Treatment

Bipolar Meds - An Introduction

How a common salt and other agents changed our lives.

Consider this: There is no bipolar pill, and maybe there will never be. People with bipolar disorder simply represent too small a market (one to two percent of the population) for a pharmaceutical company to take a gamble on investing the $800 million the industry claims takes to get a drug to market, assuming, that is, such a drug ever leaves the lab. Since most new drugs originate from public sector research in the first place, the industry would virtually have to be handed their magic bullet on a silver platter. So it is that the bipolar community must pick and choose from a menu of leftovers designed for other populations - antidepressants, antianxiety medications, antipsychotics, and anticonvulsants. Last but not least, there is a common salt.

Lithium for Treating Bipolar Disorder

The story begins in an Australian lab in 1949 when John Cade MD, senior medical officer in the Mental Hygiene Department of Victoria, 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 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 lithium on human subjects, with eye-popping results.

John Cade's discovery of lithium as a treatment for bipolar disorder may be accidental, but the simple fact that the finding came in a lab demonstrated that at least one person on the planet back then recognized that the illness carried a biological component. In those days, in a world dominated by Freudian psychiatry and the belief that bipolar was an attitude problem, Dr Cade was way ahead of his time. It would take until the 1960s before his findings were applied in Europe and yet another decade before lithium became available in the US.

Lithium can be considered the first of the mood stabilizers - an agent that reduces the severe mood swings characteristic of bipolar disorder - and today it still remains the treatment of first or second choice. It was approved by the FDA for the treatment of mania in the 1970s and until recently was the only drug approved for maintenance therapy.

Early 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, perhaps reflecting its wider use on more unwilling patients.

The drug also works moderately well for treating bipolar depression.

Because of its high toxicity, blood levels need to be very carefully monitored. Lithium can be potentially damaging to the kidneys (where it is metabolized) and the thyroid.

Lithium and other mood stabilizers are believed to work through neurotransmitters outside the brain cell, resulting in a molecular series of events that leads through the brain cell's membrane via various ion channels and inside the neuron through signal transduction pathways (which involve a number of chemical chain reactions responsible for a vast array of cellular activities).

Depakote, Tegretol, Lamictal, Trileptal, etc for Bipolar Disorder

Depakote (divaloproex sodium or valproate) became the first of the antiepileptics (or anticonvulsants) used for treating mood swings. Like lithium, its discovery was the result of accident. Valproate was initially developed by the Germans in World War II as a butter substitute, then was used as a diluent for other drugs. In 1963, its anticonvulsant properties became apparent when an experimental anticonvulsant was dissolved in valproic acid (thus revealing the true agent). European asylums in the 1960s had large populations of epileptic patients, and when synthesized valproate (Depakote) was given to these patients - voila! - the next mood stabilizer. The first published European reports based on observations came in 1975.

US studies followed a decade later. The drug was applied off-label without FDA approval, but in 1995 it was cleared for treating mania. By analogy, we know that the brains of lab animals become progressively more sensitive to seizures when induced by an electrical current into the hippocampus and amygdala of the brain. After several days, the animals experience spontaneous seizures. This corresponds to the "kindling theory" of bipolar, of a progressive worsening of the illness, if allowed to go untreated. This may explain why drugs that work so well to prevent seizures are also effective in treating bipolar.

Depakote, along with lithium, is a treatment of first choice for bipolar. Like lithium, Depakote is also potentially toxic - especially to the liver where it metabolizes - and requires blood levels to be taken regularly. The drug poses certain risks for young females, and the following warning posted on the website of the NIMH bears quoting in full:

"According to studies conducted in Finland in patients with epilepsy, valproate may increase testosterone levels in teenage girls and produce polycystic ovary syndrome in women who began taking the medication before age 20. Increased testosterone can lead to polycystic ovary syndrome with irregular or absent menses, obesity, and abnormal growth of hair. Therefore, young female patients taking valproate should be monitored carefully by a physician."

A University of Toronto study of 38 women found that half of those on Depakote reported menstrual abnormalities vs 15 percent among lithium users. Those taking Depakote had higher levels of male sex hormones, with half the overweight women with menstrual abnormalities having hyperandrogenism.

This may be prevented however by using oral contraception.

More recently, doctors have been treating their patients with newer anticonvulsants, including Lamictal, Tegretol, Trileptal, Neurontin, Felbatol, Gabatril, and Topamax, all (but Lamictal) off-label, and all with the advantage of a benign toxicity profile. The range of choices a patient now has means that there is hope even if several treatments do not work.

For the acute phase of mania, clinicians like to start patients on a "loading dose," generally in the midrange of therapeutic levels and work up or down, as the case may be. For the newer antiepileptics there is a much wider dose range, reflecting the sad fact that there is still much to learn. For the maintenance phase of treatment, slightly lower doses are recommended. Gradual tapering is standard practice before discontinuation.

Antipsychotics for Treating Bipolar Disorder

Atypical (new generation) antipsychotics such as Risperdal or Zyprexa were developed for treating schizophrenia, but are recommended as first choice treatment options for mania and psychotic mania in current treatment guidelines, either as combination or monotherapy. Zyprexa, Risperdal, and Seroquel have been approved by the FDA for treatment of mania, and their competitors are awaiting similar approval. Recent studies have found a mood stabilizer with an antipsychotic to be more efficacious than a mood stabilizer alone.

Because antipsychotics act more quickly than lithium and anticonvulsants, they are a logical first choice for bringing a person out of a florid manic or psychotic episode. Since a patient in this state is in no shape to discuss the risks vs benefits with his or her psychiatrist, it is not uncommon to find oneself on a med that may do more harm than good in the long run. Most of the atypicals (Seroquel and Abilify excepted) pose a risk of adverse motor effects, referred to collectively as EPS, including muscle stiffness and tardive dyskinesia (involuntary spasms). Zyprexa is a notorious weight-gainer as well as a diabetes risk. Other atypicals also put on pounds. All except Risperdal are horse tranquilizers (which can be good as well as bad), but Risperdal can induce raised prolactin levels, which can result in sexual dysfunction in both men and women

Accordingly, before going on an antipsychotic - or once one's mood has been stabilized after being started on one - one is advised to give his or her psychiatrist the third degree. You are entitled to full disclosure, so don't settle for ten minutes and out the door. For some, an antipsychotic may not be a long-term option. For others, these drugs can be life-savers, but only if your psychiatrist takes the trouble to find out which is the most effective and safest choice for you.

Antidepressants for Bipolar Depression

In general, anticonvulsants are not considered effective for depression while lithium may not always get the job done. Lamictal has been incorrectly touted as an antidepressant (see article), when the drug's only demonstrated effectiveness is as a mood stabilizer to help prevent depression. For some patients, adding an antidepressant may help in the short-term, but this may result in switching into mania or rapid-cycling (study numbers vary widely), which usually resolves once the antidepressant is dropped. Before going on an antidepressant, the benefits vs risks need to be very thoroughly discussed with your psychiatrist (see article).

Benzodiazepines

It is not uncommon to include benzodiazepines such as Valium (diazepam), Klonopin (clonazepam) and Ativan (lorezapam) as part of a meds cocktail, especially in situations where stabilization and the need to establish sleep is a top priority. Because of their depressant effects and dangers of addiction, these agents are generally regarded as a short term solution.
Combination Medications for Bipolar Disorder

At the 2001 National Depressive and Manic-Depressive Conference, Joseph Calabrese MD of Case Western Reserve University observed: "The main thing I have learned over the last decade is there is no one medicine that does the job." Combination therapy is now standard, with three or more drugs being normal, and the emphasis is on using meds that have complementary efficacy, such as Lamictal (which is strong against depression) and the antipsychotic Zyprexa (which works from the opposite pole on mania).

At the 2003 American Psychiatric Association annual meeting, Frederick Goodwin MD cited several rationale for using combined therapy to treat bipolar, including:

Targeting different symptom clusters. For example, a patient with a mixed state who rapid cycles and has substance dependence would suggest the need for an anticonvulsant while a risk for suicide would suggest the need for lithium. A Lamictal-lithium cocktail, on the other hand, makes for optimal prevention of depression and mania.
Different mechanisms of action. Lithium and Depakote have multiple targets in the signal transduction pathways inside the neuron that may complement one another.
Nonresponse or partial response. For example, one study of adding Zyprexa to lithium or Depakote found the combination kept patients well longer than either mood stabilizer alone.
Side effects. Adding two meds together at lower doses may keep each drug below its side effect profile. One study of 140 bipolar I patients found 59 percent compliance with Depakote monotherapy, 48 percent compliance with lithium monotherapy, but 100 percent compliance with combined therapy at less than full doses.

In one NIMH study, patients were put on either lithium or Tegretol for a year, switched for a year, then put on both medications the third year. The response rate for either drug alone was less than a third, but in combination was more than 50 percent.

Combination therapy raises the potential danger of toxic drug interactions, which can be minimized by adding new medication in modest amounts and raising the dose slowly. Lithium used with other antiepileptics appears the safest combination, in particular lithium with Depakote. When adding Lamictal to Depakote, Lamictal should be started at 50 percent the usual starting dose and increased slowly. Those on Tegretol need to consider higher does of Lamictal, Depakote, or Topamax.
Medications Treatment of Kids with Bipolar Disorder

The only bipolar medication approved by the FDA for children is lithium for the treatment of mania. The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder published in 2000, however, recommends Depakote and Tegretol, as well. Antipsychotics are common treatment. In 2003 and 2004, UK and US authorities expressed concern over the efficacy and safety of antidepressant in kids (see article). Only Prozac is approved in both countries for treating depression in kids, and that is for unipolar depression. Misdiagnosed kids prescribed an antidepressant are at high risk for manic and rapid-cycling switches. The drugs can also result in mental agitation for some patients. In addition, in 2003 and 2004, UK and US authorities

Bipolar Medications and Pregnancy

According to a panel of experts at the 2000 DBSA Conference, the dangers of taking lithium while pregnant are overstated while Depakote and Tegretol are dangerous. According to Frederick Goodwin MD, who co-authored the definitive book on bipolar with Kay Jamison, the antiepileptics involve a five percent chance of neural tube defects (such as spina bifida) while lithium runs a one in a thousand chance of a heart problem, which is correctable.

One year later, at the 2001 DBSA Conference, Dr Goodwin emphasized that a first trimester risk should not be confused with being off medications the entire pregnancy. It is very important, he said, to be back on medications well before delivery. Otherwise, one is playing catch-up. For bipolar mothers not on meds, there is a 70 percent chance of postpartum mania.

(For more on pregnancy and meds, see article.)

Breastfeeding

An article on Medscape by Dr Mohammad Masud Iqbal et al makes these recommendations:

Lithium - Should be avoided by breastfeeding mothers.
Depakote - Generally safe for breastfeeding, but monitoring of infant serum concentrations is advisable.
Tegretol - Considered safe.
Lamictal - A risk of life-threatening rashes in infants. Breastfeeding should be discontinued if this is observed.
Topamax - The potential for adverse reactions while breastfeeding is unknown.
Antipsychotics - Should be used for breastfeeding only "when the potential benefits justify the possible risks to the infant."
Rapid-Cycling

Those who rapid-cycle are subjected to mental whiplash by the steep ups and downs of the roller coaster.

In one study, only 28 percent of rapid-cycling patients responded to lithium and 19 percent to Tegretol, but 56.3 percent responded to a combination of both drugs, comparing favorably to a group of nonrapid-cyclers who also responded well to combination therapy. In other trials, rapid-cyclers responded well to a combination of lithium and Depakote and a triple combination of lithium, Depakote, and Tegretol - as well as antidepressants, antipsychotics, or antianxiety agents as required - but "this still left some 30-40 percent of our patients inadequately responsive."

Since the 1970s, the number of medications given a patient at discharge from the NIMH has increased from 1.5 on average to 3.3. The proportion of rapid-cyclers has increased from 29.4 percent to 70 percent over the same period.

A Stanley Foundation study found 60 percent of rapid-cycling patients responded well to a mood stabilizer augmented by either Wellbutrin, Effexor, or Zoloft, with six percent switching into mania in the first 10 weeks and 15 percent after one year. Those who discontinued their antidepressants were three times more likely to suffer depression.

A NIMH study of lithium non-responders found 34.9 percent of those who had experienced a good initial response eventually lost tolerance, while 13.6 percent failed to re-respond once it was reinstated. Other studies back up the observation that it is more difficult to restabilize patients after they have discontinued their lithium than during their initial treatment.

The calcium channel blocker nimodipine was successful in treating one ultra-rapid-cycling patient. The same patient also responded well to a different channel blocker, isradipine, in combination with Tegretol, which she has been taking for five years.

A recent six-week study found 52 percent of rapid-cycling patients responded well to Lamictal and 27 percent to Neurontin. Two of the seven nonresponders had a good response to combination Lamictal and Neurontin.

In a grand rounds lecture at UCLA on Oct 14, 2003 and webcast the same day, Joseph Calabrese MD of Case Western Reserve University reported on three unpublished studies concerning rapid-cycling:

The first study, he admitted, had the wrong design, as three-quarters dropped out in the open stabilization phase of the trial. Most of those who failed to respond were due to treatment-refractory depression, which he acknowledged was "a real eye-opener." The 60 patients (mostly women rapid-cyclers with bipolar II) who were stabilized and stayed in the study were randomized onto lithium or Depakote, with about the same percentage (51-56 percent) relapsing into depression or mania over the next 20 months, a finding that challenges the notion that rapid-cycling predicts a preferential response to Depakote.

The second study, of 105 substance-users who rapid-cycled, mostly bipolar I men, found that 74 percent had been charged with a legal offence, 45 percent had been convicted of a serious offence, and 34 percent had been incarcerated.

In the third study involving 139 juveniles, half who were rapid-cyclers, 43 percent responded to treatment (vs the 25 percent of adults in the initial phase of the first study), suggesting that contrary to what some experts may say, bipolar in kids in certain instances may be easier to treat. About half the kids had co-occurring ADD, but only one was intolerant to stimulants. None of the kids in the study had treatment-refractory depression, a result Dr Calabrese referred to as "astonishing," but also consistent with Emil Kraepelin’s observation that the older you get the more patients present with depression.

Bipolar II

Little study has been done on bipolar II and its treatment. A review article In the Feb 2004 Bipolar Disorders by Yatham et al of the University of British Columbia reports on the few studies that apply to bipolar II:

Lithium: A major long-term Sardinian study has found those in the sample with bipolar II fared better on lithium that those with bipolar I.
Anticonvulsants: No significant difference in one study between lithium and Tegretol for bipolar II maintenance, though there was a clear difference in the same study in favor of lithium for bipolar I maintenance. A study of rapid-cyclers on Lamictal found no significant difference between those on the drug and on a placebo, but when the bipolar II patients in the study were analyzed separately, 46 percent of patients remained stable for six months without relapse vs 18 percent on a placebo. An open study involving eight treatment-resistant depressed bipolar II patients on Lamictal found five very much improved. A 12-week trial of Depakote monotherapy on 19 bipolar II patients found significant benefit for 63 percent of the patients. Very weak evidence of adjunctive use of Neurontin.
Antipsychotics: A six-month study of bipolar II patients on Risperdal found 73 percent were responders in terms of mania and 78 percent improved or much improved in terms of depression.
Antidepressants: Conflicting studies, some finding increased likelihood of antidepressant-induced switches into hypomania or cycle acceleration, others not. One study found depressed bipolar II patients responded faster to Effexor than unipolar depressed subjects.
Dopamine agonists (pramipexole and ropirinole): Eight of 18 patients in a treatment-refractory depressive episode responded.

Experimental Meds

Again, these amount to either hand-me-down drugs or natural substances. At the 2002 APA annual meeting, Bruce Cohen MD, PhD of Harvard presented a list of drugs and nutrients being tested for bipolar and their mechanisms of action, including:

Xanomeline (muscarinic M1 agonist)
Aricept (donepezil, an Alzeimer's drug that is an anticholinesterase inhibitor)
Mirapex (pramipexole, a Parkinson's drug that is a dopamine3 receptor agonist),
Diprivan (propofol, a sedative that activates GABA-linked calcium channels)
Rilutek (riluzole) and Namentec (memantine, ALS drugs, also used for Alzheimer's, that are glutamate NMDA antagonists
Taurine (an amino acid that binds glutamate)
Pyridazines and pyrimidines (enhance mitochondrial function)
Magnesium (alters calcium influx, NDMA receptors, and kinase activity)
Mifespristone (RU-486, the morning after pill that is a cortisol/glucocorticoid antagonist).

Our Right to Recovery

The 2002 American Psychiatric Association's Revised Practice Guideline for the Treatment of Patients with Bipolar Disorder features this statement:

"Treatment is aimed at stabilization of the episode with the goal of achieving remission, defined as a complete return to baseline level of functioning and a virtual lack of symptoms."

Note that “stabilization” is generally the first thing a psychiatrist shoots for. Here, we are out of our 911 state, but we are not feeling well.

“Virtual lack of symptoms” represents an advance on stabilization, as well as “response” (a fifty percent improvement in symptoms which is the success criteria for clinical drug trials).

By incorporating “functioning” (such as the ability to work and have relationships) into its definition for remission, in essence, the APA set recovery as the goal of treatment, years before the term became vogue. To illustrate how far we’ve come, the APA Guideline from a mere eight years before virtually wrote us off:

"The specific goals of treatment are to decrease the frequency, severity, and psychosocial consequences of episodes and to improve psychosocial functioning between episodes. Some patients with severe and chronic impairments will need specific rehabilitative services."

In other words, the APA has put its members on notice that quitting on us is not an option, notwithstanding the severity of our symptoms or past treatment failures. In essence, our right to get well and stay well, with current medications and other treatments, has been codified.

You need to be symptom-free AND function. Any trade-off between symptom-reduction and medication side effects is unacceptable. Psychiatrists who like to play it safe by over-sedating their patients are operating outside the bounds of these guidelines.

Medications are unlikely to take you completely where you want to go. But a smart psychiatrist will work with you to ensure that your meds treatment promotes your recovery rather than impedes it. Finding the right meds that work for you may take time - as does the recovery process - but you have a right to hold your psychiatrist accountable every step of the way. Be smart, live well ...

Updated Feb 10, 2008

Also See

The Mood Stabilizers

The fine points

The Antipsychotics

Antipsychotics are a first option, but is this what we want?

Long Haul Bipolar Treatment

Everything we know about long-term treatment, which isn't much.

Knowledge is Necessity

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