The new focus is on maximizing benefits and minimizing side effects



Maintaining Mental Health

The new focus is on maximizing benefits and minimizing side effects

Life's just much too hard todayAnd though she's not really illThere's a little yellow pill...And it helps her on her way,
gets her through her busy day

Just as in the ageless Rolling Stones song, many people today still struggle to get through the day. We have listened to Mike Wallace and Tipper Gore recount their battles with clinical depression. Six-time Grammy Award winner Naomi Judd has related her triumph over panic disorder. And let's not forget the fearless fictional character Tony Soprano and his countless therapy sessions on overcoming his depression and panic attacks.

All these celebrity revelations, it is hoped, will help dispel some of the stigma associated with mental illnesses. The popular notion that everyone is "dysfunctional" coupled with the stigma of having a "mental illness" keeps many people from obtaining help.

According to the World Health Organization's Global Burden of Disease study, major depression ranked second only to ischemic heart disease in magnitude of disease burden. Illnesses once shrouded in fear—cancer, epilepsy, HIV/AIDS—are increasingly seen as treatable, survivable, and even curable. However, mental health is often an afterthought, and illnesses of the mind remain shrouded in fear and misunderstanding.

Nevertheless, we do seem to be making some headway. President Bush's commitment to create a National Commission on Mental Health will, it is hoped, serve as a stimulus to remove the stigma that still surrounds mental illnesses and give a higher priority to mental health and well-being.

Pharmaceutical research is also helping to transform mental illness from a misunderstood cause of shame into a highly treatable condition. A 2000 survey conducted by the Pharmaceutical Research & Manufacturers of America found 103 medicines in the pipeline to help the more than 50 million Americans who suffer from some form of mental illness—from Alzheimer's disease and depression to schizophrenia.

Research carried out in the 1990s—the Decade of the Brain—produced many advances in our knowledge about the brain and mental illness. These advances included new groups of medications, such as the selective serotonin (and norepinephrine) receptor inhibitors (SSRIs/SNRI) and the atypical antipsychotic drugs that have been a welcome addition to the constellation of therapies available for the treatment of mental illnesses.

However, controversy still exists over which agent is appropriate for each individual patient. The following will guide the pharmacist on the trends and patterns of psychiatric pharmacotherapy to show how physicians and pharmacists decide which medications will maximize the benefits of drug therapy yet minimize the adverse effects.

New directions in treating anxiety

The umbrella term anxiety disorders, affecting more than 19 million Americans, describes a range of mental health problems including panic disorder (PD), specific phobia (SP), post-traumatic stress syndrome (PTSD), obsessive-compulsive disorder (OCD), social anxiety disorder (SAD), and generalized anxiety disorder (GAD).

The demands of stressful situations or even everyday life will cause most of us to feel anxious at different points in our lives—such as during an important job interview, first date, high school reunion, or meeting future in-laws. It is only when these anxieties persist for weeks and begin to interfere with occupational or social functioning that professional intervention is needed.

Because of the overlapping pathophysiologies of the anxiety disorders, the pharmacological treatments for these disorders are very similar. A recent comprehensive study by Decision Resources Inc., a Waltham, Mass.-based pharmaceutical research and consulting company, found that the SSRIs have seized the market for therapies to treat anxiety disorders.

There are five SSRIs currently available in the United States—fluoxetine (Prozac, Lilly), sertraline (Zoloft, Pfizer), paroxetine (Paxil, GlaxoSmithKline), fluvoxamine (Luvox, Solvay), and citalopram (Celexa, Forest). The only SNRI approved in the United States is venlafaxine (Effexor, Wyeth-Ayerst). The Food & Drug Administration has not approved all of these agents for all anxiety disorders. But experts contacted by Drug Topics all agreed that "off-label" use of these agents is common.

In data released by InfoScriber's Clinical Pharmacology Network (CPN), paroxetine dominated as the treatment of choice for anxiety disorders. InfoScriber uses data collected by practicing psychiatrists in its CPN. Paroxetine captured 21% of the market share, with sertraline coming in second with 15%, followed by citalopram (12%) and fluoxetine (11%).

In the past few years, there has been an increased awareness of the comorbidity with anxiety disorders—both among the different classes defining anxiety and with other psychiatric disorders (e.g., depression). One study demonstrated that in up to 90% of cases, GAD coexists with other psychiatric disorders, most notably SAD, which affects up to 59% of GAD patients.

These patients also frequently suffer from depression and panic disorder, as well. "The SSRIs are very good at treating a broad range of disorders," commented Robert Dufresne, Ph.D., BCPS, BCPP. He is associate professor of pharmacy practice at the University of Rhode Island, whose clinical site is at the Veterans Administration Medical Center, Providence. The multiple indications for the SSRIs/SNRI offer the advantages of monotherapy in addressing these comorbidities. The table outlines the approved indications for these agents.


SSRIs/SNRI—approved indications

Bulimia nervosa


Benzodiazepines (BZDs) have been used to treat anxiety for more than 30 years. "Now, we're seeing a lot more SSRIs than BZDs being utilized for most anxiety disorders," said Jadzia Najib, Pharm.D., clinical pharmacist at St. Luke's-Roosevelt Hospital Center, New York. Conflicting opinions exist on the use of BZDs. Although these agents are effective anxiolytics, they impose significant side effects, including dependence, tolerance, sedation, impaired psychomotor function, and withdrawal.

"The advantages of the BZDs is that they have a rapid onset of action," added Dufresne. Usually the BZDs are reserved for initiation of treatment during the two- to three-week lag period before the SSRIs take effect, and then are slowly tapered off once the SSRI effect is seen. The BZDs are contraindicated for patients with a history of substance abuse.

Gary Viale, Pharm.D., FCSHP, BCPP, is assistant director of pharmacy at the Santa Clara Valley Health and Hospital System, Santa Clara, Calif. In his practice, clonazepam and lorazepam are the BZDs he recommends most often. Clonazepam, he noted, is good for the outpatient because it has less abuse potential and lasts longer. Lorazepam is excellent for the inpatient when you need control quickly, as well as for use on an as-needed basis for the outpatient.

Among the tricyclic antidepressant (TCA) class, the most popular for the anxiety disorders, according to the Decision Resources study, are amitriptyline, clomipramine, and imipramine. However, their use in the treatment of anxiety disorders and depression has been rapidly declining. While current literature often cites the TCAs as viable options in the treatment of anxiety disorders and depression, the experts interviewed by Drug Topics consider their use obsolete for treating these conditions.

"I would never recommend a TCA anymore," declared Mark Sinnet, Pharm.D. He is director of clinical and educational pharmacy services, Montefiore Medical Center, New York. TCAs are less desirable, he explained, because of their adverse effect profile (anticholinergic effects, cardiovascular effects, weight gain, and sedation), interactions with oral contraceptives and other drugs, and toxicity in overdose. Viale stated that treating depressed patients with a TCA is analogous to giving them "a loaded gun."

Another agent, buspirone (Buspar, Bristol-Myers Squibb), is efficacious for GAD. Compared with the BZDs, buspirone is not sedating, causes no psychomotor impairments, and is not associated with withdrawal or abuse. A recent study suggested that at least 30 days should elapse between discontinuing BZD therapy and the initiation of buspirone. The researchers hypothesized that the noradrenergic activity of buspirone may aggravate the BZD withdrawal symptoms. In addition, it is important to educate patients about the delay in buspirone's therapeutic effect compared with that of the BZDs.

Buspirone has its niche for GAD as a nonbenzodiazepine, nonaddicting agent, but you really have to push it to 60 mg or more in order to see an effect, remarked Viale.

Other classes of drugs (antipsychotics, hypnotics, and sedatives) are used as adjunct therapies or reserved for treatment-resistant patients.

The chronic nature of depression

The Center for the Advancement of Health reports that approximately 10% of the U.S. population suffers from depression each year, at a staggering cost of $44 billion. In the National Institute of Mental Health report The Numbers Count: Mental Disorders in America, it was estimated that one in eight people will require treatment for depression during his or her lifetime. Yet, only one-third to one-half of these people are treated.

Depression is associated with high rates of relapse and recurrence, with current data demonstrating at least 50% and as many as 85% of patients will suffer a recurrence. The Agency for Healthcare Research & Quality recommended in its guidelines for the treatment of depression that therapy continue for at least nine months after symptoms subside to help decrease the risk of relapse. But recent data revealed that most patients do not fill four continuous monthly refills of their medications, dramatically increasing the risk of relapse.

One of the barriers to successful treatment is patient noncompliance. The National Depressive & Manic-Depressive Association (NDMDA), in its research, has identified several reasons for noncompliance, including financial factors; unacceptable side effects; short-term improvement, leading to the belief that continuing the medication is unnecessary; fears of addiction; and/or ineffective relationships between patients and their health-care professionals.

In addition, Lydia Lewis, executive director of NDMDA, referred to the results from a recent study showing that 78% of patients surveyed reported their depression wasn't completely controlled. "If three-quarters of diabetes patients weren't completely controlled, there would be a public outcry," she declared.

"Pharmacists play an extremely important role in uncovering some of these issues," commented Thomas Schwenk, M.D., professor and chair of the Department of Family Medicine at the University of Michigan. He added that pharmacists could facilitate communication between patients and their physicians by encouraging compliance and discussing the potential for side effects as well as the importance of reporting side effects to their physicians.

Start low, go slow

Choosing the appropriate antidepressant has proven to be an arduous and complicated task. As Lewis pointed out, "Every antidepressant works—just not for everybody." If we look at the numbers provided by InfoScriber, fluoxetine was the CPN's antidepressant of choice, with a 15% share, followed by bupropion (Wellbutrin, GlaxoSmithKline), 13%, and paroxetine and sertraline, with 12% each.

"The choice of drugs for treating the clinically depressed patient should be tailored to the patient's needs and characteristics," said Najib. Initial treatment with antidepressants is not always effective, often necessitating a great deal of trial and error. The mantra echoed by most clinical pharmacists is "start low, go slow."

Viale stressed that the SSRIs cannot all be lumped together—there are differences in efficacy among them and compliance issues to consider with the side effects. In his experience, paroxetine has the most anticholinergic effects and is associated with withdrawal effects (e.g., flu-like symptoms, headache). Pharmacists should, therefore, counsel patients to avoid abruptly stopping this medication.

Viale and Dufresne favor citalopram for the elderly because it is "most clean" from the standpoint of drug interactions. Dufresne advised that while bupropion is a good antidepressant, it doesn't have the cross-utility for OCD or panic disorders and has a mild stimulant effect, which may predispose a patient to insomnia.

Najib voiced concern about the weight gain and sexual dysfunction associated with the SSRIs. Nonetheless, she indicated that some of her patients tolerate the side effects because the beneficial effects of the drug outweigh the adverse effects. These side effect issues need to be discussed with the patient, stressed Najib, along with the demands of long-term therapy. It is important to address the possibility of sexual dysfunction and educate the patient about alternative options.

The evidence presented at the 153rd annual meeting of the American Psychiatric Association demonstrated that three antidepressants have minimal effects on sexual functioning: bupropion, mirtazapine (Remeron, Organon), and nefazodone (Serzone, Bristol-Myers Squibb). These agents do not affect dopaminergic neurotransmitters the same way the others do, and dopamine enhances sexual functioning. Serotonin inhibits sexual functioning while norepinephrine (NE), in contrast, has no known significant effect on sexual functioning.

Physicians and pharmacists have to get pretty creative with a broad range of medications and take into consideration the pharmacokinetics of the different drugs and the mixed-receptor issues. "Don't let the history of one medication and one experience dissuade you, just as you wouldn't give up if an antihypertensive medicine didn't work," declared Schwenk.

The atypical revolution

The atypical antipsychotics were developed to maximize efficacy while minimizing extrapyramidal symptoms (EPS), which have limited the use of traditional antipsychotics. Currently there are five atypical antipsychotics on the market—clozapine (Clozaril, Novartis), olanzapine (Zyprexa, Lilly), risperidone (Risperdal, Janssen), quetiapine (Seroquel, AstraZeneca), and the newly approved ziprasidone (Geodon, Pfizer). Unquestionably, a review of the latest medical literature shows that these atypical antipsychotics offer clear advantages over the typical antipsychotics, such as haloperidol, and are now considered first-line therapies for the management of psychoses.

Once more, if we look at the numbers provided by InfoScriber's CPN, olanzapine emerges as the clear leader among the antipsychotics as monotherapy, capturing a 30% market share, followed by risperidone with an 18% share. Additional noteworthy data gathered from this survey show that more than two-thirds (69%) of the CPN cases use combination therapies to treat schizophrenia and related disorders.

The most frequent pattern is the use of an antidepressant with an antipsychotic, accounting for almost 20% of the cases. Once again, olanzapine was the leader, capturing 34% of these combination therapies, followed closely by risperidone with 29%. Fluoxetine was the most common antidepressant, with 20%, and sertraline was second, with 17% of these combination cases.

The majority of the experts contacted by Drug Topics all echoed the same response as the survey, mentioning olanzapine as the most frequently used antipsychotic in their clinical settings. The limiting features for risperidone appear to be the dose-related EPS and its association with hyperprolactinemia. However, they all believe ziprasidone will offer stiff competition because of its weight-neutral and favorable lipid profile.

As with the SSRIs, each of the atypical antipsychotics has its niche with its own set of negative factors attached to it, necessitating the fine-tuning of each agent for each individual patient, stressed Viale. He reflected that if a patient is particularly sensitive to EPS, olanzapine or quetiapine induce them the least often of all the atypicals. If the patient has a weight problem, olanzapine or clozapine should be avoided, a better choice being risperidone or quetiapine. If the patient has been refractory to previous medications, then use clozapine. That agent is reserved for treatment-resistant cases because its most serious side effect, a 1% incidence of agranulocytosis, requires weekly blood counts.

Najib stressed that "the issues that have to be addressed are the weight gain, elevated triglycerides, and the upsurge of diabetes" that have now become associated with these newer agents.

"We are in our infancy in knowledge about the diabetes associated with the novel antipsychotics," commented Sinnet. The two agents implicated in elevated glucose levels are clozapine and olanzapine. One study found that patients taking clozapine and olanzapine showed a significant increase in plasma glucose compared with those taking risperidone and the control group.

In essence, as Dufresne said, "the atypicals offer real significant advantages. But, as with any drug, you have to watch for health problems." His advice was to closely monitor patients who are at risk, such as diabetics or overweight patients or the patients who already have hyperlipidemia.

A word from the feds

The federal government has recognized that claims concerning the benefits of one antipsychotic over another have come mostly from drug trials sponsored by the drugmakers themselves. In response to the conflicting data that have emerged from these studies, the United States is going to allot $42 million for a massive independent trial led by the University of North Carolina at Chapel Hill.

In January, the National Institute of Mental Health started enrolling 1,800 patients for the study, which will randomly compare the five atypicals with one another and with an older remedy—perphenazine (Trilafon, Schering). The results, to be unveiled in about three years, may help answer the burning question, Is any one of these drugs truly better than the others?

The mood stabilizers

One of the most exciting advances in treating psychiatric problems has been the realization that anticonvulsants are effective for bipolar disorder. The anticonvulsant valproic acid, according to the experts, is beginning to surpass lithium, as the "top gun" in treating this disorder. Studies have already shown that valproic acid (VPA) is as effective as lithium. As a result, it was approved by the FDA in 1995 for the acute treatment of mania.

"It's hard enough to get a bipolar patient to take his medication," declared Viale, adding that if there are fewer adverse effects, compliance should increase. Divalproex sodium (Depakote, Abbott) is the preferred formulation due to significantly fewer gastrointestinal disturbances as compared with VPA.

Carbamazepine (Tegretol, Novartis) has also become a mainstay in psychiatry. It is often used as second-line treatment in bipolar patients not responsive to VPA or lithium, commented Henry Cohen, Pharm.D., BCPP, associate professor of pharmacy practice at Arnold & Marie Schwartz College of Pharmacy, Brooklyn, N.Y. There is substantial evidence of carbamazepine's efficacy in the treatment of acute mania and when used as maintenance therapy. One must keep in mind, Cohen stressed, the need for baseline complete blood counts (CBCs) to monitor for signs of leukopenia and to strive for a therapeutic level of carbamazepine in the range of 6-10 mg/ml.

Many times, mood stabilizers are used to augment or complement antipsychotic medications—with many of these mood stabilizers being used off-label in the treatment of schizophrenia. The additional advantage of using drugs that treat epilepsy in psychiatry is the atypicals' propensity to decrease the seizure threshold, reasoned Cohen.

Other mood stabilizers used in treating psychiatric disorders are gabapentin (Neurontin, Parke-Davis), lamotrigine (Lamictal, GlaxoSmithKline), and tiagabine (Gabitril, Abbott). These agents are reserved for refractory conditions, and more studies are clearly needed to establish their efficacy.

Reimbursement hassles

To put it bluntly, Sinnet noted, the problem with managed care and mental health is that "reimbursement is obscene." Schwenk feels the "mental health system conspires against the primary care physician" by providing "limited insurance benefits."

But efforts are under way to change this situation. If legislation recently introduced in the House and Senate becomes law, Medicare would cover mental illnesses to the same extent it covers other physical ailments, and would expand to include community-based mental health services. The bill, entitled the Medicare Mental Health Modernization Act of 2001, would eliminate Medicare's current 190-day "lifetime cap" on inpatient psychiatric services and reduce the current 50% co-pay for outpatient mental health services to the same 20% charged for other outpatient care.

Health & Human Services secretary Tommy Thompson supports parity in insurance coverage for mental health but cautions, "It's not going to happen overnight."

A look ahead

An estimated $6 billion will be spent by pharmaceutical companies this year to develop medicines targeted for diseases of the central nervous system, including mental illnesses.

While the atypicals have responded to the challenges of treating psychotic disorders, there are gaps to be filled, namely injectable and long-acting formulations. To address these needs, olanzapine and ziprasidone are awaiting FDA approval for their injectable counterparts and a depot formulation of risperidone is undergoing phase III trials.

Developing novel formulations for existing drugs seems to be another priority for the drug industry. Eli Lilly recently received approval for its once-weekly enteric-coated formulation containing 90 mg of fluoxetine for the continuation phase of depression. Forest Laboratories is working on the S-entianomer of the racemic citalopram (escitalopram) for the treatment of depression. The firm hopes escitalopram will reduce the drug-drug interactions common to the SSRIs by not interacting with the cytochrome isoenzyme system. The compound completed a phase III trial in December.

In collaboration with Elan, Solvay is developing a single-daily-dose formulation of fluvoxamine, the only SSRI that normally requires twice-daily dosing. The drug is in phase III development for OCD.

GlaxoSmithKline has received an approvable letter from the FDA for its controlled-release version of paroxetine to treat PD. But a company representative indicated the firm is waiting for approvable letters for other indications before finalizing launch plans.

Finally, Bristol-Myers Squibb is developing a transdermal patch formulation of buspirone, which may allow the administration of higher doses that are better tolerated and potentially more effective.

Bristol-Myers Squibb is also hoping to file a New Drug Application in late 2001, for its mixed-dopamine D2 receptor agonist/antagonist, aripiprazole (Abilitat) for the treatment of schizophrenia. A four-week phase III study showed comparable control for schizophrenic symptoms for 15 or 30 mg aripiprazole, compared with 10 mg haloperidol. Following close behind is Novartis' mixed serotonin (5-HT) antagonist, iloperidone (Zomaril), which is slated to complete phase III studies in the second quarter of 2001.

Lilly currently is developing a dual-receptor inhibitor of 5-HT and NE, duloxetine, which it hopes will demonstrate a more potent and balanced inhibitor of 5-HT and NE than venlafaxine. It is currently in phase III development for the treatment of depression.

Finally, a lesson from Freud

While many people today criticize Sigmund Freud's treatment techniques, there is an important lesson for everyone in his revolutionary recommendations of a century ago. Freud learned that in order to understand and effectively treat a patient, a doctor had to listen to his patients. At that time, this contribution represented a quantum leap in psychological treatment. As NDMDA's Lewis reflected, people talk to their pharmacists, and "the stigma of the illness has gone to the medication," so take the time to really listen to your patients and help dispel the stigma.

Tammy Chernin, R.Ph.


Gary Viale, Pharm.D., BCCP, FCSHP, received his certification in psychiatric pharmacy in 1995 and loves his job at the Santa Clara Valley Health and Hospital System. But there aren't enough certified psychiatric pharmacists in the United States, so he urges pharmacists to get more involved—enlist the patient as a partner in care.

"Pharmacists have no idea how valuable they are in psychiatric medicine," noted Viale. "People talk to their pharmacists." Pharmacists can help identify potential barriers to compliance, such as adverse effects—weight gain, sedation, sexual problems—and remind patients of the importance of discussing these issues with their physicians, he continued. Pharmacists need to consider the possibility of depression when patients repeatedly come in for sleeping pills or pain relievers or persistently complain of tiredness or appetite changes, added Lydia Lewis, executive director of the National Depressive & Manic-Depressive Association (NDMDA).

Many health professionals now specialize in diabetes, hypertension, and cholesterol screening, but how often do you come across a depression screening? Pharmacists can hold "depression awareness and screening days," Viale urged, and offer educational brochures on mental illness and its management. By doing this, pharmacists can help alleviate the stigma associated with mental illnesses and dispel some of the common myths that prevent patients from getting professional care. Pharmacists can make a difference, he emphasized.

For more information, contact the National Alliance for the Mentally Ill at , (703) 524-7600, or NDMDA at , 1-(800) 826-3632.


Tammy Chernin. MAINTAINING MENTAL HEALTH. Drug Topics 2001;11:33.

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