Ask me about power
and I'll tell you cigar smoke,
the way it darkens like a thunderhead

or curls thin as an assassin's wire.
I'll tell you how smoke 
sticks to your flesh

for the length of a career,
and I'll tell you about the day
the Chairman of Psychiatry

gathered us in a conference room,
pulled a Havana from his pocket, 
chewed the end, and blew

each long drag in the patient's face
shouting, "Are you crazy?"
as if the man could remove an electrode

planted in his brain by the FBI.
And when the patient finally cried,
the Chairman turned

to his audience of students and residents, 
took the cigar from his mouth,
and examined it like a surgical instrument,

slime at one end, the tip burning red.
He smiled at the cigar, chomped down,
took another suck.

Articles

Ask me about power and I'll tell you cigar smoke, the way it darkens like a thunderhead

Power

On April 18 in Boston, awards were given to a group of individuals whom some credited with raising the national consciousness of the risks of elevated cholesterol, persuading thousands of patients to discuss medical concerns with their physicians and contributing to improving the health of the nation overall.

But not everyone agrees. Their critics say these people helped raise the costs of health care, led to confusion among patients about their treatment and added to the burdens of physicians.

Among those nominated were the marketers who created advertising for products such as Claritin (loratadine), Zyrtec (cetirizine), Nexium (esomeprazole), Lipitor (atorvastatin) and Paxil (paroxetine). Their accomplishments are seen by millions of television viewers, magazine readers and newspaper subscribers. They are the leaders of a relatively new category of prescription drug sales: direct-to-consumer (DTC) advertising.

"There is a major difference of opinion," according to Gary Stein, Ph.D., director of federal regulatory affairs for the American Society of Health-System Pharmacists. He explained to 

, "There are those who believe that increased DTC advertising leads to increased patient demand for those drugs and to increased prescribing. On the other side, some people believe that increased DTC advertising causes more patients to go to their health care providers and talk about whatever conditions they may have. If the prescriber happens to write a prescription, that's fine. They also believe that in many cases the physician will prescribe something else."

Direct-to-consumer advertising has become the focal point of a major national debate over pharmaceutical marketing practices. Critics say it is a major factor in the 17.1% increase in prescription drug spending last year, and at least one member of the U.S. Congress has called for its ban. 

But supporters of DTC advertising argue that consumers have benefited from the ads. For example, a spokesperson for the Pharmaceutical Research and Manufacturers of America told a Congressional hearing, "In the two years that ads for a medicine for erectile dysfunction [Viagra] have appeared, millions of men have visited their doctors to ask for a prescription. For every million who asked for the medicine, it was discovered that some 30,000 had untreated diabetes, 140,000 had untreated high blood pressure, and 50,000 had untreated heart disease." 

Marketers spent $2.8 billion on DTC advertising in 2001, a 12% increase over the year before, according to NDCHealth, an Atlanta-based health care information services company. NDCHealth said the rate of growth in drug promotional cost slowed to 6% from 6.7% in 2000.

The 20 best-selling prescription medications in 2001 included three antidepressants -- Zoloft (sertraline), Paxil and Prozac (fluoxetine) -- and two antipsychotics -- Zyprexa (olanzapine) and Risperdal (risperidone). Paxil ranked third in DTC advertising expenditures at $95.8 million, according to NDCHealth. Another study, published in the 

, put spending on Paxil ads at $65.12 million, and DTC advertising for Zoloft at $55.93 million.

Earlier this year, the Henry J. Kaiser Family Foundation published a study titled "Trends in Direct-to-Consumer Advertising of Prescription Drugs." Among the findings: 

Spending on direct-to-consumer advertising increased from $266 million in 1994 to nearly $2.5 billion in 2000. Much of the growth can be attributed to a greater use of television commercials to promote drugs: "In 1994, television advertising accounted for roughly 13 percent of the DTC advertising spending, while in 2000 over 60 percent of the DTC advertising spending was on television advertising."

Physician promotion -- detailing, sampling conferences and journal advertising -- still accounts for nearly 85% of the total spending on prescription drug promotion. Spending on physician-oriented promotion increased by roughly 58% between 1996 and 2000, the report noted, but DTC's share of the promotional budget rose from 9% to 15% during that period.

Promotional expenditures as a percentage of total sales has remained relatively constant at around 14% a year. "Marketing budgets are not claiming a larger share of the sales dollar today than they did in the early 1990s," the report stated. Still, promotion represents a larger percentage of the sales dollar in the pharmaceutical field than it does in most other industries, and DTC's share of the pharmaceutical sales dollar has grown from 1.2% to 2.2%.

Direct-to-consumer advertising is concentrated on a relatively small number of products, but its impact is substantial. The 20 products with the highest levels of DTC spending in 2000 accounted for about 59% of the total industry spending on consumer-oriented promotion. But those 20 drugs are among the 50 best-selling prescription medications. "In addition, high DTC advertising spending appears to be associated with relatively new products that have no generic competitors," the report states. "In some cases, products at the end of their patent protection advertise directly to consumers to promote their product for a new indication or because they are switching to over-the-counter status and need to build brand equity."

According to NDCHealth, DTC advertising in 2001 accounted for 23% of the total promotional budget for all prescription medications, while journal advertising fell to only 3% of the total.

Robert Erlich, chief executive officer of Rx Insight Inc. and publisher of 

that it is not surprising that consumer-oriented advertising requires a larger budget than journal advertising. "Just look at the cost of the media. You pay $60,000 for some pages in 

 can cost $500,000 to $600,000. You pay $2 million a minute for the Super Bowl. That's more than your whole journal budget for a year."

 or spot ads during the Super Bowl have also raised the visibility of DTC advertising, leading some critics to call for its regulation or elimination. Rep. Henry Waxman (D-Calif.), the ranking minority member of the House Governmental Reform Committee, told a hearing, "Whatever your view of whether these ads should be allowed (and frankly I don't believe they should), most of us would agree that we should have a system that ensures that direct-to-consumer drug ads are accurate and fair. We do not have such a system."

Sidney M. Wolfe, M.D., director of the Public Citizen Health Research Group, in a letter to the 

, said, "The education of patients -- or physicians -- is too important to be left to the pharmaceutical industry." Wolfe called on the National Institutes of Health and the U.S. Food and Drug Administration to "replace tainted drug company 'education' with scientifically based, useful information that will stimulate better conversations between doctors and patients and lead to true empowerment."

The American Medical Association, while refusing to petition the government to ban DTC advertising, has called for a regulation requiring ads to feature the sentence, "Your physician may recommend other appropriate treatments." In addition, the AMA plans to collaborate with the National Council for Patient Information and Education to create and distribute materials that will educate consumers and physicians about the risks, benefits and potentially misleading information in drug ads.

Critics of consumer-oriented promotion of prescription drugs say that ads are changing the physician-patient relationship and that physicians will feel pressured to prescribe drugs that patients ask about based on advertising. One study in 

 concluded, "Clinical quality of care is harmed by DTC advertising." However, while definitive studies of the effect of advertising are only beginning, the preliminary findings do not seem to support the critics' worst-case fears.

Researchers led by Meredith Rosenthal, Ph.D., of the Harvard School of Public Health wrote in the 

, "The relatively moderate emphasis on direct-to-consumer advertising by the pharmaceutical industry contrasts with the apparent degree of concern about it among physicians and policy makers."

One survey Rosenthal cited "found that 71 percent of family physicians believe that direct-to-consumer advertising pressures physicians into prescribing drugs that they would not ordinarily prescribe." 

Rosenthal's team found "relatively few people surveyed (less than 6 percent), however, actually received a prescription for the advertised drug after being prompted by direct-to-consumer advertising to ask their doctor about the drug."

A study by Woodie M. Zachry III, Ph.D., and others in the 

American Journal of Health Systems Pharmacists

 raised further questions about the effectiveness of DTC advertising. It analyzed the relationship between advertising expenditures and sales of the drugs being promoted. While some medications showed a positive correlation, the effect was not consistent.

Using data from 1992 to 1997, Zachry and colleagues found, "Analyses related to the antihypertensives and BPH [benign prostate hypertrophy] medications produced no statistically significant associations between advertising expenditures and the number of prescriptions written or diagnoses. 

"A significant relationship was found between the monthly number of diagnoses for hyperlipidemia and the amount of money spent advertising the NDCD [national drug code directory] class of antilipemics (

=0.008). A statistically significant relationship was found between the monthly number of antilipemic medications prescribed and the amount spent advertising all antilipemic drugs (

=0.003)...Every $1000 spent advertising antilipemics was associated with approximately 32 people diagnosed with hyperlipidemia and 41 antilipemic prescriptions written."

While "every $1000 spent advertising antihistamines was associated with 24 prescriptions written for Claritin, [there were also] approximately 20 fewer prescriptions for Seldane [terfenadine], and 7 fewer prescriptions for Hismanal [astemizole]." 

(Both Seldane and Hismanal were removed from the market -- Ed.)

In addition, "A significant negative association was found between the monthly number of prescriptions written for Zantac [ranitidine] and the amount of money spent advertising acid-peptic disorder medicationsEvery $1000 spent on advertising acid-peptic disorder medications was associated with approximately 59 fewer prescriptions written for Zantac."

The researchers said that DTC advertising "may not be a factor in the provision of care for every condition. When a statistically significant association was found, direct-to-consumer advertising expenditures accounted for a modest amount of the variance (approximately 10-30 percent) associated with diagnosing and prescribing."

While there are reasons to fear the impact of DTC advertising, so far the data do not tend to support those fears. A family practitioner, Robert D. Swift, M.D., said his main concern about DTC advertising was the impact of the warning messages mandated by the FDA in its 1967 guidelines. He told PT, "I have patients who are taking some of those drugs because they need them, and they are scared to death because they've heard all of the negatives in the advertising. And for some people, if you read about the side effects, you'll suddenly get them."

 ran six articles in two days about the impact of DTC advertising. On its Web site, the newspaper provided a feedback box for readers to respond to the question, "Does advertising influence your use of prescription drugs?" While it hardly constitutes a scientific survey, the results may indicate that the public is more savvy than policy-makers give them credit for: 62% of the respondents checked the answer "I rely solely on my doctor's advice." 

(For more information on DTC Advertising, please see the PT Online Exclusive article "

Patient Drug Information From Mass Media Sources

The increased money being spent on marketing pharmaceuticals directly to patients is raising questions. Are patients indeed benefiting by becoming more aware of their health, or are they simply being used as a target market for the latest drug?

Does DTC Advertising Benefit Patients?

Patient demand for specific prescription medications is a growing phenomenon. In a social context, this demand has been influenced greatly by changes in pharmaceutical marketing, in the amount and nature of medication information directly accessible to patients, and in the ways in which "drug discoveries" are reported in the mass media. Knowledge, attitudes and behaviors involving medications are often based on the perceptions that people hold regarding specific drug products. Great differences in these perceptions can occur between patients and health care professionals (Montagne, 2001; 1996).

Mass Media and Perceptions of Drugs and Drug Use

Prescription drug use is an everyday occurrence for most people. Knowledge creates perceptions about medications and the intent to use them to solve health problems. What is the impact of various sources of information, including mass media, on the creation of perceptions about drugs and drug use?

Collective social knowledge has become instrumental in the development and transmission of perceptions about prescription medications, including psychoactive drugs (Montagne, 2001, 1996). Social knowledge refers to the collective accumulation of information and past experiences about a specific topic. What an individual or group of drug-users knows about drugs from reading information, listening to the media and promotional campaigns, receiving descriptions of others' experiences, and recalling their own previous experiences, will affect the actual use of drugs (Montagne, 2001; 1996).

Social knowledge also has a symbolic component (Montagne, 2001; 1996). The nature and meaning of drug use often is described, remembered and transmitted through society in symbolic form, as images, representations or metaphors. The imagery and symbolism in advertising and mass media sometimes suggest to patients that a specific medication promises to solve health and life problems in magical ways.

In addition to reports in the mass media, including electronic media, perceptions about drugs are derived through advertising (Montagne, 1992). In the United States, direct-to-consumer advertising (DTCA) is increasingly popular, wherein the availability and characteristics of a prescription drug product are promoted to the general public through mass media. These advertisements inform or increase awareness about certain diseases and the availability of treatment options. 

It is estimated that the number of prescriptions written in the United States will increase from 2.9 billion to an estimated 4 billion by 2004, which includes an increase in the number of prescriptions for psychiatric medications. Anecdotally, pharmacists have reported that the day or two after a news story or new DTCA for a medication comes out, they will see a massive increase in the number of prescriptions for that specific medication.

Media Representations of Antidepressant Medications

A recent study (Montagne, 2001) examined what we know about certain antidepressant drugs and how we have arrived at our current collective knowledge. The primary goal of this study was to identify specific media representations of antidepressant drugs and to examine these images in comparison with known clinical information regarding them.

The results of this analysis portray an extensive and deeply rooted cultural awareness of these drugs. Over the past 20 years, the frequency of magazine and newspaper accounts and reports of antidepressant use peaked during three time periods: 1) 1977 to 1978, during a time of increased societal concern about depression; 2) 1980 to 1982, when a new generation of antidepressant drugs (tetracyclics like trazodone [Desyrel]) were introduced; and 3) 1990 to 1994, which represented the Prozac (fluoxetine) phenomenon.

By the spring of 1990, Prozac was on the cover of 

 and was being proclaimed as the new wonder drug and a new weapon in the fight against depression. In fact, the appearance of a Prozac capsule floating over a dry landscape on the cover of 

 was the first time any prescription pharmaceutical product (and any drug other than heroin, cocaine or marijuana) had been shown on that magazine's cover. Between 1992 and 1994, Prozac exploded into the mass media and the public's consciousness (1992-1994) with a number of popular books (e.g., 

 [Wurtzel, 1994]), a theatrical play (Prozac Sisters), an electronic video game (

) and talk show visits by enthused therapists (Montagne, 2001).

Media accounts suggested that Prozac did a lot more than just influence serotonin in a person's body, extending perceptions of the indications of use beyond those recognized and accepted by most health care professionals (Montagne, 2001). For antidepressant users, this drug obviously relieved conditions such as depression and premenstrual syndrome, and certain symptoms such as anxiety. Users, however, also reported that Prozac produced other types of effects such as: elevated or changed mood, nervousness, anorexia, insomnia, enhanced performance, calmness, reversed shyness, reduced or enhanced sex drive, changed personality even in nondepressed people ("cosmetic psychopharmacology"), enhanced spirituality, mania, drowsiness, tremor, dizziness, weight gain or weight loss, feeling "out of it," excessive laughing or weeping, and a loss of concentration (Elfenbein, 1995; Karp, 1997; Montagne, 2001). Early media reports referred to Prozac as the pill that will "cheer you up without side effects" and described "how science will let you change your personality with a pill" (Beyond Prozac, 1994).

In these media reports, Prozac was referred to primarily as the Happy Pill, the Feel-Good Pill and the Personality Pill. It also was presented in some accounts as an "upper." Patients used a variety of images and metaphors to understand and describe their reasons for using Prozac and for the effects they experienced (Montagne, 2001). These metaphors ranged from "magic bullets" to "like insulin for my mind/mood." In March 1994, Eli Lilly and Company launched an advertising campaign to condemn and counter the ever-growing role of mass media in exaggerating the drug's effectiveness (Listening to Eli Lilly, 1994).

A popular book of anecdotal accounts from Prozac users, almost a decade after its introduction, suggested other therapeutic uses for Prozac including: attention-deficit/hyperactivity disorder, obesity, chronic fatigue syndrome, ulcers and other gastrointestinal disorders, and chronic pain (Elfenbein, 1995; Montagne, 2001). The rationale for these uses, as stated by a promotional blurb on the book's back cover, is, "In these pages, the real expert--sthose who are taking antidepressants nowoffer frank testimonies that explore what it is like for them to take Prozac."

Mass media heighten public interest about certain types of medication use, through its ability to provide opportunities for the expression of expert and lay viewpoints (Cohen, 1983; Morgan, 1983). Knowledge about depression and its treatment is created through a process in which fragmentary, restricted knowledge is continually transformed into certain and consistent fact.

It seems mass media are becoming the primary source of drug information for many consumers. In the real world of medication use, humans often are not rational in making decisions to use drugs. Patients often are not aware, nor made aware by health care professionals, of all possible treatment options in arriving at a therapeutic plan.

However, not all patients will enter the clinical encounter with specific demands for medications. Those that do are probably in the process of developing a relationship with a psychiatrist or have tried a variety of treatments without success. Patients in good relationships with their psychiatrists and on beneficial treatments will be reluctant to change based solely on information from mass media (although they may ask some questions). 

Expectations do affect patient care and outcomes. Psychiatrists probably are the best trained of all physicians to be willing to listen carefully to what their patients are saying (time constraints in managed care settings and other barriers aside). If patients do not raise questions or issues that are coming from mass media (will my antidepressant make me commit suicide?), then there is little concern. It is to those patients who bring notions and expectations, based on what they learn from mass media, to the encounter that the psychiatrist will need to listen and attend.

Imagery and symbolism of antidepressant drug advertisements can generate ideas in the minds of health care professionals and patients that problems are easily or magically resolved by a pill. The notion develops that there is a pill for every problem.

Clearly, the media have raised awareness and focused attention on various psychiatric conditions and the stigma that surrounds them. Reaction to mental illness among the general public is probably based on the nature of the specific media report or DTCA (positive, supportive, caring versus negative, neglectful, bewildering, unsupportive).

Future research must focus on the growing impact of mass media accounts on both patients' and health care professionals' perceptions of antidepressant drugs. While the generation of media representations of antidepressant drugs is clearly connected to users' perceptions, their actual dependence on these notions with regard to decisions to use these drugs still remains unclear. The impact ultimately of these perceptions on actual experiences with antidepressant drugs may be the foundation to understanding the future of treatment approaches to depression.

 Beyond Prozac (1994), Newsweek. Feb. 7, pp36-40.
 

 Breggin PR (1995), Talking Back to Prozac. New York: St. Martin's Press.
 

 Cohen S (1983), Current attitudes about benzodiazepines: trial by media. J Psychoactive Drugs 15(1-2):109-113.
 

 Elfenbein D, ed. (1995), Living With Prozac, and Other Selective Serotonin-Reuptake Inhibitors: Personal Accounts of Life on Antidepressants. San Francisco: HarperCollins.
 

 Karp DA (1997), Speaking of Sadness: Depression, Disconnection, and the Meanings of Illness. New York: Oxford University Press.
 

 Kramer PD (1993), Listening to Prozac. New York: Viking Press.
Listening to Eli Lilly: Prozac hysteria has gone too far (1994), Wall Street Journal, March 31, pB1.
 

 Montagne M, ed. (1992), Drug advertising and promotion: an introduction. Journal of Drug Issues 22:195-480.
 

 Montagne M (1996), The pharmakon phenomenon: cultural conceptions of drugs and drug use. In: Contested Ground: Public Concern and Private Interest in the Regulation of Pharmaceuticals, Davis P, ed. New York: Oxford University Press, pp11-25.
 

 Montagne M (2001), Mass media representations as drug information for patients: the Prozac phenomenon. Subst Use Misuse 36(9-10):1261-1274.
 

 Morgan JP (1983), Cultural and medical attitudes toward benzodiazepines: conflicting metaphors. J Psychoactive Drugs 15(1-2):115-120.
 

 Wurtzel E (1994), Prozac Nation. Boston: Houghton-Mifflin.   © CME LLC
5/02

Progress in developing medications and strategies for treating addiction were juxtaposed with the challenges of implementing accessible and effective treatment programs at The State of the Art in Addiction Medicine conference conducted by the American Society of Addiction Medicine (ASAM) Nov. 1-3, 2001, in Washington, D.C. The conference, themed "From Molecules to Managed Care," was co-sponsored by the Center for Substance Abuse Treatment (SAT), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the National Institute on Drug Abuse (NIDA).

Evaluating New Medications for Addiction Treatment

Ahmed el-Kashef, M.D., acting chief of the clinical/medical branch of the division of treatment research and development in NIDA, described NIDA's efforts to develop and evaluate agents to treat addiction. The program currently involves 55 medications in different phases of development, ranging from products marketed for other indications to new molecular entities developed for specific addictions. Among the agents being evaluated by NIDA for stimulant addiction are two investigational monoamine uptake inhibitors (MAOIs); the MAOI selegiline (Zelapar, Eldepryl); the antidepressants desipramine (Norpramin), sertraline (Zoloft) and venlafaxine (Effexor); dopamine agonists cabergoline (Dostinex) and amantadine (Symmetrel); serotonin antagonist ondansetron (Zofran); g-aminobutyric acid agonists tiagabine (Gabitril) and gabapentin (Neurontin); and catechol-O-methyltransferase inhibitor tolcapone (Tasmar). El-Kashef characterized the opioid agonist-antagonist buprenorphine (Subutex) -- alone and in combination with antagonist naloxone (Narcan) -- as well as the opioid antagonist naltrexone in depot formulation (Depotrex) as very promising agents for treatment of opiate addiction. 

Although naltrexone (ReVia) is principally being evaluated as a means to support abstinence from opiate use, researchers outside the United States have employed it in protocols for rapid opiate detoxification. In a July 2001 press release, researchers in Brisbane, Australia, discussed findings from the first controlled trial of heroin-addiction treatment, contrasting rapid opiate detoxification with naltrexone and general anesthesia to methadone maintenance. The researchers characterized the naltrexone approach as less expensive and more effective at reducing heroin usage than conventional treatments. One of the researchers in the Australian study, John Saunders, M.D., professor of alcohol and drug studies at University of Queensland in Brisbane, commented to the press, "I am hoping that these trials and their results will provide considerable impetus to establish rapid detoxification and naltrexone-supported abstinence treatment as a viable treatment option."

El-Kashef indicated that NIDA is also investigating neuroendocrine, electrophysiological and neuroimage changes in response to addictive drugs and remedial measures. "New interest has arisen in biological markers of addiction to identify subtypes of patients who may respond differently to specific medications," he noted. "This approach may be promising in maximizing medication effect, or predicting relapse."

Also at the 2001 conference, Raye Litten, Ph.D., chief of the treatment research branch in the division of clinical and prevention research of NIAAA, described naltrexone and the glutamatergic modulator acamprosate (Campral) as the most promising and successful medications developed to date to treat alcoholism. "Although naltrexone is not a 'magic bullet,'" Litten explained, "it appears to have a moderate effect in reducing drinking, particularly decreasing relapse to heavy drinking." 

The success of naltrexone for alcoholism may depend in part upon patient characteristics. A recently published trial (Krystal et al., 2001) in a mostly male Veterans Affairs population with chronic, severe alcohol dependence did not evidence benefit from naltrexone. In the multicenter, double-blind trial, 627 patients were randomized to receive either 12 months of naltrexone, 50 mg daily; three months of naltrexone followed by nine months of placebo; or 12 months of placebo. All patients were offered counseling and were encouraged to comply with the study medication regimen and attend Alcoholics Anonymous meetings.

At 13 weeks, the investigators found no significant differences between the groups in the number of days to relapse. Also, after 52 weeks, no difference in the groups was found in the percentage of days drinking or the number of drinks per drinking day. In an accompanying commentary supporting the use of naltrexone and offering reasons why the results from the Krystal et al. study may not be generalizable to all populations, Fuller and Gordis (2001) pointed out that recovering alcoholics who are married and employed are more likely to remain abstinent and that only one-third of this population had a spouse or live-in partner and, apparent from the disability pensions, only two-thirds appeared to be employed, both which possibly affected their motivation to stop drinking. Fuller and Gordis also questioned the adequacy of counseling in this study. 

While naltrexone is only the second agent to be approved by the U.S. Food and Drug Administration for treating alcoholism, some 50 years after approval of disulfiram (Antabuse), it is anticipated that acamprosate will soon be the third. Acamprosate is now approved for this indication in 40 countries. A New Drug Application is expected to be filed with the FDA in this year, according to Forest Laboratories, which would market acamprosate in the United States.

Acamprosate would offer not only a third option of therapeutic agents for alcoholism, but also a mechanism that differs from both the "reward circuit" blunting ascribed to naltrexone and the aversive effects of disulfiram. Acamprosate is thought "to inhibit the stimuli that can make alcohol 'negatively reinforcing,'" as alcohol levels in the central nervous system recede (Littleton and Mayer, 1999). In animals, it appears highly effective in inhibiting alcohol consumption prompted either by alcohol withdrawal or restriction.

In addition to affecting aspects of alcohol withdrawal, however, acamprosate exerts clinical effects independent of the presence of alcohol. At the 1999 State of the Art Conference, John Littleton, M.D., Ph.D., professor of pharmacology at University of Kentucky, described clinical findings with acamprosate. "Relapse actually seems to be prevented in many cases, rather than just ameliorated," he told attendees. "For this reason, it has been suggested that acamprosate may inhibit those cue-induced signs and symptoms that are very similar to withdrawal and that may precipitate relapse in abstinent alcohol dependent patients."

Litten has been enthusiastic about the clinical experience with acamprosate since that conference in 1999. "Alcoholic patients treated with acamprosate are more likely to complete treatment, have longer times to their first drink, and have higher abstinence rates than placebo-treated patients," he noted at the 2001 conference.

Litten also indicated that NIAAA is now investigating whether the combination of naltrexone and acamprosate is synergistic in treating alcoholism. The multi-site protocol contains tracks with acamprosate alone and in combination with naltrexone, and it also compares two types of behavioral/psychosocial therapies. Other promising agents under NIAAA research, Litten disclosed, include another opioid antagonist, nalmefene (Revex), and the serotonin (5-HT

"Development of more effective medications has the potential to vastly improve treatment outcome and reduce the suffering of millions of alcoholic patients and their families," Litten concluded.

Accessing and Succeeding in Treatment Programs

A recurrent issue at the conference was the gap between promising new treatments and the health and social policies that fail to provide addicts access to effective treatment programs. Suggesting one means of bridging the gap, Lee Dixon, director of the National Conference of State Legislatures' Health Policy Tracking Service, discussed recent RAND center research, indicating that the addition of full parity benefits for substance abuse and mental health care to private insurance plans can be accomplished with only a 3% to 4% increase in premium. The addition of only substance abuse benefits was estimated to result in a 0.3% increase.

The RAND study director, Roland Sturm, Ph.D., testified in July 2001, "Our results suggest that parity in employer-sponsored health plans is not very costly under comprehensively managed care, which is the standard arrangement in today's market place."

Substantial barriers to successful treatment outcome are also presented by the addicted patients themselves, and several speakers at the ASAM conference described intervention modalities that motivate or facilitate participation. Carlo DiClemente, Ph.D., chair of the department of psychology at University of Maryland, Baltimore County, discussed Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity) and research with motivational enhancement therapy (MET) to promote treatment participation and successful recovery from substance abuse.

DiClemente (1999) previously suggested that the readiness of drug dependent patients for treatment and successful recovery occurs in stages: considering change (precontemplation stage); intermediate decision-making (contemplation stage); planning (preparation stage); making the change (action stage); and sustaining the change over time (maintenance stage). "Most treatment programs are action-oriented," DiClemente pointed out to conference attendees, "but clients seeking treatment at these programs are not always ready for action."

DiClemente (1999) distinguished between imposed and intentional change, noting that the former is often short-lived. Although supportive of therapeutic interventions within the corrections-penal system, he also noted that court-mandated attendance at treatment programs does not indicate that individuals are necessarily motivated to change substance-abusing behavior. DiClemente also contrasted readiness for change to readiness for treatment. He notes that many substance-dependent patients will relapse after the first attempt at treatment and suggested that treatment, as a time-limited event, should be considered as a part of the larger process of change.

One method to increase the level of participation intensity and the likelihood of treatment success is to incorporate contingency management, according to a presentation at the ASAM conference by Nancy Petry, Ph.D., associate professor at University of Connecticut Health Center. Petry and colleagues (2001) recently argued, "A primary benefit of positive-incentive contingency management approaches is that they increase the percent of patients who respond favorably to treatment."

Often taking the form of contingency contracting with the patient, this treatment strategy involves frequent monitoring of target behaviors, such as drug abstinence and obtaining employment; tangible, positive reinforcers for the target behavior; and withdrawal of the reinforcer when the target behavior does not occur. 

(For more information on contingency management, please see related article "

Contingency Management in Addiction Treatment

Petry has acknowledged criticism of contingency management approaches, however, on the basis of cost and the question of their applicability in community-based treatment programs. Clinics without research funding are unlikely to be able to offer voucher programs or other tangible reinforcers, and less expensive approaches may be necessary for adaptation in community-based settings.

Still, as noted in their research, Petry and colleagues (2001) remain hopeful:

As more and more clinicians and researchers apply contingency management procedures to treat substance-abusing patients, new developments and refinement in the techniques may emerge. We may discover less expensive yet efficacious reinforcers, determine the best behaviors to target, and evaluate the time course and optimal duration of interventions.

David Gastfriend, M.D., assistant professor of psychiatry at Massachusetts General Hospital and co-chair of the 2001 ASAM conference, discussed treatment-placement considerations. He distinguished between the matching of patients with an optimal theoretical treatment modality, as evaluated in Project MATCH, and placement matching for the least restrictive setting and resource intensity.

Criteria for placement match have been developed by ASAM, Gastfriend noted, and relate patient requirements to such treatment factors as hours of supervision and presence of medical and other specialties.

Despite progress in determining appropriate matches, Gastfriend et al. (2000) reported difficulty in implementing the solutions in the market-driven system of services reimbursement within the United States:

To solve many of these problems, it will be necessary in the future to move from a model in which levels of care are predetermined and patient's needs are clustered to fit these criteria, to a patient-based model in which patient assessment is the starting point for determining the optimal service to provide.

 DiClemente CC (1999), Motivation for change: implications for substance abuse treatment. Psychological Science 10:209-213.
 

 Fuller RK, Gordis E (2001), Naltrexone treatment for alcohol dependence. N Engl J Med 345(24):1770-1771 [letter].
 

 Gastfriend DR, Lu SH, Sharon E (2000), Placement matching: challenges and technical progress. Subst Use Misuse 35(12-14):2191-2213.
 

 Krystal JH, Cramer JA, Krol WF et al. (2001), Naltrexone in the treatment of alcohol dependence. N Engl J Med 345(24):1734-1739.
 

 Littleton J, Mayer S (1999), Acamprosate and alcohol dependence: another glimmer of hope? Presented at the ASAM State of the Art Conference. Washington, D.C., Nov. 5.
 

 Petry NM, Petrakis I, Trevisan L et al. (2001), Contingency management interventions: from research to practice. Am J Psychiatry; 158(5):694-702.
 

 Sturm R (2001), The Costs of Covering Mental Health and Substance Abuse Care at the Same Level As Medical Care in Private Insurance Plans. Testimony presented to the Health Insurance Committee at the National Conference of Insurance Legislators. Chicago; July 13.

New medications for the treatment of various addictions are currently under investigation. However, there are still substantial barriers, on the part of health and social policies and the patients themselves, to patients receiving these new treatments. Many of these issues were explored at the 2001 American Society of Addiction Medicine's State of the Art in Addiction Medicine conference.

Addiction Treatment Progress and Obstacles

Before deciding that a patient has treatment-resistant schizophrenia, one must first determine that the patient is compliant with medication. Covert noncompliance or partial noncompliance can be missed. A trial with a depot antipsychotic can be helpful in ruling out noncompliance. Similarly, there can be large variations in plasma levels of antipsychotics, even with the same dose. Therapeutic levels of most typical and atypical antipsychotics have not been determined, but blood levels of medications may help determine whether a patient is a rapid metabolizer (or noncompliant).

Effective treatment also presupposes an accurate diagnosis. Conditions such as temporal-lobe epilepsy may mimic symptoms of schizophrenia, while comorbid conditions such as endocrinopathies can impact response. Before determining that a patient has treatment-resistant schizophrenia, it is always useful to carefully review the diagnosis.

Beyond these considerations, discussion of treatment-resistant schizophrenia must start with definitions of what constitutes an adequate trial of an antipsychotic medication, how many trials are necessary and whether certain medications or classes of medications are needed before a patient is determined to be resistant to treatment. Defining what constitutes an inadequate response is also necessary. Unfortunately, there is no unanimity concerning any of these issues.

Research protocols typically define an inadequate response as scores above a certain level on commonly used validated inventories such as the Brief Psychiatric Rating Scale (BPRS) or the Positive and Negative Syndrome Scale (PANSS) and/or an inadequate decrease in score after a defined course of treatment. Although more formal, these research definitions overlap the informal, clinical criteria of persistent target problems such as positive, negative or disorganized symptoms; persistent poor functioning; or frequent relapses despite adequate doses of medication (determined, for example, by using depot antipsychotics). For purposes of this discussion, treatment resistance is defined as an inadequate response from one adequate trial of a typical antipsychotic medication and two of the atypical antipsychotics, excluding clozapine (Clozaril). Since an adequate trial of a typical antipsychotic is defined differently than for the atypicals, each will be discussed separately.

Accumulated evidence suggests that response to each of the typical or first-generation antipsychotics will be similar if they are given at equivalent doses. For example, Kane et al. (1998) showed that fewer than 5% of patients with a documented history of treatment resistance showed any response when treated with haloperidol (Haldol). Further, other research has consistently shown that high-dose strategies lead to greater side effects without measurably improving the response (Thompson, 1994).

An adequate trial of a typical antipsychotic is often defined as six weeks at a dosage level of 1000 mg/day in chlorpromazine (Thorazine) equivalents. Based on the previously cited research, we recommend only one adequate trial of a typical antipsychotic, and we do not recommend heroic doses. As an example, little or no response to 20 mg/day of haloperidol after six to eight weeks should be considered a failure. An inadequate response should lead to trials of the atypical antipsychotics.

The second-generation or atypical antipsychotics currently available include risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel) and ziprasidone (Geodon). Clozapine will be discussed separately. These agents all appear to have superior efficacy in several symptom and side-effect dimensions than do the typical antipsychotics. Although these four atypicals differ on important side effects such as extrapyramidal symptoms (EPS), weight gain, QT

 widening, and glucose and lipid control, there is no convincing evidence that any of these medications have superiority to the others. Also, unlike the typical agents, it is unclear whether these atypicals are basically interchangeable in their therapeutic response, so failure of one does not preclude a trial with another one. At this point, more research exists for the increased efficacy of clozapine, risperidone and olanzapine, although evidence of the increased efficacy of ziprasidone is beginning to appear.

An adequate trial of an atypical antipsychotic should be at least eight to 12 weeks on a higher dose of the medication -- for example 12 mg/day of risperidone, 40 mg/day of olanzapine, 800 mg/day of quetiapine or 200 mg/day of ziprasidone. We recommend two full trials with atypicals before abandoning this group of medications as the single therapeutic agent. However, we do not have a hierarchical ordering of preferences, believing that side effects should influence selections. We would stress two trials since there seems little to be gained in trying a third before moving on to clozapine. Some would suggest that a trial with quetiapine should not be counted as one of the two trials due to the lack of supportive clinical data for quetiapine.

Failure from these trials should lead to a trial with clozapine, which has generally been found superior to other available agents. Because of its many side effects -- including agranulocytosis and lowered seizure threshold -- and the requirement for weekly blood monitoring (which may enhance compliance) for at least the first six months (with biweekly monitoring thereafter), clozapine is only approved for treatment-resistant schizophrenia despite its greater efficacy.

The superiority of clozapine may take time to emerge. Therefore, a minimum trial of three or four months should be undertaken, although some would recommend longer trials of six months or a year before concluding that a person is unresponsive to clozapine. Typical clozapine doses range from 300 mg/day to 500 mg/day, and doses of up to 900 mg/day can be used. Some data suggest that minimum plasma levels between 350 ng/ml and 500 ng/ml are associated with increased therapeutic response (Kronig et al., 1995). A lack of noticeable response at two months may be better assessed with a clozapine blood level.

Strategies to use in the face of failure to respond adequately to clozapine have received little empirical evaluation, although published case studies and expert opinions have suggested some therapeutic possibilities. Treatment options after clozapine trials typically involve an augmentation strategy where a second medication or therapeutic strategy is used concurrently with another antipsychotic medication. Multiple different combinations are possible; most have little empirical support; and none have been shown superior to clozapine as of yet. Therefore, as stated, a clozapine trial is recommended before using augmentation strategies, except when patient objections or medical contraindications rule out the use of clozapine. 

Because there is little research supporting augmentation strategies, such trials should be viewed as mini-experiments in which specific target symptoms are tracked. If there is little or no improvement after a reasonable trial, the augmenting agent should be withdrawn and another strategy pursued. For example, if divalproex sodium (Depakote) is added at therapeutic plasma levels for six to eight weeks and minimal improvement is noted, it should be discontinued before a different strategy is tried. Otherwise, there is the danger of having patients on ever-increasing lists of medications with few benefits and the possibilities of increased side effects and interactions. We have seen many cases of patients with schizophrenia taking three different antipsychotics, several mood stabilizers, benzodiazepines and an antidepressant without any clear documentation of improvement -- a strategy we have termed irrational polypharmacy (Kingsbury et al., 2001).

A number of augmentation strategies have been proposed, which include the addition of lithium, an anticonvulsant, a second antipsychotic, a benzodiazepine or a course of electroconvulsive therapy (ECT). Psychosocial treatment may also be used as an augmentation strategy. No data support a specific ordering of these choices, but each deserves specific comment.

Lithium has not been shown to be an effective augmenting agent for schizophrenia in the few trials conducted, although some case studies have suggested its effectiveness. With clozapine, lithium may raise low leukocyte counts but mask other myeloid processes associated with agranulocytosis. This strategy appears to be used less frequently at present, and we would rate this as a less useful strategy.

Although there are a number of anticonvulsants, there are few published reports of the use of many of the newer ones for augmenting response in schizophrenia. Divalproex is commonly used, although there are inconsistent reports of its effectiveness. Casey et al. (2001) published a preliminary report of a large multicenter study that used this strategy and found it effective early in treatment. It should be noted, however, that the improvement had dissipated by week 4 of the study. Divalproex may affect the levels of other medications and is frequently used as protection for clozapine-induced seizures. Because of its independent risk of agranulocytosis, carbamazepine (Tegretol) use with clozapine is contraindicated. At present, a trial testing the addition of divalproex would seem preferred to the other anticonvulsants until more data accumulate.

Using more than one antipsychotic simultaneously is a common practice, although evidence supporting this practice comes only from case studies and case series. There appears to be no justification for using more than one typical antipsychotic at the same time. Since some of the atypical antipsychotics such as clozapine and quetiapine have relatively weak dopamine (D2) antagonism, there may be some justification for adding a more potent D2 antagonist such as haloperidol, risperidone or olanzapine to augment an inadequate response. Adding even a relatively small dose of a typical antipsychotic, such as 2 mg to 4 mg of haloperidol, to an atypical antipsychotic may augment the therapeutic response at the cost of losing some of the advantages of the atypicals such as low EPS or lack of prolactin elevation.

Although g-aminobutyric acid circuits have been discussed as affecting D2 circuits and some research has been conducted, benzodiazepines have generally not been found to be of value, beyond their nonspecific calming and sedating properties, in treating schizophrenia when used alone or as augmenting agents. Further, there are concerns about their addiction potential and their possible pharmacodynamic interactions with clozapine. Only short-term use of the benzodiazepines in schizophrenia is recommended.

Giving ECT concomitantly with antipsychotic medications has been found to be an effective augmentation strategy (Krueger and Sackeim, 1995). Results appear better when the antipsychotic medication is not discontinued during the course of ECT. This strategy has some research support but appears to be underutilized. We recommend a trial of ECT be considered as a possibly preferred augmentation strategy.

Unlike the other augmentation strategies discussed here, psychosocial treatments are useful and recommended whether or not the patient is resistant to medication treatment. Research clearly supports such interventions as ameliorative for a number of problems, including some aspects of negative symptoms. Like the medications, effective approaches continue to be developed.

Finally, it must be realized that some patients with schizophrenia may remain poorly responsive to treatment despite optimal trials of medications and artful use of augmentation strategies. At such times, it may be necessary to settle for a suboptimal response. Heroic efforts with long lists of medications at higher than useful doses can cause more harm than good. Help in such cases will await further progress in psychopharmacology and in our understanding of the pathophysiology of schizophrenia.

 Casey DE, Daniel D, Tracy K et al. (2001), Improved antipsychotic effect of divalproex combined with risperidone or olanzapine for schizophrenia. Poster No. 437. Presented at the 26th Biennial Congress of the World Federation for Mental Health. Vancouver, British Columbia; July 24.
 

 Kane JM, Aguglia E, Altamura AC et al. (1998), Guidelines for depot antipsychotic treatment in schizophrenia. European Neuropsychopharmacology Consensus Conference in Siena, England. Eur Neuropsychopharmacol 8(1):55-66.
 

 Kingsbury SJ, Yi D, Simpson GM (2001), Psychopharmacology: rational and irrational polypharmacy. Psychiatr Serv 52(8):1033-1036.
 

 Kronig MH, Munne RA, Szymanski S et al. (1995), Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 152(2):179-182.
 

 Krueger RB, Sackeim HA (1995), Electroconvulsive therapy and schizophrenia. In: Schizophrenia, Hirsch SR, Weinberger DR, eds. Oxford, England: Blackwell Science, pp503-545.
 

 Thompson C (1994), The use of high-dose antipsychotic medication. Br J Psychiatry 164(4):448-458 [see comments].

Several confounding factors need to be taken into account before labeling a patient as treatment-resistant. What options are available for treating a patient with schizophrenia who has been diagnosed as such?

Treatment-Resistant Schizophrenia: Making the Determination

Over the past decade, reports about obsessive-compulsive disorder (OCD) have gradually moved from the traditional and somewhat pessimistic points of view to a more defined and optimistic line of research: the "rare and intractable illness" has now become a paradigm for valid hypotheses in neurobiology and clinical psychopharmacology.

Data in the literature support the so-called "serotonin (5-HT) hypothesis" of OCD (Barr et al., 1992): peripheral markers of serotonin function (Bastani et al., 1991), pharmacologic challenge studies with serotonin agonists (Erzegovesi et al., 2001b) and, above all, drug-response data from serotonin reuptake inhibitors (SRIs) (Greist et al., 1995).

According to the serotonin hypothesis, patients with OCD have a dysregulation in the serotonergic system, with a hypersensitivity of postsynaptic 5-HT receptors, which could account for a different mechanism of action of SRIs in OCD (Billett et al., 1997; Zohar et al., 1987). For example, onset of therapeutic action is 10 to 12 weeks in OCD, compared to three to four weeks for mood disorders.

At the present time, SRIs represent the first-line strategy in drug treatment of OCD. Efficacy and tolerability have been proven in several controlled studies (Greist et al., 1995; Mundo et al., 1997; Tollefson et al., 1994; Zohar and Judge, 1996). According to available data, the different SRIs seem to be equivalent in treating OCD if employed at equivalent dosages.

However, a major concern in the clinical pharmacology of OCD is the number of non-responders to drug therapy. As many as 40% to 60% of patients treated with SRIs at full dosages for at least 12 weeks did not show a significant improvement in OC symptoms and global functioning.

How can we define good response to SRIs in patients with OCD? According to the literature, good response can be defined as at least a 35% reduction in total scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).

In the last 10 years, several studies tried to identify possible response profiles among patients with OCD on SRI treatment (Ackerman et al., 1994; Baer et al., 1992; Carrasco et al., 1992; Cavedini et al., 1997; Mataix-Cols et al., 1999; McDougle et al., 1993; Ravizza et al., 1995). Early identification of good or poor responders could help physicians to optimize treatment with SRIs or make alternative choices such as add-on therapies.

The Table illustrates several clinical features related to a poorer response to drug therapy. Some of these features (i.e., comorbid tic disorder, comorbid schizotypal personality disorder) seem to hypothesize different biological substrates in OCD. Beyond serotonin, other neurotransmitters (e.g., dopamine) may be involved in OCD's pathophysiology. In fact, such comorbid conditions show a preferential response to an association therapy with SRIs and low-dose dopamine antagonists.

On the other hand, presence of early SRI-related side effects seems to be a positive predictor of response in OCD. According to the serotonin hypothesis of OCD, a hypersensitivity in post-synaptic serotonin receptors could account for some of this early response, for example initial nervousness and sexual complaints (Ackerman et al., 1999).

We have found that a positive family history for OCD in patients' first-degree relatives could be a predictor of good response (Erzegovesi et al., 2001a). To explain this result, we can hypothesize, in a biological and genetic perspective, that OCD is actually a heterogeneous disorder. Familial OCD could have a stronger biological liability, e.g., a greater serotonergic sensitivity, and therefore a greater sensitivity to the therapeutic effect of SRIs.

Another indirect support to the heterogeneity of OCD is the issue of poor insight. According to DSM-IV, there is a subgroup of patients with OCD who do not consider their symptoms to be senseless or excessive. This subtype, associated with a poorer response to SRIs treatment, could be the phenomenological expression of an underlying biological difference, e.g., the involvement of other neurotransmission systems such as dopamine (Erzegovesi et al., 2001a). Dopamine itself indirectly places a link between OCD and the comorbid conditions (tic disorders and schizotypal personality disorders) cited earlier as further negative predictors of response to antiobsessional therapy.

Somatic obsessions are a further confirmation of the significance of insight scoring in OCD (Erzegovesi et al., 2001a). Patients with somatic symptoms often show a poorer insight score.

These negative predictors can perhaps explain the growing interest in add-on therapies for non-responding patients. Several reports showed a significant effect of dopamine antagonists in SRI-resistant patients, either for typical (e.g., haloperidol [Haldol]) or atypical (e.g., risperidone [Risperdal], olanzapine [Zyprexa]) antipsychotics (Koran et al., 2000; McDougle et al., 2000; McDougle et al., 1994; Ravizza et al., 1996; Saxena et al., 1996). Add-on therapies could confirm the presence of biologically heterogeneous subgroups of patients who are linked to biological markers other than serotonin.

In conclusion, recent findings about clinical psychopharmacology of OCD point out the importance of an accurate collection of clinical and familial data in the pretreatment assessment of patients. Collection of possible clinical predictors of drug response could be a valuable tool in the psychopharmacology of OCD. Before starting drug therapy with SRIs, the presence of some predictors can help us to foresee the final response or, alternatively, to set up an appropriate add-on therapy.

As for future perspectives on treating OCD, prospective follow-up studies are needed to identify specific subgroups of patients and, accordingly, to define a wide range of specific treatment strategies that improve the long-term outcome of patients with OCD.

 Ackerman DL, Greenland S, Bystritsky A (1999), Side effects as predictors of drug response in obsessive-compulsive disorder. J Clin Psychopharmacol 19(5):459-465.
 

 Ackerman DL, Greenland S, Bystritsky A et al. (1994), Predictors of treatment response in obsessive-compulsive disorder: multivariate analyses from a multicenter trial of clomipramine. J Clin Psychopharmacol 14(4):247-254.
 

 Baer L, Jenike MA, Black DW et al. (1992), Effect of axis II diagnoses on treatment outcome with clomipramine in 55 patients with obsessive-compulsive disorder. Arch Gen Psychiatry 49(11):862-866.
 

 Barr LC, Goodman WK, Price LH et al. (1992), The serotonin hypothesis of obsessive compulsive disorder: implications of pharmacologic challenge studies. J Clin Psychiatry 53(suppl):17-28.
 

 Bastani B, Arora RC, Meltzer HY (1991), Serotonin uptake and imipramine binding in the blood platelets of obsessive-compulsive disorder patients. Biol Psychiatry 30(2):131-139.
 

 Billett EA, Richter MA, King N et al. (1997), Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene. Mol Psychiatry 2(5):403-406. 
 

 Carrasco JL, Hollander E, Schneier FR, Liebowitz MR (1992), Treatment outcome of obsessive-compulsive disorder with comorbid social phobia. J Clin Psychiatry 53(11):387-391.
 

 Cavedini P, Erzegovesi S, Ronchi P, Bellodi L (1997), Predictive value of obsessive-compulsive personality disorder in antiobsessional pharmacological treatment. Eur Neuropsychopharmacol 7(1):45-49.
 

 Erzegovesi S, Cavallini MC, Cavedini P et al. (2001a), Clinical predictors of drug response in obsessive-compulsive disorder. J Clin Psychopharmacol 21(5):488-492.
 

 Erzegovesi S, Martucci L, Henin M, Bellodi L (2001b), Low versus standard dose mCPP challenge in obsessive-compulsive patients. Neuropsychopharmacology 24(1):31-36.
 

 Greist JH, Jefferson JW, Kobak KA et al. (1995), Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis. Arch Gen Psychiatry 52(1):53-60 [see comment].
 

 Koran LM, Ringold AL, Elliott MA (2000), Olanzapine augmentation for treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry 61(7):514-517.
 

 Mataix-Cols D, Rauch SL, Manzo PA et al. (1999), Use of factor-analyzed symptom dimensions to predict outcome with serotonin reuptake inhibitors and placebo in the treatment of obsessive-compulsive disorder. Am J Psychiatry 156(9):1409-1416.
 

 McDougle CJ, Epperson CN, Pelton GH et al. (2000), A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 57(8):794-801.
 

 McDougle CJ, Goodman WK, Leckman JF et al. (1993), The efficacy of fluvoxamine in obsessive-compulsive disorder: effects of comorbid chronic tic disorder. J Clin Psychopharmacol 13(5):354-358.
 

 McDougle CJ, Goodman WK, Leckman JF et al. (1994), Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder. A double-blind, placebo-controlled study in patients with and without tics. Arch Gen Psychiatry 51(4):302-308.
 

 Mundo E, Bianchi L, Bellodi L (1997), Efficacy of fluvoxamine, paroxetine, and citalopram in the treatment of obsessive-compulsive disorder: a single-blind study. J Clin Psychopharmacol 17(4):267-271.
 

 Ravizza L, Barzega G, Bellino S et al. (1995), Predictors of drug treatment response in obsessive-compulsive disorder. J Clin Psychiatry 56(8):368-373.
 

 Ravizza L, Barzega G, Bellino S et al. (1996), Therapeutic effect and safety of adjunctive risperidone in refractory obsessive-compulsive disorder (OCD). Psychopharmacol Bull 32(4):677-682.
 

 Saxena S, Wang D, Bystritsky A, Baxter LR Jr (1996), Risperidone augmentation of SRI treatment for refractory obsessive-compulsive disorder. J Clin Psychiatry 57(7):303-306 [see comment].
 

 Tollefson GD, Rampey AH Jr, Potvin JH et al. (1994), A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder. [Published erratum Arch Gen Psychiatry 51(11):864.] Arch Gen Psychiatry 51(7):559-567.
 

 Zohar J, Judge R (1996), Paroxetine versus clomipramine in the treatment of obsessive-compulsive disorder. OCD Paroxetine Study Investigators. Br J Psychiatry 169(4):468-474.
 

 Zohar J, Mueller EA, Insel TR et al. (1987), Serotonergic responsivity in obsessive-compulsive disorder. Comparison of patients and healthy controls. Arch Gen Psychiatry 44(11):946-951.

Although treatment of obsessive-compulsive disorder has improved, a large percentage of patients do not respond to pharmacological therapy. What familial or comorbid factors might influence the outcome for these patients?

Psychiatric Times Vol 19 No 5

Power

Does DTC Advertising Benefit Patients?

Patient Drug Information From Mass Media Sources

Addiction Treatment Progress and Obstacles

Treatment-Resistant Schizophrenia: Making the Determination

Identifying Predictors of Drug Response in Patients With OCD

Managing Compliance

Renegotiating the 'Contract for Safety' in the ER