Treatment

Bipolar Meds - The Antipsychotics

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

Antipsychotic drugs are yet another second-hand medication that people with bipolar disorder have to put up with, though the clear overlap between schizophrenia and bipolar disorder makes them obvious choices. Psychotic symptoms are fairly common in mania. Meanwhile, genetic researchers are turning up many of the same candidate genes in both bipolar and schizophrenia populations.

The efficacy of the newer antipsychotics for treating mania is similar to mood stabilizers and each other (about 50 percent responding), but Alan Mendelowitz MD of Albert Einstein University at a 2004 American Psychiatric Association symposium observed this is proven only for moderately ill patients, as the sicker ones (such as those deemed treatment-refractory or a suicide risk) are excluded from trials.

The drugs first came on the market to treat schizophrenia, but all but Clozaril were later approved for treating mania. Zyprexa is approved by the FDA to treat both acute (initial phase) mania and maintenance (ongoing prevention) bipolar disorder. Risperdal, Seroquel, Geodon, and Abilify are approved to treat acute mania. Zyprexa is now on an equal footing with both lithium and the mood stabilizer Depakote as a first-choice treatment for acute mania in a practice guideline published by the APA in 2002 and enjoys similar status in the Texas Implementation of Medication Algorithms (TIMA) put out in 2001. Other antipsychotics are likely to find their way to the top as more studies become available.

Recent studies have also found that these meds also have antidepressant effects. A Zyprexa-Prozac combination known as Symbyax in 2003 became the first med ever FDA approved for the treatment of bipolar depression, and in 2006 Seroquel received an indication for treating bipolar depression.

Antipsychotics were discovered by accident in the 1940s. The drugs bind to the brain cells’ dopamine D2 receptors, blocking dopamine transmission, thus dampening the over-stimulation of the brain that dopamine is implicated in. The new generation drugs also bind to the histamine H1 receptors, inducing sedation (which can either be good or bad). The atypicals' antidepressant effects are accounted for by their actions on dopamine and serotonin pathways.

NIMH real world trials from 2006 on schizophenia patients found that the new generation meds were no more efficacious that the older ones, while many of their side effects (such as weight gain) raised clear red flags. Moreover, in one of the long-term trials there was a 100 percent drop-out rate, meaning no one finished the study. This corresponds with other long-term trials showing attrition rates of 60 to 100 percent. In other words, there is much not to like about these meds.

All of this information had long been available to the psychiatruc profession, but only in light of CATIE are they actually beginning to pay attention.

Basically, the pharmaceutical industry oversold psychiatry on the new generation meds. Psychiatrists, in turn, paid more attention to smooth-talking drug reps than to their patients. Whether this generates less enthusiasm for prescribing these meds, particularly with patents due to expire, remains to be seen. We know these work. It's just we that we need to be prudent in using them.

Antipsychotics Side Effects

The atypicals pose risk of EPS, sedation, weight gain, diabetes, impotence and raised prolactin, cognitive dulling, and heart rhythm irregularity. Some of these effects involve just one drug, others more than one.

EPS and Tardive Dyskinesia: An antipsychotic medication needs to occupy 65 percent of the brain's dopamine D2 receptors for resolution of psychotic symptoms. If a drug reaches 80 percent occupancy, most patients will experience initial and often transient adverse motor effects, referred to collectively as EPS, including muscle stiffness and involuntary spasms).

Tardive dyskinesia refers to similar side effects that set in after about six months.

For the older antipsychotics such as Haldol, the narrow dose range makes it easy to overshoot the 80 percent occupancy threshold. With second-generation drugs, finding the target range with the right dose is easier.

A German study of six patients receiving both vitamins E and C found the vitamins reduced the tardive dyskinesia effects of the antipsychotics they were taking. High dose vitamin E with its pro-oxidative effects carries cardiac risks. Vitamin C may reduce this risk by interacting with vitamin E. A New York University study of 36 men with tardive dyskinesia found those who took high dose branched-chain amino acids, vital to muscle tissue maintenance, showed a significant reduction in their symptoms.

Older antipsychotics attach firmly to the D2 receptor and block it for a day while the atypicals bind loosely, allowing the normal transmission of the brain's dopamine (and thus permitting pleasure and arousal). The new atypical antipsychotic, Abilify (aripiprazole) - which in 2002 received approval for schizophrenia from the FDA - has high affinity to the dopamine receptors, but permits some dopamine to cross over to the postsynaptic cell, which largely avoids EPS.

With atypicals, risk of EPS and tardive dyskinesia is greatly reduced, but still remains a worry. According to Zyprexa's labeling, 32 percent of patients report at least one EPS effect at approx 15 mg a day, 25 percent at approx 10 mg a day, and 15 percent at approx 5 mg a day. Risperdal and Geodon also have dose-related EPS effects. Seroquel has no increase in EPS with any dose, though there is a small risk, and Abilify only has small initial akasthisia (a type of mental restlessness) .Clozaril runs a negligible risk of EPS.

Dosing recommendations when the atypicals first hit the market were either too high or too low or too vague, but it is now generally accepted that the following doses equate to eight mg of the old generation Haldol: Zyprexa (15 mg), Seroquel (500 mg), Risperdal (three mg), Geodon (!00 mg), and Abilify (15 mg).

Pre-CATIE studies have challenged the claim that the newer atypicals are more efficacious and have better side effects than the older antipsychotics. A 2000 Oxford analysis of 52 studies published in the British Medical Journal found no difference in effectiveness between the newer and older drugs. A 2003 German review published in The Lancet found only Clozaril had fewer side effects than the older drugs. A 2003 US Veterans Affairs study of 309 patients with schizophrenia or schizoaffective disorder taking either Zyprexa or Haldol for 12 months found "no significant differences" between the two groups in terms of schizophrenia symptoms, drop-out rates, quality of life, or EPS. Those on Zyprexa fared slightly better in terms of reduced akathisia (motor restlessness) and tardive dyskinesia, but encountered greater weight gain and significantly greater VA costs, ranging from $3,000 to $9,000 annually.

Other recent studies lend credence to the claims made by manufacturers of the atypicals:

A 2003 University of Chicago/Stanford meta-analysis of 124 trials found Clozaril, amisulpride (available in Europe), Risperdal, and Zyprexa "significantly more efficacious than first generation antipsychotics." Clozaril produced the best results. Other atypicals, however, including Seroquel, Geodon, Abilify, remoxipride, and sertindole were similar in efficacy to the older drugs such as Haldol. A 2003 Eli Lilly study comparing Zyprexa to Haldol found similar efficacy in manic patients, but better tolerability for Zyprexa (more on this further down). Finally, a multi-center meta-analysis of 11 long-term studies involving 2,769 patients receiving atypical antipsychotics or Haldol found that those on the atypicals had a reduced risk of tardive dyskinesia compared to those on Haldol (0.0 to 1.5 percent vs 5.4 percent), though the doses of Haldol in the studies were relatively high.

Sedation: All the atypicals but Risperdal are horse tranquilizers, often merely in the initial phase of treatment before the body has a chance to adjust, but severe enough to be worrying, especially in these days of hit and run psychiatry where patients are sent out onto the streets disoriented and confused after maybe one or two nights in the hospital. Psychiatrists see Seroquel's sedating effects as an asset, however, often prescribing it (sometimes on an "as needed" basis) for sleep.

Sexual dysfunction: Approximately half of men and women taking antipsychotics complain of sexual dysfunction. Risperdal appears responsible for the most erectile failures while Clozaril appears to least troublesome. Risperdal and the older antipsychotics are responsible for raised prolactin levels, which can result in loss of sexual function and related effects in both men and women (more on this under Risperdal below).

Weight gain: A 1999 study by Allison et al found that Clozaril resulted in a mean weight gain of 9.8 pounds in ten weeks, 9.1 for Zyprexa, 6.4 for Risperdal, and negligible for Geodon. Seroquel wasn’t evaluated and Abilify was unavailable at the time. A 1997 study by Nemeroff found patients on Zyprexa gained 27 pounds over one year. Other one-year studies found weight gain leveled off in the single figures for Risperdal and Seroquel and was negligible for Geodon and Abilify. Product labeling shows nearly 30 percent of Zyprexa users added seven percent or more weight. Twenty percent of Seroquel users, more than 15 percent of Risperdal users, around 10 percent of Geodon users, and less than 10 percent of Abilify users crossed this "clinically significant" threshold.

Current Psychiatry reports that the good news is much of that weight can come off: One study found behavioral intervention helped patients who had gained more than 20 pounds to lose at least 10. Another study found Zyprexa users benefited from Weight Watchers.

With Zyprexa, weight gain reportedly plateaus after about 39 weeks, with the most rapid gain in the first 12, indicating the benefits of early intervention. One small study found Zyprexa patients who received education prior to treatment gained one pound in four weeks compared to 6.4 for the standard care group. (Now if doctors would only warn their patients when they prescribe these meds.) Axid (nizatidine), Topamax, and Symmetrel (amantadine) are known weight reducers when taken with antipsychotics.

Diabetes: With weight gain comes the risk of diabetes. According to an April 2003 Wall Street Journal front page article in on Zyprexa:

"Of the millions of patients who took the drug over an eight-year period that ended in 2002, 288 are reported to have developed diabetes. Seventy-five of those people became severely ill, and 23 died."

Those figures were taken from studies by Elizabeth Koller MD, a former FDA official, and P Murali Doraiswamy MD of Duke, first published in the July 2002 Pharmacotherapy, which in turn were based on voluntary reports to the FDA, which experts believe represent from one to 10 percent of actual cases.

Koller and Doraiswamy also fingered Risperdal, which was found to be linked to 132 diabetes cases, 31 life-threatening, and five ending in death over a nine-year period. Earlier, Dr Koller found a diabetes risk in Clozaril - 384 cases, 55 serious, 25 fatal - which has carried warnings since 1997. At the 2003 APA meeting, the two authors implicated Seroquel, involving 34 patients with newly-diagnosed hyperglycemia. There were 21 cases of diabetic ketoacidosis resulting in 11 deaths.

In 2003, a joint panel of the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity issued a consensus statement advising that patients taking atypical antipsychotics may be at increased risk for obesity, diabetes, high cholesterol, and heart disease. The panel recommended that doctors screen and monitor their patients on atypical antipsychotics for: 1) personal and family history of obesity diabetes, high cholesterol, hypertension, or cardiovascular disease; 2) weight and height; 3) waist circumference; 4) blood pressure; 5) fasting blood glucose; 6) fasting blood cholesterol.

The panel also advised doctors to refer their patients to specialists, if necessary.

In 2003, Eli Lilly and the other manufacturers added a diabetes warning to their product labeling that included:

"Antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,and weakness."

Costs of Antipsychotics

Perhaps the most pronounced side effect is the one you will feel in your back pocket if you are not covered by a health plan. RXUSA lists the unit cost of 15 mg Zyprexa at $13.99.

Other cost ranges, from RXUSA:

Risperdal: $2.65 to $7.10.
Seroquel: $1.39 to $6.48.
Geodon: $3.83.
Abilify: $9.17 to $13.00.

By contrast, Haldol, which has gone generic, retails for $1.05 for 10 mg, which would explain why many states have been considering excluding the atypicals from their formularies. The savings, however, may be illusory. Those who viewed Bellevue Inside Out on HBO witnessed the absurdity of the psychiatrists prescribing Haldol, generally against the patient's will, with the obvious outcome of noncompliance and future hospitalization. One study comparing Risperdal to the older antipsychotics found annual costs about the same (approx $2,500) when the greater hospitalization rate for those taking the older antipsychotics was taken into account.

Antipsychotics and Pregnancy

According to an article on Medscape by Mary Seeman MD, DSc of the University of Toronto, women trying to conceive "should stay away from drugs with high D2 affinity." These drugs raise prolactin levels, which lowers gonadal steroid production and makes conception difficult. These include all first generation drugs and Risperdal. On the other hand, Zyprexa and Seroquel are unproven in pregnancy, and Clozaril is unwise for a number of reasons. The authors recommend a drug-free first trimester. If antipsychotics are necessary, low dose Haldol has the best safety record.

Combination Therapy with an Antipsychotic

Combination therapy with an antipsychotic and a mood stabilizer (including lithium) together is recommended as a first choice for severe mania by the APA guideline while the TIMA algorithm and Evidence-based Guidelines for Treating Bipolar Disorder recommends a combination mood stabilizer/antipsychotic should initial monotherapy with either type of drug fail. A series of Harvard University studies has found that Risperdal with a mood stabilizer, Haldol with a mood stabilizer, Zyprexa with a mood stabilizer, and Seroquel with a mood stabilizer outperformed a mood stabilizer alone.

Zyprexa

Zyprexa (olanzapine) is the best-studied of the atypicals and was the first by several years to be FDA-approved for the treatment of acute mania (which means passing two double-blind placebo-controlled trials). Another study found it effective for mixed mania. The drug also has an antidepressant effect, with Eli Lilly having obtained FDA approval for a Zyprexa-Prozac combo (Symbyax) to treat bipolar depression. In Jan 2004, the FDA approved Zyprexa for bipolar maintenance (ongoing treatment). A double blind trial showed a lower rate of relapse into mania or depression over 52 weeks when compared to a placebo (16.4 percent vs 41.2 percent and 34.7 percent vs 47.8 percent, respectively).

A second relapse prevention study, involving 431 patients, found fewer Zyprexa patients relapsing into mania (14.3 vs 28 percent) than those on lithium while the depression rates were about the same (16.1 vs 15.4). Nineteen percent of the Zyprexa users dropped out due to an adverse event vs 25.7 in the lithium group.

A secondary analysis of 344 patients with dysphoric mania found those who added Zyprexa to a mood stabilizer had greater improvement in their depression scores than those on just a mood stabilizer.

A review of seven trials involving 1467 patients found Zyprexa improved mania scores both as mono and combination therapy, but did not do better than Haldol. Dropout rates ranged from 29 to 65 percent.

A 2003 Eli Lilly study compared the two drugs on 453 patients with bipolar mania over 12 weeks, finding: 1) Rates of remission after six weeks were similar for both groups (52.1 percent for the Zyprexa group vs 46.1 percent for those on Haldol); 2) For patients without psychotic features, rates of remission were greater for the Zyprexa group (56.7 percent vs 41.6 percent; 3) Relapse into an episode occurred in 23.1 percent and 14.8 percent of Zyprexa and Haldol patients, respectively; 4) Switch to depression occurred significantly more rapidly with Haldol; 5) Significantly more Haldol patients experienced worsening of extrapyramidal symptoms; 6) Weight gain was noticeably greater in the Zyprexa group (2.82 vs 0.02 kg); and 7) The Zyprexa group had significant improvement in quality of life on several measures compared to the Haldol group.

A telling statistic: Forty-four percent of the patients (about the same from each group) dropped out of the study, most frequently for lack of efficacy.

An open trial of 36 rapid-cycling patients found that Zyprexa with or without a mood stabilizer resulted in moderate to marked improvement in half of them at week eight, with a further eight showing improvement at week 12. Greater benefits were noted in depressive symptoms.

The most notorious side effect of both Zyprexa and Clozaril (clozapine) is weight gain (3.55 kg over 12 weeks in one Zyprexa study). The drug also increases cholesterol and insulin levels, adding to hyperglycemia and diabetes risk.

The other risk is EPS, with 32 percent of patients reporting at least one EPS effect at approx 15 mg a day, 25 percent at approx 10 mg a day, and 15 percent at approx 5 mg a day. Somnolence also looms large, with 29 percent of patients complaining of this side effect in clinical trials.

Dueling studies illustrate Eli Lilly's efforts to tap into Depakote patients, and Abbott's response: An Eli Lilly study found 47.2 percent of patients treated with Zyprexa achieved remission from mania compared to 34.1 percent for Depakote. In addition, the Zyprexa patients remitted in 14 days on average compared to 62 days with Depakote. (Another Eli Lilly study found that patients were significantly less likely to lapse into mania than lithium patients over one year.) An Abbot-sponsored study, on the other hand, found Depakote worked just as well as Zyprexa over 12 weeks, with fewer adverse events.

Lilly, however, has the competition covered: In 2003, the FDA approved Zyprexa for treating acute mania in combination with lithium or Depakote. One study of 344 manic patients found that 67.7 percent of patients responded to combined therapy vs 47.7 percent in the mood stabilizer alone group. Another Eli Lilly study found that 25 percent of patients on Zyprexa added to lithium or Depakote relapsed into depression after 155 days compared to 27 days for those on lithium or Depakote alone.

Symbyax

Symbyax - Eli Lilly was the first to exploit Zyprexa as a depression treatment, using the drug in a combination pill with Prozac. A series of studies presented at the 2002 American Psychiatric Association annual meeting looked at Symbyax (the trade name for the combination pill), low dose (six mg) Zyprexa and normal dose (25 mg) Prozac. Three other dosing options are 12/25 Zyprexa/Prozac, 6/50, and 12/50. The studies found that Symbyax worked for psychotic depression, treatment-resistant depression, and bipolar depression. At the 2003 APA meeting, Eli Lilly presented three large Symbyax studies, the first showing a 64.8 percent response for bipolar depression after eight weeks, with eight days to partial response. The second found a 77.8 percent response after eight weeks for depressed rapid-cyclers. A third study followed those depressed bipolar patients who had remitted on Symbyax through an open label maintenance phase over six months, finding 62.5 percent remained free from relapse. A 2003, Eli Lilly study of 833 patients with bipolar depression found that those on Symbyax showed greater improvement than the Zyprexa alone group and those on a placebo. Nearly 49 percent of the Symbyax patients remitted vs 32.8 percent of the Zyprexa alone patients vs 25.5 percent on a placebo. MADRS depression scores dropped by 15, 18.5, and 11.9 points, respectively. Switches into mania were about the same for all three groups (about six percent).

Eli Lilly advises that patients remain on the drug long-term, though patients experiencing severe metabolic effects may have other ideas.

In late Dec 2003, the FDA approved Symbyax to treat bipolar depression.

The product labeling states that the exact mechanism of Symbyax is unknown, but that animal studies show that the Zyprexa-Prozac combination produces "synergistic increases in norepinephrine and dopamine release in the prefrontal cortex compared with either component alone, as well as increases in serotonin."

The same worries about diabetes and hyperglycemia, drowsiness, and weight gain and EPS in Zyprexa also apply to Symbyax. The product labeling carries a similar diabetes/hyperglycemia warning to the one found on the Zyprexa labeling (a remote risk). The labeling also says somnolence occurred in 25 percent of Symbyax patients, leading to discontinuation in two percent. In the eight-week clinical trials, Symbyax patients gained 7.9 pounds (3.6 kg), 14 percent of them adding more than ten percent their baseline weight. The labeling reports that the incidence of tardive dyskinesia for Symbyax was infrequent (perhaps due to the low Zyprexa dose).

Ten percent of patients discontinued Symbyax due to adverse events compared to 4.6 in the placebo group.

The labeling advises that women who are pregnant or intend to get pregnant notify their physician, further advising to stay on the med only if the benefit outweighs the risks. Breast-feeding is not recommended.

Clozaril

Clozaril (clozapine) - Clozaril is the first of the atypicals, but because weekly blood work is required due to risk of damage to white blood cells (agranulocytosis), the drug is regarded as a last treatment option. The black box on the product labeling also carries warnings of the risk of seizures, fatal myocarditis, and other cardiovascular and respiratory effects.

In one study of 200 bipolar and schizoaffective patients, of the 17 successfully contacted 16 months after the initiation of therapy, 65 percent remained on Clozaril alone with no subsequent rehospitalization or affective episode. Clozaril has both an antimania and antidepressant effect. Compared to Zyprexa, it requires a much lower dose. In November 2002, the FDA gave preliminary approval for manufacturer Novartis to label the drug for suicide prevention, which would make it the first drug indicated for such a use (a large trial found the drug outperformed Zyprexa, with fewer patients involved in suicidal episodes and related hospitalizations).

With 39 percent of patients in clinical trials complaining of somnolence, the drug can be as subtle as a horse tranquilizer. It is also a potential diabetes risk and weight-gainer. On the good side, there is virtually no EPS risk.

Risperdal

Risperdal (risperidone) - In Dec 2003, manufacturer Janssen (part of Johnson&Johnon) received FDA approval to market Risperdal for acute mania and mixed episodes. A trial of 290 manic patients found 41.7 achieved remission after three weeks on Risperdal. Another trial of 283 patients found a drop in mania scores of 50 percent over 12 weeks. A three-week trial of 156 manic patients found those who received Risperdal plus a mood stabilizer showed a greater response than a mood stabilizer alone, and showed higher remission over the next 10 weeks.

In the trials submitted to the FDA: In one three-week trial of 246 patients (including some with psychotic symptoms), 43 percent achieved at least a 50 percent reduction in their mania scores, while a similar three-week trial (involving 286 patients) found a 73 percent response (with a pretty impressive 36 percent response for the placebo). A third trial - which included some with mixed episodes, psychotic features, and rapid cycling - found 57 percent of those on Risperdal in combination with either lithium, Depakote, or Tegretol achieved a response.

The drug has a 17 to 34 percent risk of EPS, depending on dose, and an initial weight gain that levels off. The drug is not associated with somnolence. In a study clearly designed to avoid being singled out by the FDA, Eli Lilly, makers of Zyprexa, sponsored a study showing Risperdal carries a similar diabetes risk.

A 2000 FDA briefing document reported that Risperdal elevated blood prolactin to more than 90, well above Haldol at less than 30 and Zyprexa at a borderline less than 20. The other atypicals did not result in significantly high prolactin levels. Hyperprolactinemia turns off ovaries and testes function, increasing risk of breast lactation and breast enlargement, leading to disrupted menstrual function and impaired sexual function in women and impotence and loss of libido in men. To combat this, an article in Current Psychiatry suggests less than five mg/day Parlodel (bromocriptine) or .25 mg weekly or twice weekly of Dostinex (cabergoline), or for nonsmoking women under 35 birth control pills.

The Risperdal labeling carries a hyperprolactinemia precaution, but states that "the clinical significance of elevated prolactin levels is unknown for most patients." A 2003 study by Knegtering et al reports that 60 percent of Risperdal patients reported sexual side effects vs about 27 percent for Zyprexa and about 44 percent for old generation antipsychotics.

In 2003, Janssen announced it would strengthen the stroke risk in elderly patients warning on its labeling.

An open study of 25 rapid-cycling patients receiving Risperdal added to a mood stabilizer found seven of nine improved their depressive symptoms and eight of 14 their mania symptoms.

Invega

In Dec 2006, J&J's "Son of Risperdal" (paliperidone) received FDA approval for treatment of schizophrenia, just as the company's patent on Risperdal was running out. The drug is already being applied off-label to treat mania, and an FDA indication for that purpose is probably not far behind. The drug is an active metabolite of Risperdal, which in theory indicates a cleaner version of the old drug and in practice means J&J gets to milk more profits from what is essentially the same compound. The drug's labeling carries the same hyperprolactinemia warning found on the Risperdal labeling.

Nevertheless, whern it comes to antipsychotics, even the slightest differences can have a huge impact. Patients who have had a bad experience with Risperdal may find Invega a life-saver.

Seroquel

Seroquel (quetiapine) - In January 2004, the FDA approved Seroquel for the treatment of acute mania, either as monotherapy or as an adjunct to lithium or Depakote. This was based on pooled data from two trials that found 48.1 percent of patients on the med achieved a response after three weeks and 37.5 percent achieved remission.

A 12-week trial involving 302 manic patients found those on Seroquel achieved a better response than those on the placebo and had less EPS than those on Haldol. A study of 302 manic patients found 53.3 percent responded to Seroquel by day 21.

Two trials involving nearly 500 manic patients found that Seroquel added to a mood stabilizer was more effective than a mood stabilizer alone.

An open trial of 41 rapid-cycling bipolar I patients found Seroquel was effective for manic and depressive symptoms over 18 weeks from week two onwards.

A study of 531 bipolar I and II patients with depression found that 300 or 600/mg/day of Seroquel resulted in drops in HAM-D scores of 13.8 and 13.4 (vs 8.5 placebo) and drops in MADRS scores of 16.7 and 16.4 (vs 10.2 placebo). A second trial yielded an FDA indication for treating bipolar depression.

The drug amounts to another possible horse tranquilizer, with 34 percent of those in clinical trials complaining of somnolence, but this is seen as an apparent asset by psychiatrists, who often prescribe it in very low doses for sleep. The drug has a low EPS risk of four to six percent. Weight gain is not a cause for alarm and the drug carries a remote diabetes risk.

Geodon

Geodon (ziprasidone) In Aug 2004, the FDA approved Geodon for treating acute mania and mixed episodes. A three-week 2003 double-blind study of 210 bipolar I patients (manic or mixed) found 50 percent of those on Geodon achieved a response, with a clinical benefit showing at day two. There were, however, EPS issues (though the product labeling shows only a five percent risk of EPS).

A small pilot study found the drug in combination with Zoloft useful for treating treatment-resistant depression.

The FDA delayed approving the drug for several years due to worries over heart rhythms (lengthening of the so-called QTC interval of the heartbeat), but Pfizer succeeded in convincing the FDA that its benign weight profile and therapeutic benefits outweighed the cardiac risks. The drug's labeling contains warnings about QTC prolongation and the possible risk of sudden death, but does not include the dreaded "black box" warning. In April 2002, Pfizer revised its labeling, warning against taking Geodon with other drugs that prolong the QTC interval. As of 2004, with two million patients treated on Geodon and no QTC-related deaths, psychiatrists are regarding the QTC issue as behind them.

Fourteen percent of those in clinical trials complained of somnolence, but weight was not an issue.

Abilify

Abilify (aripiprazole) received FDA approval for treating acute mania and mixed episodes in Oct 2004.. The drug has been called, "the first next-generation atypical antipsychotic," with a unique mechanism of action (a dopamine-serotonin system stabilizer) that, according a Bristol-Myers Squibb, "is mediated through a combination of partial agonist activity at dopamine D2 receptors and serotonin 5HT1A receptors, and antagonist activity at serotonin 5HT2A receptors. Partial agonism refers to the ability to both block a receptor if it is overstimulated and to stimulate a receptor when activity is needed."

This presumably has translated into a relatively benign side effects profile. According to the product labeling, only six percent of patients reported EPS effects, in sharp contrast to Zyprexa's 15 to 32 percent range. Company-sponsored trials also found Abilify showed "very significant" improvement for Parkinson's-like tremors and akathisia (motor restlessness) and "modest improvement" for tardive dyskinesia. The drug also passed muster on weight, heart rhythm, and serum prolactin. But before you ask your doctor to take you off your current antipsychotic, the product labeling shows a similar drop-out rate (six percent) compared to the other atypicals, with causes ranging from nausea and vomiting to headache to somnolence (11 percent of those in the clinical trials complained of somnolence).

Two company-sponsored studies involving more than 900 patients with acute mania found a response rate of 40 percent after three weeks. Another study failed, while a fourth, involving 347 patients over 12 weeks, resulted in a 50 percent response.

An open-label study of five patients who failed to respond to their antidepressant found four of them responded two weeks after adding low to full dose Abilify. In another study, 14 of 30 responded to low doses of the drug.

Conclusion

During the continuance or maintenance phase of treatment, the APA guidelines recommend weaning off an antipsychotic unless there are reasons not to while the TIMA algorithm recommends simplifying the meds regimen. Unfortunately, it is easier to add new meds or keep the old ones than to drop a med. According to an NIMH study, 3.3 percent of recently discharged patients were on three or more meds in 1974-1979. In 1990-1995 that figure was 43.8 percent.

At the 2003 Fifth International Conference on Bipolar Disorder, Gary Sachs MD of Harvard and principal investigator of STEP-BD reported on some early data from bipolar patients enrolled in STEP in 22 centers throughout the US, including the fact 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.

Updated Feb 10, 2008

Also Keep in Mind

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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