-BD. The therapists who delivered care in the psychosocial treatment study received STEP-BD training in the different psychosocial therapies by experts in the field. The training and ongoing supervision was of low intensity, consistent with what is typically available in clinical practice.

3. Q. How were participants selected for inclusion in the psychosocial treatment trial?

A. While enrolled in the STEP-BD Best Practice Pathway, participants were evaluated for depression at every follow-up visit. These clinic visits recorded and tracked participants’ treatment and assessed their symptoms and clinical status for the duration of participation in the study. If the study participants experienced a depressive episode, they could choose to leave the Best Practice Pathway and enter the randomized portion of STEP-BD; 366 participants did so.

The randomized acute depression study lasted 26 weeks and addressed the question of whether adding an antidepressant medication (buproprion or paroxetine) to an existing mood stabilizing medication is more effective for treating acute bipolar-related depression than adding a placebo pill. All participants in this portion were required to be on a mood stabilizing medication, such as lithium, valproate, carbamazepine or other mood stabilizer approved by the U.S. Food and Drug Administration.

These 366 participants also had the option of participating in the randomized psychosocial treatment study in which they would receive psychosocial treatment in addition to their medication treatment. Of the 366 participants who entered the randomized depression trial, 236 chose to enter the psychosocial portion. In addition, 57 STEP-BD participants who were enrolled in the Best Practice Pathway, but who were not part of the medication portion of the randomized depression trial, chose to enter the psychosocial study as well. Altogether, 293 participants took part in the psychosocial treatment study. Many of those who chose not to participate in the psychosocial portion of the study were already receiving psychotherapy on their own.

4. Q. What psychosocial interventions did participants receive?

A. Researchers randomly assigned participants to receive either a short-term collaborative care intervention or one of three longer-term intensive therapies that have been shown to help stabilize bipolar symptoms—cognitive-behavioral therapy (CBT), interpersonal and social rhythm therapy (IPSRT), or family-focused treatment (FFT). Collaborative care was considered the “control” intervention, meaning that the outcomes of this therapy were used as a baseline by which to compare the other three intensive therapies. All of these therapies focused on education about the illness, relapse prevention planning, and bipolar illness management interventions, and all but collaborative care consisted of up to 30, 50-minute sessions that took place over nine months.

Collaborative care, which consisted of three, 50-minute sessions over six weeks, provided participants with a workbook, an educational videotape and other information that aimed to help them understand and manage the illness, maintain adherence to medications, and develop a treatment contract geared toward preventing bipolar episodes.

In the CBT intervention group, participants received education about the illness. They learned to challenge negative thoughts or beliefs about bipolar disorder or its associated stressful life circumstances, developed schedules to stay active, and developed strategies to detect and cope with mood swings.

The focus of IPSRT was on attaining and maintaining regular social rhythms (daily routines and sleep/wake cycles) and the relationship of daily activities to mood and levels of social stimulation. IPSRT therapists encouraged participants to keep track of their daily routines (e.g., when they went to sleep, when they woke up, etc.) while working toward establishing stable social rhythms. Patients also worked to resolve key interpersonal problems related to grief, role transitions, interpersonal disputes, or interpersonal skill deficits.

In FFT, participants and their relatives (e.g., spouses and parents) were taught an understanding of bipolar illness, its course, treatment and management. Family members were taught how to recognize early warning signs that might predict an oncoming depressive or manic episode in the person with bipolar illness, and strategies to intervene when these warning signs occurred. Treatment included enhancing communication between the participants and their family members to improve the quality of family interactions, and problem-solving to manage conflicts related to the illness.

5. Q. What do the results from the STEP-BD psychosocial treatment trial tell us about the treatment of bipolar disorder?

A. The outcome measures that were used to evaluate success of the treatments were “time to recovery” (e.g., how quickly did people get well) and the total amount of time during the study year that participants remained “well” (measured by the probability of being well during any given month). To be considered “well” in the study, participants had to have no more than two symptoms of mild or moderate mania or depression.

Of the 293 STEP-BD participants in the psychosocial treatment study, 59 percent recovered from their depression; 41 percent either did not recover or left the study early.

Over the course of the study year, participants in the intensive psychotherapies (FFT, IPSRT, CBT) had a more successful recovery rate (64 percent) compared to the individuals in the collaborative care group (52 percent). Also, participants in the intensive psychotherapies who recovered did so faster (on average, after about 113 days) than those in the collaborative care group (after about 146 days). Furthermore, the participants in the intensive psychotherapies were one and a half times more likely to remain well during any given month of the study year than those in the collaborative care group.

The study also showed that in each of the four psychosocial treatment groups, participants who were also enrolled in the randomized medication portion of the trial got well faster than those who were not, even though all patients were receiving some type of medication. In addition, recovery time was faster in all four groups for those participants who had family supports available.

Differences among the three intensive psychosocial interventions were not statistically significant, but they are worth noting. Over the yearlong study, 77 percent of participants in the FFT recovered, compared to 65 percent of participants in IPSRT and 60 percent in CBT.

6. Q. What do the results mean for people with bipolar depression and the doctors who provide care for them?

A. This one-year study showed that, in conjunction with adequate mood stabilizing medications, intensive psychotherapy is more effective in helping people recover from a depressive episode, and stay well over a one-year period, than a brief collaborative care treatment. All three types of intensive psychosocial treatments had comparable benefits.

Overall, psychotherapy appears to be a vital part of the effort to stabilize episodes of depression in bipolar illness. These findings should help clinicians plan treatments for individuals recovering from an episode of bipolar depression.

Antipsychotic medicines are sometimes used together with mood stabilisers to help treat an episode of high mood (mania).

They are used as an initial treatment to help control the symptoms while the mood stabiliser begins to work.

Antipsychotic medicines can also treat mania with psychotic symptoms such as hallucinations, delusions or hearing voices.

The antipsychotic is usually stopped once the symptoms are under control, and treatment is continued with mood stabilisers.

However, some antipsychotics may also stabilise mood, and these medicines have a role as maintenance treatments to prevent episodes of ill health.

There are two types of antipsychotic medicine:

• typical antipsychotics
• atypical antipsychotics.

How do they work?

Antipsychotics are sometimes described as ‘major tranquillisers’, but this term is fairly misleading, as this type of medicine is not just a tranquilliser, and any tranquillising effect is not as important as the main way they work in psychiatric illness.

Recommended

Xanax (alprazolam)

Antipsychotic medicines work by affecting the activity of chemicals called neurotransmitters that are found in the brain. In particular, they decrease the activity of dopamine, a neurotransmitter that is involved in controlling mood and behaviour.

Levels of dopamine have been shown to be raised in the brains of people going through a manic episode, and blocking the activity of this dopamine is thought to be the main way in which antipsychotic medicines work to control manic symptoms.

How long do they take to work?

Antipsychotics work very quickly to control manic behaviour, particularly if they are given by injection.

Once the manic episode is controlled, the length of time the antipsychotic is continued for depends on individual circumstances, including whether the medicine will be continued long-term as a mood stabiliser. In any case, treatment should not usually be stopped abruptly as this could cause the manic symptoms to come back, or on rare occasions, withdrawal symptoms.

People who will be continuing treatment with other mood stabilisers may have their antipsychotic dose tapered down over a four week period. People who will not be continuing other mood stabilisers may need to reduce their antipsychotic more slowly – usually over three months – to avoid a relapse.

Typical antipsychotics

This is the older group of medicines that includes drugs such as haloperidol (eg Haldol) and chlorpromazine.

These medicines are very effective for controlling episodes of mania, but are less commonly used because they can have many unpleasant side effects. The most troublesome are abnormal involuntary facial and body movements that can occur after just a few doses.

Other side effects include:

• drowsiness and sedation
• muscle tremor and rigidity
• agitation
• insomnia
• dry mouth
• constipation
• blurred vision
• confusion
• dizziness
• effects on the heart
• weight gain
• impotence
• increases in levels of the hormone prolactin that may result in development of breasts and milk production.

Atypical antipsychotics

Atypical antipsychotics are newer medicines that are more likely to be used than the older antipsychotics. They are better tolerated than the older antipsychotics because they have fewer troublesome side effects.

Atypicals include medicines such as aripiprazole (Abilify), clozapine (eg Clozaril),olanzapine (Zyprexa), quetiapine (Seroquel) and risperidone (Risperdal).

Aripiprazole, olanzapine, quetiapine and risperidone are all licensed to treat episodes of mania.

Aripiprazole and olanzapine are also licensed to prevent recurrence of mania in people whose manic episode responded to initial treatment with the medicine.

Quetiapine is licensed to prevent both manic and depressive relapses in people whose manic, depressive or mixed episode responded to initial treatment.

Clozapine is reserved for treating people with bipolar disorder who are highly unresponsive to other drugs, because it can cause serious side effects on the blood. It requires regular monitoring with blood tests.

Further research is ongoing into the use of atypical antipsychotics in bipolar disorder and particularly in bipolar depression.

Atypical antipsychotics cause less abnormal body and facial movements than the older drugs and have less effect on prolactin levels, though they still have the potential to cause these problems. Other side effects include:

• sleepiness and sedation
• weight gain
• raised blood sugar levels and diabetes
• raised cholesterol levels
• sexual dysfunction
• abnormal heart rhythms
• dry mouth
• constipation
• blurred vision
• drop in blood pressure and dizziness on standing up.

During long-term treatment with atypical antipsychotics your doctor will want you to have regular check-ups to monitor things such as the levels of glucose, lipids and prolactin in blood count.

Bottom line: there are at least 9 alternatives with at least as much evidence as antidepressants for effectiveness in bipolar depression, that don’t make bipolar disorder worse, as is clearly a risk with antidepressants. So most of these questions are nearly moot, in my opinion. Just skip the antidepressants unless you’re backed into them by not getting better on less potentially risky stuff.  But that’s not widely agreed upon, even after 10 years of direct study. Here are the specific areas of controversy.

1. Do antidepressants even work in bipolar depression? Yes, but it’s not very well, except perhaps in Bipolar II, depending on who you listen to. 
2. Can antidepressants trigger manic symptoms? Yes, that’s completely agreed upon. But how often? That’s not agreed upon at all.
3. Are antidepressants “mood de-stabilizers” ? This is a crucial question, at least as important as #2. Answer: uh, it’s complicated?
4. If you’re on an antidepressant and doing well, should you stay on or taper off?  First, don’t do anything without talking with whoever prescribed it.  If you have more than 4 mood episodes per year — then maybe taper off? Careful here!

1. Do antidepressants even work in bipolar depression?

No. Yes. Maybe. Only in Bipolar II. Depends on how long you watch — and how you define “work”.

Let’s try that again. There are two big lines of research about this. In one, which led to a formal study that took years and was supposed to answer this question directly, antidepressants were no better than placebos for bipolar depression.^Sachs

But in a whole series of studies in Bipolar II (no Bipolar I patients in these studies), antidepressants not only worked better than placebo, they worked better than lithium! (The Amsterdam studies; more on those herein).

Overall, nearly everyone would agree: it’s suprising how little evidence we have in support of using antidepressants for bipolar depression, especially given how often they’re used. When there’s very little evidence to consider, it’s easy for controversies to persist. Thus there are loud voices on both sides of this issue.

But in 2013 the International Society for Bipolar Disorders (ISBD) issued a very clear set of recommendations.^Pachiarotti Simplified: don’t use antidepressants, except in patients who’ve:

1. done well on them before
2. get worse when they’re stopped
3. have bipolar II (noting even this is controversial)

And finally, in 2014 editorial entitled “Never without a mood stabilizer”, a highly respected researcher asks strongly why:

• 35% of bipolar patients get antidepressants without mood stabilizers
• antidepressants aren’t stopped when patients are manic
• antidepressants are given when patients are in mixed states ^Vieta   

More on this controversy…

2. Can antidepressants trigger manic symptoms?

Yes. Almost universal agreement. But, how often does this happen? Some say 4% of the time^Gjisman, some say 44% of the time^Truman in some circumstances. Yet it doesn’t really make much difference, you see:   yes, there is significant risk, at least 1 per 25 users, maybe more like 1 per 3 or even 1 per 2 for some people.  But because there are at least 9 alternativesto using an antidepressant to treat bipolar depression, most patients with bipolarity do not have to decide whether to take the pro-mania/hypomania risk of an antidepressant. They can just use something else.

Here are some groups of people who are at greater risk for having hypomanic or manic symptoms if they use an antidepressant:

• Bipolar I
• Female
• Frequent mood shifts (e.g. monthly or more often)
• It happened before
• It happened to someone in your family
• Someone in your family has bipolar disorder
• Your first depression was between the ages of 18 and 24
• You’ve had a post-partum depression
• You’ve been psychotic without street drugs

More on this controversy…

But remember: there are at least 9 alternatives.

3. Are antidepressants “mood de-stabilizers” ?

Quoting from an editorial in the American Journal of Psychiatry, March 2008, by Nassir Ghaemi, one of the principal investigators in the STEP-BD, a large bipolar research trial (emphases mine):

Mood destabilization with antidepressants should be distinguished from an acute manic “switch.” Antidepressant-induced mania, or switch, is a short-term phenomenon; one might define it as happening within 2 months of the beginning of antidepressant treatment. Mood destabilization is a long-term phenomenon, reflecting more mood episodes over time than would have occurred by natural history.

Antidepressants may cause long-term mood destabilization without a short-term manic switch, and vice versa. Although some agents may have low rates of acute manic switch, especially when used with mood stabilizers, the data from STEP-BD suggest that even the new generation of antidepressants can produce long-term mood destabilization.

In that editorial, Dr. Ghaemi also emphasizes an approach I’ve been espousing for years: if a mood stabilizer is tried with an antidepressant also in use at the same time, and the mood stabilizer “doesn’t work”, that was an unfair trial of the mood stabilizer. It will need to be tried again later with no antidepressant in the picture.

If you’re skeptical about these conclusions I’ll show you some data I think supports them, but it’s pretty technical stuff.  Before I invite you there, does anyone think antidepressants have a stabilizing effect? Well, in Bipolar II,  Dr. Gordon Parker thinks so.^Parker So do Drs. Amsterdam and Shults, whose 2013 study is similar but much bigger (however, read the Comments you’ll see linked at the bottom of their abstract; very telling, I think.)

I think they’re right, that antidepressants can have a stabilizing effect — for a while.  Consider two cases.

When people ask me “how long does it take for an antidepressant to cause manic or hypomanic symptoms?”, I answer with the experience of two patients. First, one guy told me “20 minutes after my first dose of Paxil I felt like I was shot out of a cannon.” So that’s the fastest it can happen, I figure.

The second I wrote up as a case report, it was so telling. ^Phelps One of my patients went 7 years on sertraline/Zoloft, doing really well, much better than on other antidepressants she’d tried. She’d “joined the human race”, she said, after years of depression. Then she developed anxiety. So her primary care provider increased her antidepressant (because antidepressants are used to treat anxiety; not an unreasonable move).

Ka-boom, she had horrible anxiety, agitation (like wanting to crawl out of her skin), suicidal ideation, terrible insomnia, and restlessness). This did not subside until she tapered off sertraline, despite desperate attempts with a bunch of medications including antipsychotics, anti-anxiety medications, and mood stabilizers. But the clincher was when she tried, about a year later, going back on sertraline, trying to get that “normal” feeling back.  One quarter of the dose she did so well on for 7 years produced the same agitated state within three days.

So, I think antidepressants can work quite well, for a while. Somewhere between 20 minutes and 7 years… But then they can cause mixed states and suicidal ideation, at least in some people. How many people? that’s a complete unknown. I don’t get to see the folks who are doing great years later, so I can’t judge by all the patients I see whose antidepressants seem like part of the problem. My colleague Dr. Manipod and I published a case series of 12 people who looked “unipolar”, i.e. not bipolar, but who got much better when their antidepressant was stopped.^{Phelps/Manipod} 

Other colleagues have reported similar findings, e.g. 15 more cases.^Sharma One has gone so far as to publish a couple of papers describing what he calls “tardive dysphoria” .  Short explanation of the term: he’s describing what happened to my patient above who did so well on sertraline for 7 years. ^El-Mallakh 

Want to see more data on this question? Dr. Ghaemi refers to two randomized trials.  More….

     (3b: Kindling and Long-term Worsening)

Could antidepressants cause kindling”? The phrase “kindling” is borrowed from neurology, where it has been used to describe forms of epilepsy, which appear to worsen with time. In this model, it is as though each episode of illness makes later episodes both more likely and more severe. It is clear that some patients’ bipolar disorder worsens as they get older, with more frequent and more severe episodes. Could this kind of pattern be triggered by antidepressants, at least in some susceptible patients?  This is hard to study, but some evidence supports kindling, at least^Kemner; the antidepressant question is harder to nail down.

Here is good visual example of the phenomenon we’re talking about here. The graph shows the mood episodes of a man whose bipolar disorder seemed to clearly worsen with time (his age is shown at the bottom of the timeline; red means hospitalized, up is manic and down is depressed, of course):

Note the pattern: after each episode, the next episodes tend to come sooner and become more severe. This is the “kindling” pattern, though this man’s experience alone of course does not prove that the illness itself can do this. There could have been some other factors, such as alcohol or other drugs, etc.

However, suppose some forms of bipolar disorder really do “kindle” themselves. If that is so, then any worsening has the potential to be a “permanent” worsening. What if the patient above had been treated with psychotherapy at age 18, during that first depression? Compare what might have happened if he had been given an antidepressant, triggering a manic episode: might his graph have changed from the course we saw just above (a real patient’s experience):

to this (a hypothetical example):

The difference, as you can see, is that this hypothetical patient lost 5 years of symptom free life. And he arrives at a nearly continuous course of illness by age 35, instead of age 40.

This “kindling” concern is very rarely raised in the bipolar literature, at least as regards the risks of antidepressants. Wouldn’t you think that if antidepressants could really cause or accelerate the course of bipolar disorders, that we should be freaked out about using them? and really careful to indentify anyone who might have that happen to them?  But no, it’s not a big deal in the literature.

So I invited people to tell their story, if it had happened to them. The good news is that over years, I received only a handful. Here’s one that seems to me a perfect example. But remember, he’s only one case and there were plenty of people who read that invitation.

Mr. B (direct quote from an email, used by permission):

Before my first use of an antidepressant, I had never suffered mania. I had been diagnosed with depression and anxiety, but not bipolar disorder. I was prescribed Lexapro for anxiety (I had never used psychiatric medication before) and used it for five or six days, taking a small dose (half tablet each day). It induced mania so I was hospitalized for a week or so.

 

Since then, I have steadily had irrational grandiose thoughts. In hindsight, I can see that I had some irrational grandiose thoughts before my Lexapro use, but since my Lexapro use they are far stronger. As far as permanence goes, so far I have not noticed any improvement at all coming simply from time passing (although therapy and other active approaches have been helpful). I had a second manic episode less than a year later (I was not on any medication at the time).

So there’s one case. There is also one published example of a patient given steroids for colitis, with a similar course.^PiesHere’s another widely regarded expert expressing the same concern — in a different contex, but same resulting worry, from a 2008 New York Times article…

Kiki Chang, director of the pediatric bipolar-disorders program at Stanford, has embraced the kindling theory. “We are interested in looking at medication not just to treat and prevent future episodes, but also to get in early and — this is the controversial part — to prevent the manic episode,” he told me. “Once you’ve had a manic episode, you’ve already crossed the threshold, you’ve jumped off the bridge: it’s done. The chances that you’re going to have another episode are extremely high.”

More…

4. If you’re on an antidepressant and doing well, should you stay on or taper off?

Three studies address this issue directly — and they have different conclusions! Make sure you know about the second one, the results of which are a more reliable guidepost by standard criteria for judgement (randomized trials trump naturalistic studies).

1. Altshuler et al , Am J Psych 2003 – naturalistic
2. Ghaemi, STEP-BD – randomized
3. Altshuler et al, J Clin Psych 2009 – randomized? no, even though it looks like it

Bottom line: the randomized trial says “if you have had rapid cycling (more than 4 mood episodes in a year), you should try tapering off.” For patients with more rare episodes, they actually did slightly better staying on (but not much, and it’s another long-term medication to carry, so I figure even those folks ought to try tapering off at least once, really really slowly).

For more, we’re digging into those studies, if you’re up to it: more….

 Conclusions

1. There are a lot of alternatives to antidepressants for the treatment of bipolar depression, most of which have at least as much evidence for their effectiveness in bipolar depression as antidepressants do. Use those alternatives first, all that are workable (some may not be) — especially if you’ve already had several antidepressants and you’re not better. Here’s a page with nine such alternatives.

2. Do not use antidepressants if rapid cycling or severe insomnia/agitation/irritability is already present.

3. Almost every patient with bipolar disorder who is taking an antidepressant deserves a trial off of that antidepressant to see if things are more stable (or at least, no worse). When trying this, taper off the antidepressant very slowly: four months, 25% per month, is a good rate (agreed upon in 31 ways by two psychiatrists!).

It’s one of the most missed diagnoses in psychiatry. Bipolar disorder, involving moods that swing between the highs of mania and the lows of depression, is typically confused with everything from unipolar depression to schizophrenia to substance abuse, to borderline personality disorder, with just about all stops in between. Patients themselves often resist diagnosis, because they may not see as pathologic the surge in energy that accompanies the mania or hypomania that distinguishes the condition.

But on a few points consensus is emerging. Bipolar disorder is a chronically recurring illness. And the age of onset is dropping—in less than one generation it has gone from age 32 to 19. Whether there is a genuine increase in prevalence of the disorder is a matter of some debate, but there does seem to be a genuine increase among the young.

What’s more, the depression of manic-depression is emerging as a particularly thorny problem for both patients and their doctors.

“Depression is the bane of treatment of bipolar disorder,” says Robert M.A. Hirschfeld, M.D., head of psychiatry at the University of Texas Medical Branch in Galveston.

It’s what is most likely to motivate patients to accept care. People spend more time in the depression phase of the disorder. And unlike unipolar depression, the depression of bipolar illness tends to be treatment-resistant.

“Antidepressants don’t work very well in bipolar depression,” says Dr. Hirschfeld. “They are underwhelming in their ability to treat the depression.” In fact, a shift away from antidepressants is formally recognized in new treatment guidelines for bipolar disorder just released by the American Psychiatric Association.

As physicians gain experience in treating the disorder, they are discovering that antidepressants have two negative effects on the course of the disorder. Used by themselves, antidepressants can induce manic episodes. And over time they can accelerate mood cycling, increasing the frequency of episodes of depression or of mania followed by depression.

Instead, research points to the value of drugs that work as mood stabilizers for the depression of bipolar disorder, either alone or in combination with antidepressants. If antidepressants have any use at all in bipolar disorder, it may be as acute treatment for bouts of severe depression before mood stabilizers are added or substituted.

Even in cases of severe depression, the new guidelines favor increasing the dosage of mood stabilizers over other strategies.

Not so long ago, mood stabilizers could be summed up in a single word—lithium, in use since the 1960s to tame mania. But research has additionally demonstrated the effectiveness of divalproex sodium (Depakote) and lamotrigine (Lamictal), drugs that were initially developed for use as anticonvulsants in seizure disorders. Divalproex sodium has been approved for use as a mood stabilizer in bipolar disorder for several years, while lamotrigine is undergoing clinical trials for such an application.

“Optimizing the dose of lithium or divalproex has good antidepressant effects,” reports Dr. Hirschfeld. “We also now know that divalproex and lamotrigine are very good for preventing recurrence in bipolar patients.” A study showed that lamotrigine not only delays the time to any mood events but is notably effective against the depressive lows of bipolar illness.

No one knows for sure exactly how anticonvulsants work in bipolar disorder. For that matter, the condition has been described since the time of Hippocrates, but it is still not clear what goes awry in manic-depression.

Despite the unknowns, medications for treating the disorder are proliferating. In contrast to downplaying antidepressants in the depressive phase of the disorder, clinical research is ramping up the value of antipsychotic drugs for combating the manic phase, albeit a new generation of such drugs, collectively called atypical antipsychotics. Chief among them are olanzapine (Zyprexa) and risperidone (Risperdal). They are now considered a first-line approach to acute mania, and adjuncts for long-term therapy along with mood stabilizers.

In the long term, however, observes Nassir Ghaemi, M.D., assistant professor of psychiatry at Harvard and head of bipolar research at Cambridge Hospital, medication goes only so far. “Drugs are not effective enough. It may have to do with the overuse of antidepressants; they interfere with the benefits of mood stabilizers.

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“Medications don’t take you to the finish line.” There seem to be residual symptoms of depression that don’t clear. Even when patients stabilize into a normal, or euthymic, mood state, he says, some troubling signs can appear.

“Sometimes we see in euthymic patients cognitive dysfunction that we didn’t expect in the past—word-finding difficulties, trouble maintaining concentration,” Dr. Ghaemi explains. “Cumulative cognitive impairment seems to emerge with time. It may be related to findings of decreased size of the hippocampus, a brain structure that serves memory. We are on the verge of recognizing long-term cognitive impairment as a result of bipolar disorder.”

He believes there is a role for aggressive psychotherapy for keeping patients well, for keeping everyday ups and downs from becoming full-blown episodes. At the very least, he finds, psychotherapy can help patients resolve the work and relationship problems that often outlast symptoms.

In addition, psychotherapy can help patients learn new coping styles and interpersonal habits. “Many of the ways patients deal with their illness are not relevant when they are well,” explains Dr. Ghaemi.

For example, he says, many people develop the habit of staying up late as a way of coping with the manic symptoms. “What they couldn’t change before because of the illness needs to be changed after treatment if, for example, it bothers a spouse. People have to learn to change. But the longer one is ill, the harder it is to become completely well, because the harder it is to change the habits of one’s life.”

And for young people diagnosed with bipolar illness, he considers psychotherapy essential. “The younger patients are, the less convinced they are that they have bipolar disorder,” he says. “They have impaired insight. They’re especially concerned about the need to take medications. They should be in psychotherapy to get educated about the illness and medication.”

He also stresses the value of support groups, especially for young people. “It’s another, important layer of validation.”

Below you will find a list of the medications currently referred to as “mood stabilizers” , or at least regularly named as treatment options for bipolar disorder. (Here are some thoughts on what ought to be called a “mood stabilizer“).

Pregnancy reminder/warning: with the probable exception of fish oil and low-dose thyroid, none of these options is known for certain to be safe during pregnancy. The strategy for women wanting to become pregnant is very complicated and requires a knowledgeable psychiatrist. Therefore: any woman taking any of the medications below should have avery reliable plan for avoiding pregnancy (you know how that works, I’m sure you do . . . Oh, I suppose I could add the old adage: “if in doubt, ask your doctor”).

You can click links in the first table below for details about each one (or you can walk you through how the main medications are used, and how we choose between them, in the Treatment section of this website). If you’d like to see them listed by how you might choose, based on your needs, see the second table. If you’d like a comparison of all of them, try the third table.

To make sure this information matches current other mood specialists’ opinion, compare my lists to the recently updated expert consensus guidelines.

Before we begin, let’s just take a couple of medications off the table, because randomized trials showed them no better than a placebo in the treatment of bipolar disorder (they have other uses, and benefits, but they aren’t “mood stabilizers”): gabapentin/Neurontin; topiramate/Topomax; and tiagabine/Gabatril.

Table of the main options

Use the links in the table to get more information on each medication.  Each column shows what makes the medication in that group distinctive. These are generalizations, and my opinions — but overall I think these are fair classifications.

*along with all the traditional “antidepressants” like fluoxetine/Prozac, sertraline/Zoloft, etc., etc.

**here’s an essay on why randomized trials are so important in evaluating treatments, from panic disorder research

Gets pretty confusing, doesn’t it? It used to be simpler, just lithium and divalproex, maybe carbamazepine if those didn’t work. Now we have all these choices.

However, for Bipolar II, one option really stands out, in my view: lamotrigine/Lamictal. Until 2008, I could not state this strongly because I was using the manufacturer’s money to support my talks about bipolar disorder (see Funding). I had to hold back lest I seem biased by their money. But now lamotrigine is generic, and their marketing efforts are over. Since I will not be taking any money from GlaxoSmithKline (haven’t since 2008), I can finally speak with my full enthusiasm about lamotrigine.

Think about it: in Bipolar II, the main problem is repeated episodes of depression. That is precisely what lamotrigine is best at treating. Secondly, lamotrigine does not cause weight gain. Nearly all of the other options can cause very significant weight gain. The weight issue alone propels lamotrigine to the very top of the list, as long as no anti-manic component is crucial (because it does not protect against manic symptoms, except indirectly, by preventing cycling. The anti-cycling effect can be enough, fortunately, for many people). Third, lamotrigine causes no side effects at all in the vast majority of people who take it (there are always a few who will get something, headache or hair loss perhaps). Fourth, to our knowledge at present, there are no major long-term risks of staying on lamotrigine for years. It has been used for nearly 15 years as an anti-seizure medication, so we have a pretty solid basis for concluding that long-term use is relatively safe. Only a few other mood stabilizer options have this many years of observation, and each of them has recognized long-term problems. taken together, all of these factors make lamotrigine the obvious best choice amongst mood stabilizers — as long as you do not need an anti-manic component.

Yet some people will not respond to lamotrigine, and about one in 20-30 people will actually get worse on it. (Worse? yes, in my experience, and that of numerous other psychiatrists who have used a lot of lamotrigine; the worsening is an increase in anxiety, irritability, or sleep problems, as though a lamotrigine was acting too much like an antidepressant). So, many people will have to consider or move on to other mood stabilizer options. How to choose among these?

How might you choose?

The table below presents another way to view this choice, followed by a more detailed discussion of each option. Please understand that these are only suggestions based on the literature and experience with patients, not “guidelines” for choosing.

Where to start?

Here’s a more wordy, more referenced version of the table you just read.  (Do you really need this?)

Since the BALANCE study by a wonderful collaboration of investigators led by two great British researchers^Geddes (you can tell I think these guys are great to have set this up and run it), this question is a little easier. Lithium and valproate/divalproex had been running neck-and-neck for years for “where to start?” In this study, the combination was best but if you were to start with one alone, lithium was well ahead of valproate/divalproex.

Lithium has a clear track record of reducing the risk of suicide, which can be as high as 10% in bipolar disorder. But valproate may have a slight edge in treating “mixed state” symptoms and rapid cycling.^Bowden You should start by educating yourself about the benefits and risks of each (use links from first table above). Ending up on low doses of each is very common.

Lithium is even effective as an “add-on” medication in unipolar and “treatment resistant” depression, so can be a good approach when a bipolar component is not crystal clear. Lamotrigine has been stunningly effective, in my experience, for patients whose mood problems look like “highly recurrent unipolar” or “recurrent depression with just a hint of or rare hypomanic phases” — that is, where depression is by far the more predominant problem.

On the other hand, if sleep problems and anxiety are prominent, valproate/divalproex/Depakote may be a better starting place: it almost always helps at least a little with insomnia, even at the low doses discussed here (unless you are on an antidepressant). We have a great deal of experience with it, and we know what problems to anticipate; and we know from years of experience that it works, especially when irritability and lability (changeable, brittle moods) are present, or when anxiety is prominent. But it now seems clear that divalproex can cause a hormone problem called polycystic ovarian syndrome in women of reproductive age (here are those PCOS data), so I generally use it only in men and post-menopausal women.

Oxcarbazepine/Trileptal caught everyone’s attention when it became available in the United States (after nearly 10 years in Europe). Because carbamazepine can be so tricky to use because of side effects (risks as well as nuisance symptoms), oxcarbazepine looked really good at first. It has less risk than carbamazepine and fewer side effects initially (more later, though). Oxcarbazepine is somewhat similar to carbamazepine in terms of those who it helps, though there is concern that it just doesn’t have as much “punch”, i.e. that is is not as fully effective. Every time I revise this I have fewer patients on Trileptal alone. I think it might be zero, or very close, now.

(Some of you might be old enough to remember a Bud Light commercial in which football guys debate: “tastes great!” vs. “less filling!”  Well, oxcarbazepine has been called “Carbamazepine Light”: “less side effects!” vs. “less effective“!  You can tell I’m not a big fan. But the child/adolescent psychiatrists use it a lot: no blood tests)

Finally, olanzapine /Zyprexa has been shown to be a very effective mood stabilizer.^Tohen But it causes dramatic weight gain in a very large number of people who take it, and it can cause diabetes in some cases even without extreme weight gain. ^{Gianfrancesco},^{Caro, Hedenmalm} However, for short term almost immediate control of severe symptoms, this is an outstanding medication: people can feel benefit within an hour, and other than weight gain, there appear to be very fewshort-term risks with this medication. Long-term is a different story.

So, the bottom line here is: learn about your options and work closely with your doctor making the choice among them (here’s that essay on how to talk to your doctor again).

Which one is the best?

For one more way to look at all these options, here are the same medications listed by their specific advantages. Some of these advantages might be more important to one person than another. There really is no “best one”. Over time, you might end up taking several of them, one at a time or together.

Warning — the following table is subjective in some places, based on my personal experience: see the notes below. For simplicity, only significant benefits are listed (negatives are even more subjective and are not ranked, just left as blanks). Sorry about all the notes. Somebody was going to ask or raise a fuss otherwise. Here’s the key:

And the table:

Further comments on this last table:

1. This is based on my experience using these medications. It is nearly impossible to compare these medications directly in an objective way. Low dose lithium would merit a ” + ” on this scale; high dose lithium is probably the worst on this list for short-term side effects, setting the standard by which to judge the rest. Clozapine would be similar to high-dose lithium. Lamotrigine gets one ” + ” because apart from the significant risk of a severe skin rash, it has very few other common side effects.

2. Similarly, long term risk is a subjective matter, though perhaps less so than the common immediate side effects. Lamotrigine gets a ” + +” because its main risk, the rash, was listed as an immediate side effect problem; beyond 8 weeks the rash risk falls to very low levels.

3. Some might consider Zyprexa and perhaps other new-generation antipsychotics as safe in pregnancy.  The Harvard Women’s Mental Health clinic does not. It’s easier to say which are clearly not safe: lithium, divalproex, and carbamazepine. Oh, that’s interesting, notice that’s all the old ones? Maybe it just takes that long to really find out what’s safe?

4. Valproate and carbamazepine have been listed by the American Academy of Pediatrics as safe for breastfeeding but a more recent review by Chaudron and Jefferson ^Chaudron calls this into question because the number of infants studied was so small, and there were some problems observed in a few children among those small groups. This leaves no mood stabilizer clearly safe for use while breastfeeding — except for maybe lamotrigine.^MGH  Fish oil in the doses used in research studies has not been studied. There is reason to think it might be safe — possibly even beneficial^Innis — in both pregnancy and breastfeeding, at least at doses approximating human historical fish consumption.

FDA approved or not

The FDA has approved few of these medications for the treatment of bipolar disorder. Why not? Here’s a short version of a complicated answer.

A medication cannot be advertised for a specific purpose (like treating bipolar disorder) until it is FDA-approved for that purpose. To get FDA approved, strict research guidelines must be met, including the “gold standard” randomized controlled trial as described above on this page. These trials cost millions of dollars. So if the manufacturer is not in a position to earn millions of dollars from promoting use of their product, there is a strong reason not to bother to get FDA approval — it costs them money they’ll not see coming back in return.

Therefore the FDA-approved drugs are those where the manufacturer stands to benefit by supporting the expensive research. These tend to be the newer drugs — because the patent may have run out, or will soon, on many of the older medications. So these older drugs (e.g. carbamazepine; Trileptal; verapamil; and certainly thyroid) are not likely ever to be “FDA approved”.

Therefore all the medications above except lithium, Depakote, Zyprexa and Lamictal are used “off label” in bipolar disorder (7/2004). This does not mean they don’t work, or carry more risk than other options. Those medications which have been around a long time may actually be even better understood in terms of their risks, such as carbamazepine. However, FDA approval does tell you that the medication has been studied directly for the purpose described and meets rigorous standards of evidence. (well, fairly rigorous, anyway. Watch out, here comes a Phelps’ Soapbox, you can probably safely leave now…)

Lately companies have been using a research approach called “enriched design” which massively biases the results in favor of their medication. The FDA approved their drugs based on such research. Unfortunately, one of the medications that I find especially
effective was studied in this way, lamotrigine. It would be very nice to see this particular medication studied under truly “randomized” conditions, as I think it would still come out looking great. But to do the research this way means the company runs the risk of spending millions of dollars for results that don’t look so hot, as occurred in the biggest long-term study of Depakote, scaring a lot of companies into using this looks-scientific-but-takes-fewer-risks design. To their credit, the makers of quetiapine did not do this in their recent longer-term research. Interestingly, the same brilliant guy, Joseph Calabrese, directed both studies. It would be really interesting to know how these design choices were made. Ah well, they certainly aren’t listening to me go on and on; so let’s move on . . .

Have a look at the three main mood stabilizers — well, in my practice, anyway.

Specifics: lamotrigine

A few more details to add to my favorable diatribe above:

Just don’t be in a hurry. The primary risk of this medication is a bad rash, Stevens Johnson Syndrome. It can be bad enough to put you in the hospital, in the intensive care unit. It is like having a severe burn. The risk of this reaction is generally given as about one in 1000, although some experts use a number as low as one in 3,000. On the other hand, if you have had allergic reactions to other medications in the past, the risk might be higher, e.g. maybe even like double — two in a thousand.  See what I mean? it’s a small risk; you can double it and it’s still small.  But it’s bad. And the risk is dramatically increased if you go faster than the usual manufacturer recommendations. So don’t be in a hurry.

Here are my slightly-more-conservative-than-the-manufacturer’s-recommended starting doses:

Your doctor will need to prescribe about 100 25 mg pills for this slow increase, then a 200 mg pill once daily. However, you must not miss more than three doses of this medication in a row, where you have to start the increase all over again from the beginning. If after four days or more of missed doses you just jump in again at the full dose you were supposed to be taking, you have a risk of getting the Stevens Johnson Syndrome rash much like when you started. So make surethat you do not run out.

People think that this slow “titration” means having to wait for a long time for the benefits of this medication. However, we already know that 50 mg is more effective than a placebo (from a randomized trial years ago). Indeed, I was pretty sure I had seen people respond even in the first week, and this was shown in a recent study.^Brown Since the result is so stunning, and so few psychiatrists know about it, allow me to show you please.

A competitor’s manufacturer sponsored a study comparing lamotrigine with “olanzapine/fluoxetine combination” (a combination of Zyprexa and Prozac they call Symbyax). It was already known that this is a very good medication, particularly a good antidepressant and bipolar disorder (except for the massive weight gain that can result, which is why I don’t use it at all). The manufacturer surely thought that Symbyax would trounce lamotrigine, at least in the first several weeks while the dose of lamotrigine was being slowly increased. But as you can see in the graph below, Symbyax had a slight edge throughout the study, but lamotrigine did not lag behind: it showed benefits in the very first week (decreasing scores are good, reflecting less depression; lamotrigine is the dark rectangle, Symbyax the gray circle).

Back to the rash story: unfortunately, a mild allergic reaction, appearing as a mild skin rash, is common. About one person in 10 gets it. This rash poses no major risk — unlike the severe Stevens Johnson Syndrome version. So, as you can imagine, the issue of “rash” comes up frequently this medication. Your doctor will have to determine, if you get a rash, whether you might be getting the bad one, Stevens Johnson Syndrome. The simplest way to manage this problem is simply to tell everyone to stop the medication
entirely if they get a rash. No further doses, that’s it, you’re done. That is what the manufacturer recommends.

Instead, as many other mood experts have described, I tell my patients: “if you get a rash of any kind, or a fever, call me and describe what is going on, and do not take any further doses until you hear back from me”. Your doctor may also feel comfortable trying to tell the difference between the bad rash and the benign rash, or she/he might refer you to a dermatologist. In any case, you have to be extremely careful about all this. Here is more detail about handling this rash issue.

In general, the target dose for most people is 200 mg. This probably provides more insurance against relapse than lower doses, even if depression is completely gone at a lower dose. I do have a few patients who are maintained at lower doses. If depression comes back at 200 mg, it is possible to move the dose up (I use 50 mg steps per week) to a maximum of 400 mg. At 300 mg and below, most patients have no side effects at all. But at the higher doses, many people get side effects. However, these side effects can be quite subtle and sometimes it takes a while to figure out that they are really happening, and that they are coming from the medication. These effects include: difficulty finding simple words you know very well (this has been called “word searching”), trouble remembering people’s names whom you know quite well; mild dizziness, or mild balance problems. I instruct my patients to turn their dose back down if they run into one of these problems.

Specifics: lithium

With any of these medications, the goal is 100% symptom control, with 0% side effects. Some people can reach that goal with lithium. There is a lot of variation in side effects with lithium: some people can handle blood levels above 1.2 mmol/L without any side effects at all (e.g. doses of 2100 mg), where others will have severe side effects with 300 mg alone.

Over the last 10 years I’ve waffled back and forth as to whether it’s better to start with immediate release lithium (IR) or the slow-release (SR), now that the SR is generic. But it doesn’t seem to make much difference where I start: some people have nausea, which is relieved by switching to the SR. Some people have diarrhea, which is often relieved by switching to the IR. Go figure. It’s about 50/50.

Understanding when to have a lithium level can be complicated. Generally, if the level on 600mg is less than 0.7 mmol/L, severe side effects are unlikely with a 300mg step up. Minor side effects such as dry mouth and urinating a lot, including having to get up at night to urinate, are common. These side effects generally increase with each dose increase, but most people can handle moderate levels of these effects.

There are three side effects that commonly limit lithium dosing before dangerous side effects show up:

1. loose stool, progressing to diarrhea (worse with slow-release forms; try switching to regular)
2. tremor
3. mental dulling

None of these is likely to decrease with time: most people have to reduce the dose (try twice a day dosing first).

Lithium should not be used if you have kidney problems, unless very carefully regulated by someone who knows what to watch for. The levels may rise unpredictably to a dangerous range. Non-steroidal anti-inflammatories” (e.g. ibuprofen/Motrin, naproxen/Naprosyn, many others) and many blood pressure medications all can raise the risk of getting too high a blood level.

Specifics: valproate/divalproex

(If you are a woman between the ages of 12 and 50, unfortunately you should probably take this medication off your list of options, for two reasons. First, there may be a risk for women due to a possible shift in reproductive hormone regulation. For a discussion of the latest data on this risk, read about divalproex and PCOS. Secondly, this medication can cause abnormalities in developing children, so very effective precautions against becoming pregnant must be used for women who could become pregnant while taking it.)

Remember, the goal is 100% symptom control, with 0% side effects. In general, with slow-release valproate ( called divalproex), there are very few side effect problems. About 1 person in every 10 will have some nausea when starting, reduced if the medication is taken with meals. About 1 in 30 (in my experience) will have severe nausea. Even these folks can get used to the medication if the smallest size (125mg “sprinkles”) are used and increased by one pill per week or so. Other than nausea, however, other side effects are very uncommon — except weight gain, discussed in detail below.

Divalproex can be “loaded” with a large dose in the first day, to get it working faster (technically 20 mg per kilogram of body weight, but in practice it’s about 1500 mg in the first 24 hrs; some rare inpatient doc’s might give that as a single dose for a “loading strategy”. Going slower, to find the lowest dose that actually helps, may help prevent the most frequent problem with this medication: an appetite increase that leads to increased weight. Weight gain obviously carries health risks.

Many male patients can take 1500 or even 2000mg of valproate and not gain weight. Fewer women can, though, and many patients seem to hit a “weight gain threshold” somewhere around 1000mg. This threshold seems clearly to be higher when the new ER version is used; it looks like more patients can reach solid doses like 1500 mg with the new form. In my experience, more than 50% of women will gain weight at 1250mg or above (1500 or above with the ER version). Is this an appetite increase, as patients almost all experience when gaining weight? Or is there some metabolic shift, such as “metabolic syndrome“? The basis for this problem is still unknown. Some psychiatrists have tried using low doses of topiramate, another anti-seizure medication that tends to decrease appetite but has its own side effect problems, as an “antidote” to this appetite effect.

Fortunately, the appetite increase shows when this problem is going to occur. I have seen very few patients gain weight who did not experience the appetite increase. When people lower their dose, they can tell when their appetite returns to normal, and they do not seem to gain weight. So, I tell patients that if they get an abnormal appetite, they should lower their dose until their appetite returns to normal. The “threshold” seems to lie between 1000 mg and 1500 mg per day for most patients (if using the “ER” version). I don’t think I’ve seen a patient who experienced weight gain at 500 mg per day (there probably is one somewhere).

Divalproex at 500mg/day is not generally enough for symptom control, but when combined with low-dose lithium, it can be a very effective medication. And, not all patients will experience the weight gain problem. Hair loss is also common when people hit the weight gain range, but the dose decreases required for appetite control generally take people out of the “hair loss range” as well. For a bit more on this issue, read divalproex and hair loss.

Remember, after considering lithium and lamotrigine and divalproex, there are also other mood stabilizer options, fromaripiprazole to ziprasidone,so to speak.

Does your child go through intense mood changes? Does your child have extreme behavior changes? Does your child get much more excited and active than other kids his or her age? Do other people say your child is too excited or too moody? Do you notice he or she has highs and lows much more often than other children? Do these mood changes affect how your child acts at school or at home?

Some children and teens with these symptoms may have bipolar disorder, a serious mental illness. This brochure will give you more information.