Wall Street Journal (8.9.04).

Drug Cocktails Hit Psychiatry.

In Largely Untested Method, Doctors Mix Several Medicines To Treat Some Mental Illness.

By LEILA ABBOUD

Psychiatrists are increasingly crafting drug cocktails of multiple medicines to treat depression, bipolar disorder and schizophrenia.

The approach, called "polypharmacy," aims to help people who don't respond to a single drug by putting them on several drugs that target different brain chemicals. The approach -- driven in part by the shortcomings of many available medications -- is psychiatry's answer to HIV/AIDS drug cocktails and combinations of cancer drugs.

But there are some key differences. Unlike HIV and cancer -- whose underlying cell biology is fairly well understood and that have been the subject of clinical trials involving drug combinations -- the causes of mental illness remain largely a mystery. Little research has been done about how to administer polypharmacy or whether it even works in some cases. Multiple drugs also mean multiple side effects -- and multiple prescription bills.

Doctors arrive at the right mix by tinkering with a sequence of different drugs based on past experiences, word of mouth and drug-company marketing that informs them about the strengths and weaknesses of each drug. A common combination pairs

Eli Lilly & Co.'s Prozac, which acts on the neurotransmitter serotonin, and GlaxoSmithKline PLC's Wellbutrin, which is thought to hit norepinephrine and dopamine. If that doesn't work, a doctor could pluck something else off the shelf such as low doses of thyroid hormone, lithium, antipsychotic drugs and stimulants.

Many psychiatrists believe that polypharmacy offers some of the sickest patients their best shot at recovering. "To a large extent, you do it out of desperation when everything else has failed," said Norman Sussman, a psychiatrist in New York.

Polypharmacy grows out of the evolving thinking in psychiatry that mental illness is at least partly rooted in biology -- the result of imbalances of brain chemicals that can be corrected with drugs. In addition, many drugs on the market today have fewer and milder side effects than older generations of medications, and doctors are less leery of prescribing multilayered concoctions than they once were.

One of Dr. Sussman's patients says she wouldn't be alive today if it weren't for the unique blend of drugs that she received. For years, Catherine W., who asked that her full name not be used, had suffered from debilitating depression, an eating disorder and a traumatic childhood history of sexual abuse. She was on the brink of suicide three times. Various doctors tried 18 separate medications with little success.

Dr. Sussman experimented with different drugs for several months before finding a combination that worked. The drug regimen included Klonopin for anxiety, Lamictal to stabilize mood, the antipsychotic Seroquel, the antidepressant Effexor, and a low dose of codeine, which releases opiates in the brain and which Catherine says helps curb her tendency to hurt herself.

Though there are side effects associated with each of these medication, Catherine says she hasn't experienced any while on the cocktail: "It has kept me stable for 3½ years now, which is pretty unbelievable for someone like me."

But some psychiatrists question whether more drugs are necessarily better. Gabor Keitner, professor of Psychiatry and Human Behavior at Brown University in Providence, R.I., thinks polypharmacy has gone too far. Patients are plied for years with a dizzying sequence of drugs that have side effects ranging from insomnia to lack of libido to weight gain. "I think we are overmedicating people," he says.

Dr. Keitner, who directs the inpatient mood-disorder clinic at Rhode Island Hospital, also worries that patients are getting the false hope that some magic combination of drugs will cure them. It may be better, Dr. Keitner says, to teach patients how to manage their conditions and emphasize continuing therapy. "This is leading us down a path that may not be good for patients or the profession," he says.

Still, for many, the cocktails provide long sought-after relief. Noreen Fraser, a 50-year-old mother of two from Los Angeles, was treated for depression with multiple drugs during her three-year battle with breast cancer. The powerful cancer drugs she took abruptly halted her body's production of estrogen, sending the normally animated television producer into a deep depression. "I couldn't even help my children with their homework," Ms. Fraser said.

Her psychiatrist, Andy Leuchter of the UCLA Neuropsychiatric Institute, tried combining two antidepressants. That worked only for a while.

Then last fall, Dr. Leuchter added a low dose of the antipsychotic medication, Zyprexa, into the mix. Within two days, Ms. Fraser felt better than she had in years. "It was like a cloud lifted," she said. She is still struggling with cancer, and she still takes the drug cocktail. Ms. Fraser didn't have a big problem with side effects, although she did gain about five pounds after starting on Zyprexa.

Of course, not all patients respond to the new approach. Dr. Leuchter had one patient in her early 40s, whom he treated with five different drug regimens over two years. Her problems persisted. It was impossible to find a combination that lifted her depression without side effects like sedation or an exacerbation of her anxiety. "It's sad," Dr. Leuchter says. "Depression has become a way of life for her."

There is one area of psychiatry where there is some scientific evidence of polypharmacy's efficacy: bipolar disorder, which is characterized by alternating periods of mania and depression. Significant evidence supports pairing a mood stabilizer such as lithium, Depakote or Lamictal with an antipsychotic such as Seroquel or Risperdal, says S. Nassir Ghaemi, a psychiatrist who wrote a book on polypharmacy.

Using multiple drugs to treat mental illnesses has become controversial partly because of the cost involved -- especially with schizophrenia. The standard therapy for schizophrenia today is the use of "atypical" antipsychotics, which have milder side effects than older drugs, but are relatively expensive. A month's worth of Bristol-Myers Squibb Co.'s atypical antipsychotic Abilify, for instance, costs $352 whereas generic clozapine, an older drug, costs $152. If a schizophrenic patient doesn't improve on one drug alone, doctors may add another atypical antipsychotic or one of the older "typical" drugs.

In some states, public-health programs have balked at paying for combinations of psychiatric drugs without evidence that the treatment actually works.

Insight on how to use combinations of drugs to treat resistant cases of depression may be provided by a large government-funded trial just completed that tested various prescribing strategies. But results of the trial, conducted with 4,000 depressed people in 13 states, aren't expected until May 2005.

Multiple Medications.

Here are some drug combinations that psychiatrists may try for various conditions if a patient doesn't respond to a single psychiatric drug:

Condition/Combination	Rationale	Comment
Depression: Two antidepressants, Prozac and Wellbutrin, are often used.	The hypothesis is that the two drugs hit different brain chemicals that are thought to play a role in depression. Prozac affects serotonin, while Wellbutrin works on dopamine and norepinephrine.	Some people may get the side effects associated with one or both of the drugs, including sleeplessness and weight gain. But Wellbutrin frequently reverses the sexual dysfunction associated with drugs like Prozac.
Bipolar disorder with frequent manic episodes: Lithium and an atypical antipsychotic such as Zyprexa or Seroquel.	Lithium stabilizes the alternating manic and depressed periods that characterize bipolar disorder. The atypical antipsychotic is thought to have similar effects.	Polypharmacy is common in bipolar disorder because treatment with only one drug is often ineffective. Significant evidence supports combination treatments for bipolar, more than for other disorders.
Bipolar with frequent depressive episodes: Lithium, an antidepressant such as Zoloft, and an atypical antipsychotic such as Zyprexa.	Lithium stabilizes mood, while the antidepressant keeps depressed periods at bay. Zyprexa also appears to stabilize mood and boosts the effectiveness of the antidepressant.	Use of triple drug combinations may significantly increase side effects such as sedation and weight gain.
Anxiety: Klonopin and the antidepressant Paxil.	Klonopin reduces anxiety while the antidepressant may elevate mood.	Benzodiazepines, the class of anti-anxiety drugs, can be habit-forming.
Attention Deficit Disorder: Strattera and Concerta together.	These drugs are thought to work differently in the brain so doctors think pairing them boosts effectiveness. Concerta is a stimulant while Strattera isn't.	The disadvantage of this combination is that both drugs may cause kids to have less of an appetite.
Schizophrenia: Two atypical antipsychotics such as Risperdal and Seroquel with an anti-anxiety drug such as Klonopin.	Lower doses of two different antipsychotics may avoid the severe side effects of a high dose of one medication. The Klonopin may help control the agitation sometimes caused by antipsychotics.	Getting people with schizophrenia to take a single medication is already difficult and adding drugs could make it even harder.