Your doctor has confidence in these meds. You need to be skeptical.

by John McManamy


THIS ARTICLE, and the companion article on antipsychotics, is meant to be read with the other articles in this series. Reading about various meds in isolation - with no regard to treatment strategies and recovery goals - is like trying to appreciate a book by only looking at the letters. You've been warned ...


The story begins in an Australian lab in 1949 when John Cade had a hunch that urea would be effective in the treatment of bipolar disorder. He needed an agent to help the substance dissolve in water, which turned out to be the common salt lithium. He quickly found the solution had a calming affect on guinea pigs, but further experimentation showed that it was the lithium and not the urea that was the active ingredient. He then tried the agent on human subjects, with eye-popping results.

There the story might have ended, but for the efforts of Danish psychiatrist Mogens Schou, who demonstrated lithium's efficacy as a preventive agent (including for those with recurrent depression) in a number of studies conducted over the 1950s and 60s. This set the scene for regulatory approval in Europe and the US in the early 1970s.

The success of lithium - along with the introduction of antidepressants and antipsychotics at about the same time - opened up a new era of biological psychiatry.

Early lithium studies reported success rates of up to 80 percent for the treatment of mania, but more recent results show lithium to be effective in about 40 to 50 percent of subjects. There are a number of theories for this drop-off, but the most credible one comes from Frederick Goodwin MD, former head of the NIMH and co-author of Manic-Depressive Illness.

"The illness has been altered," he told a session at the 2008 American Psychiatric Association annual meeting. (I was in the audience, but I'm using Robert Whitaker's account, here.) He went on to say:

Today we have a lot more rapid cycling than we described in the first edition [which came out in 1990], a lot more mixed states than we described in the first edition, a lot more lithium resistance, and a lot more lithium treatment failure than there was in the first edition. The illness is not what Kraepelin described anymore, and the biggest factor, I think, is that most patients who have the illness get an antidepressant before they ever get exposed to a mood stabilizer.

At an APA session six years earlier, Dr Goodwin chastised the psychiatric profession for opting for the newer mood stabilizers promoted by the drug companies. (No drug company owns the rights to lithium.) A major problem, he said, is doctors who can't be bothered with the careful blood monitoring lithium requires, owing to its high toxicity. (The med can be potentially damaging to the kidneys, where it is metabolized, and also the thyroid).

Dr Goodwin's beef was not over whether doctors preferred to use another mood stabilizer first, but that so many chose not to use lithium at all, especially younger practitioners. The patients Dr Goodwin sees tend to be those referred to him by other doctors, who have presumably tried their patient on everything and failed - except, to Dr Goodwin's utter dismay - lithium, by far the most researched bipolar med.

Lithium has demonstrated efficacy across all phases of treatment, including acute and maintenance mania, and acute and maintenance depression, though its effect appears to be weaker on the depressive end. This qualifies lithium as the only true "mood stabilizer," though the term is loosely applied to the other bipolar meds. The compound also has demonstrated anti-suicide effects above those of other bipolar meds.

Lithium is believed to influence the activity of the inhibitory and excititory neurotransmitters GABA and glutamate, which together play a key role in regulating homeostasis in neural networks. The mechanisms are complex and varied, including actions in the neuron's ion channels (pores in the cell membrane) and inside the cell through various "signal transduction pathways" involved in setting off various bio-chemical chain reactions.



The Other Mood Stabilizers

According to psychiatric historian David Healy, the term mood stabilizer was invented by Abbott in the mid-1990s to market Depakote. Prior to that, according to Dr Healy, there was no mention of the term in the psychiatric literature.

Ironically, since Depakote has only demonstrated efficacy for the manic phase of the illness, the med does not qualify as a mood stabilizer. Nevertheless, the term is useful to distinguish Depakote and its sister meds from antipsychotic agents such as Seroquel and Zyprexa. Other mood stabilizers include Tegretol, Trileptal (Son of Tegretol), and Lamictal. All of these mood stabilizers first came on the market to treat epilepsy.

Like Depakote, Tegretol and Trileptal have demonstrated efficacy on the mania end. Psychiatry got behind GSK in promoting Lamictal as the silver bullet for treating bipolar depression, but GSK-sponsored clinical trials failed to live up to the hype. (Contrary to popular belief, its FDA indication is for "bipolar maintenance," not bipolar depression.) Nevertheless, the med may prove to be your personal magic bullet - such is the way business gets done in a field plagued by unknowns.




Mood Stabilizer Side Effects

The following is not meant to be read as a complete run-down. Moreover, you may experience no side effects at all, or just minor ones. Here are the more common major ones:

Mood stabilizers in general: Sedation, loss of mental edge, blunted awareness.

Lithium: Tremors, weight gain, highly toxic at above recommended blood levels, long-term risk of kidney and thyroid damage, regular blood tests required. To avoid dehydration and toxicity, drinking copious amounts of water is a must. Exercise, excessive heat, and physical illness can affect hydration levels. Always have a water bottle handy.

Depakote: Tremors, major weight gain, risk of liver damage, occasional blood tests required.

Tegretol: May affect the metabolism of other drugs and reduce their efficacy, including other psychiatric drugs and oral contraceptives. Accordingly, those taking other meds may need to consider raising the doses. Meanwhile, other drugs may raise Tegretol levels.

The drug's labeling warns that dual administration of Tegretol and lithium may increase the risk of neurotoxic side effects.

The drug contains a black box warning about risk of agranulocytosis (affecting white blood cells), but that risk is extremely remote.

Lamictal: Contains a black box warning about risk of serious rash, found in .08 percent of adults receiving Lamictal as initial therapy for bipolar. The risk of rash is greater in children and adolescents, and is only approved for this group in treating a certain form of epilepsy. The labeling recommends that the drug be discontinued at the first sign of rash and not be restarted unless the potential benefits clearly outweigh the risks.

Owing to risk of serious rash, GSK recommends gradual increases to a full dose over a six-week period, starting at 25 mg/day for the first two weeks and building up to 200 mg/day for week six. If also on Depakote, GSK recommends starting at 25 mg every other day for the first week and building to 100 mg/day for week six.

Mood Stabilizers and Pregnancy

No decision is risk-free. Please consult with both your psychiatrist and personal physician. The following is a general guideline, drawn from a number of expert sources, and should not be construed as medical advice:

The mood stabilizers fall into the FDA Categories C and D for safety during pregnancy. In Category C, either no adequate animal studies have been conducted or risk has been shown in animal studies with inadequate human data. In Category D, evidence of human fetal risk exists but benefits may outweigh risks in certain situations.

Planned pregnancy is the safest option, with tapering and discontinuing mood stabilizers prior to conceiving. Stopping mood stabilizers on discovering one is pregnant (say after five weeks) may be too late, as one is well into the teratogenic (birth defects) phase by this time. Going back on a mood stabilizer is recommended for the second and third trimesters.

Being stabilized prior to giving birth is critical, as the risk for postpartum relapse for bipolar patients who are ill during pregnancy is nearly 70 percent, according to a 1998 Harvard study, as opposed to 27.8 percent for those who stay well during pregnancy.

Lithium: The risk of fetal heart defects, especially Ebstein's anomaly, is .05 percent in the first trimester, 10 to 20 times that of the general population. Should be avoided by breastfeeding mothers. Category C.

Depakote: There is a three to five percent risk of fetal spina bifida in the first trimester, and an unspecified risk of heart defects and behavioral abnormalities. Four grams of folate is recommended (one gram if not on Depakote). Generally safe for breastfeeding, but monitoring of infant serum concentrations is advisable. Category D.

Tegretol and Trileptal: During the first trimester of pregnancy, there is a one to two percent risk of fetal spina bifida in the first trimester, and more than double the risk of major congenital anomalies. Considered safe for breastfeeding. Category D.

Lamictal: Greatest evidence of safety in pregnancy. Breastfeeding should be discontinued if rashes are observed in the infant. Category C.



Combination Therapy

The ideal of any mood stabilizer strategy is to control the cycle, preferably with just one med. In practice, clinicians aim for treating symptoms in the up and down phases of the cycle, which results in a long-term maintenance strategy that typically involves two mood stabilizers, for instance lithium (to control mania) with Lamictal (to control depression) or to maximize therapeutic effect (such as lithium with Depakote). To account for additive effects of using two drugs, lower than full doses of each are recommended.

Clinicians also apply similar rationale in combining a mood stabilizer with an antipsychotic med, though there are complications (which we explore in our companion article on antipsychotics).

Combining a mood stabilizer with an antidepressant has largely fallen out of favor (see Treating Bipolar Depression).

Since bipolar tends to come wrapped in anxiety and psychosis and problems with sleep, not to mention fatigue and cognitive impairments, there is no limit in theory to the number of pills that can go into a meds cocktail. (Discussions on these meds are provided in the respective hyperlinked articles.) A thoughtful clinician will work with you in implementing a cocktail that works for you, but the onus is on you to find one.

At the 2003 Fifth International Conference on Bipolar Disorder, Gary Sachs MD of Harvard and principal investigator of STEP-BD reported that patients entering the program were being treated with an average of 4.2 meds. Five percent were on eight meds or more and four percent were on 10 meds or more, leading him to comment on "exotic polypharmacy." Less than 20 percent were on just one drug.

Going Off Your Mood Stabilizer?

As a general rule, doctors encourage patients to remain on their mood stabilizer to prevent future episodes. This advice tends to be based on clinical observation from patients who suddently go off their meds. Inevitably, the patient has a relapse and winds up in the hospital.

With hard scientific evidence regarding the efficacy of staying on mood stabilizers over the long term sorely lacking, both doctors and patients are flying in the dark. You may have a legitmate reason for wanting to go off your mood stabilizer. The one firm rule is that suddenly quitting your medication is asking for trouble. A long slow wean - over many months, perhaps a year - under the care of an enlightened psychiatrist is the preferred option.

The understanding here is that an expert patient has developed sufficient skills in managing his or her illness through various lifestyle practices and other means. By this time, the mood stabilizer is no longer doing the heavy lifting. Moreover, once the slow wean begins, this same expert patient is sufficiently mindful to oberve subtle changes as they occur, and to re-up the dose as the situation demands. And, should the wean be successful, the pills still remain in the medicine cabinet.

This bears emphasis: Going off your mood stabilizer is not for beginners. Much as well-meaning friends and acquaintances may urge otherwise, I have heard way too many horror stories to justify any instant decisions. Be smart, live well ...

See also: Antipsychotics * The Problem with Bipolar Meds * Treating Mania * Treating Hypomania * Treating Bipolar Depression

For a more global look at managing bipolar, check out the other articles under Treatment , as well as the articles in the Recovery section.

Revised July 1, 2016


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