In these stressed-out times, new pharmacotherapies are offering relief to anxious patients




In these stressed-out times, new pharmacotherapies are offering relief to patients

Terrorist alerts, the war in Iraq; SARS; West Nile virus; sniper attacks in Washington, D.C.; a poor economy: So far, it's been quite a stressful year. It's no surprise that Americans are anxious.

"I think what most people are experiencing is a normal kind of anxiety reaction that with time will abate," said Jerilyn Ross, M.A., LICSW, president and CEO of the Anxiety Disorders Association of America and director of the Ross Center for Anxiety and Related Disorders, Washington, D.C. "But for many people with a predisposition and a history of anxiety, these events did bring on an exacerbation of their symptoms," she said.

"Anxiety comes in many manifestations," explained Philip Ninan, M.D., professor of psychiatry, Emory University. "The core aspect is an emotion of anxiety which is very distressing—it's angst. There's a cognitive component, when people think in very catastrophic terms. Many people experience anxiety, not in terms of emotional symptoms, but more in terms of somatic symptoms. The fourth component is the behavior—when people are anxious, they are agitated, they are restless," he said.

"I think of anxiety on a continuum," said Robert Harris, R.Ph., BCPP, staff pharmacist at Cayuga Medical Center, Ithaca, N.Y. "I try to teach patients to rate where they are along that continuum. Once they continuously get into the severe anxiety, they move into consideration for one of the anxiety disorders."

Anxiety disorders afflict 15.7 million people in the United States annually, and as many as 30 million people in the United States at sometime in their life. The most recent (1990) cost estimate placed the societal cost, direct and indirect, at $42.3 billion. But "statistics show that only 25% of patients who have anxiety disorders are treated," said Cynthia Kirkwood, Pharm.D., BCPP, associate professor and vice-chair for education, department of pharmacy, Virginia Commonwealth University, Richmond.

"Anxiety needs to be taken more seriously," Ross agreed. "Not treating [an anxiety disorder] could lead not only to an increase in symptoms of anxiety but also to a higher risk of developing depression and substance abuse." And, Ninan commented, sometimes, "people kill themselves."

Some people don't seek treatment for anxiety disorders because of the stigma associated with mental illness. Others are deterred by cost and lack of insurance coverage. However, "the American Psychiatric Association and others would tell you one of the barriers is that anxiety disorders are not being recognized," said Nathaniel Rickels, Pharm.D., Ph.D., BCPP, assistant professor of the social and administrative sciences, Long Island University, Brooklyn, N.Y. "The fact is that we do need to do a better job of screening patients."

Clinicians distinguish between anxiety and anxiety disorders by the criteria of the Diagnostic and Statistical Manual of Mental Disorders IV. In the current manual, anxiety disorders are classified by their symptoms, frequency of occurrence, and recurrence as generalized anxiety disorder (GAD), panic disorder, obsessive-compulsive disorder (OCD), social and other phobias, posttraumatic stress disorder (PTSD), and acute stress disorder (see Table 1).


Table 1
Anxiety disorders at a glance

Generalized anxiety disorder (GAD)
Ongoing, exaggerated worry or tension
Panic disorder
Repeated and unexpected panic attacks—bouts of overwhelming fear of being in danger that are accompanied by at least four symptoms: pounding heart, chest pain, sweating trembling, shortness of breath, sensation of choking, nausea or abdominal pain dizziness or lightheadedness, feeling unreal or disconnected from oneself, fear of losing control or “going crazy” or dying, numbness, chills, or hot flashes
Posttraumatic stress disorder (PTSD)
When individuals who have survived a severe or terrifying physical or emotional event reexperience it through nightmares, or memories with extreme emotional, mental and physical distress
Uncontrollable, irrational, and persistent fear of a specific object, situation, or activity

Specific phobia

Social phobia


Obsessive-compulsive disorder (OCD)
Obsessions (irrational thoughts that recur and cause great anxiety but cannot be controlled by reasoning) that lead to repetitious, ritualized behavior to control anxiety


Ninan explained, however, that although there are clear boundaries in diagnosing these disorders, "in clinical practice, most patients who have one disorder are likely to have another. So, the majority of patients who are seen clinically have multiple disorders. Is that because the diagnostic boundaries aren't as clear-cut as the definitions would imply? Or is it that the diagnoses don't match exactly the biology that separates some of these illnesses? The last is probably the case."

Drug therapy for anxiety disorders has traditionally consisted of the benzodiazepines, buspirone, the selective serotonin reuptake inhibitors (SSRIs), and antihistamines. Approved indications are as shown in Table 2, although not all drugs used to treat anxiety have approved indications. For example, atypical antipsychotics and antiepileptics are used off-label. And some individuals self-medicate their anxiety with herbs. Each of these treatments has limitations.

Benzodiazepines are highly effective in treating anxiety. But, as Teri Gabel, Pharm.D., BCPP, Drug Therapy Consultants, PC, Omaha, pointed out, "One problem with the 'benzos' is that they work really well. And the other problem with them is that they work really well. So, there's psychological dependence as well as the physical dependence/tolerance when you stop them. People have withdrawal."

Harris commented, "We want to avoid the benzos in those who have substance abuse histories and alcoholism, or who are recovered alcoholics." These concerns, coupled with the chronic nature of anxiety disorders, have largely caused benzodiazepines to fall from favor—except for short-term use—although, in some patients, they are still used chronically.

"The other short-term alternative acute treatment is the antihistamines, such as diphenhydramine or hydroxyzine," said Harris. "But they come with their own set of problems, such as anticholinergic activity, sedation, and so forth. So what else do we have? Buspirone, but that's long-term treatment; it's not a fast onset."

Increasingly, and often very effectively, the SSRIs are being prescribed for anxiety disorders. Approved indications are as shown in Table 2. The advantage of SSRIs in anxiety may well be their versatility in treating multiple types of anxiety disorders—and depression as well. Unfortunately, SSRIs typically don't reach full effect in treating depression for three to six weeks—and may take up to eight to 12 weeks to reach full effect for some anxiety disorders.


Table 2
Drugs with approved indications for anxiety disorders

Effexor ER
OCD, panic disorder, social anxiety disorder, GAD, PTSD
OCD, panic disorder
OCD, panic disorder, PTSD
Anxiety disorders or short-term relief of anxiety symptoms

Xanax (alprazolam)

Ativan (lorazepam)

Valium (diazepam)

Serax (oxazepam)

Tranxene (chlorazepate)

Librium (chlordiazepoxide)

Panic disorder
Management of anxiety disorders or short-term relief of symptoms of anxiety
Nonpsychotic anxiety
Anxiety and tension


This limitation has caused some clinicians to advocate combination therapy, using a benzodiazepine short-term until the SSRI reaches full effect. Gabel warned, "That can be a catch-22 if you don't have the person who's able to give up that benzo."

Harris stated, "What we emphasize during the first few days of anxiety treatment are coping skills and breathing exercises and reading, writing, journaling, music, touch therapy, pet therapy, and things of that nature. Coping skills are from within, and then there's external support." Such external support can come from therapists, counselors, clergy, teachers, coaches, guidance counselors, doctors, nurses, or pharmacists.

All of the pharmacists interviewed by Drug Topics agreed that anxious people are often very sensitive people, and very susceptible to medication side effects. The maxim "start low and go slow" on doses was cited repeatedly.

To address the sensitivity of patients with anxiety disorders to medication levels, both Pfizer and GlaxoSmithKline have recently introduced long-acting forms of alprazolam (Xanax XR) and paroxetine (Paxil CR). Xanax XR for panic disorder (with or without agoraphobia) is a once-a-day formulation. As such, it reduces the peaks and troughs in drug levels that result from multiple daily doses. With more uniform drug levels, patients have less anxiety when medication is wearing off and less potential for breakthrough panic attacks between doses. Paxil CR, a controlled-release formulation, minimizes variances in drug levels that can contribute to adverse effects. It is indicated for panic disorder and is showing promise in clinical trials for social anxiety disorder.

To allow patients with panic disorder more flexibility and privacy in dosing, clonazepam (Klonopin, Solvay Pharmaceuticals/Hoffmann-La Roche) has recently been released in a new quick-dissolve formulation that can be ingested without water. The new formulation is available in five strengths (0.125, 0.25, 0.5, 1, and 2 mg).

Advances in our understanding of neuroscience and the etiology of anxiety have provided new targets for anxiolytic agents. Some of these are the following:

• Understanding of the gamma-aminobutyric acid (GABA) system is facilitating development of partial benzodiazepine-GABA receptor antagonists and agents that target specific subunits of the GABA-A receptor and that manipulate GABA levels.

• Because antidepressants benefit anxious patients who are not necessarily depressed, research is continuing into agents that affect the serotonin and norepinephrine levels.

• Some neurotransmitters (e.g., corticotropin-releasing factor and substance P) appear to be abnormally regulated in individuals with anxiety disorders, so antagonists might prove useful.

• Antistress and antianxiety effects may be possible through neurogenesis by using agents that decrease glutamate neurotransmission (i.e., metabotropic glutamate receptor agonists).

• Stimulating neurotrophic factors (e.g., brain-derived neurotrophic factor) that may enhance neurogenesis might also reduce anxiety.

The next anxiety drug to market may be pregabalin. Pfizer plans to submit a drug application for pregabalin during 2003 as an add-on drug in epilepsy, for neuropathic pain, and for GAD. Pregabalin differs from existing therapy in mechanism; it is believed to work by modulating a subtype of the calcium ion channel in the nervous system.

In head-to-head trials for GAD with alprazolam and venlafaxine, pregabalin demonstrated onset within one week. It significantly improved psychic and somatic symptoms faster than venlafaxine and improved somatic symptoms faster than alprazolam. Pregabalin showed a greater incidence of dizziness than either alprazolam or venlafaxine, but the incidence of other adverse effects (e.g., nausea and headaches) was similar.

Two other antianxiety drugs that appear in the medical literature with studies demonstrating efficacy in treating GAD are mexazolam (Bial, Portugal) and opipramol (Germany). However, neither appears to be in trials in this country at present.

In addition, several drugs are used off-label for anxiety. Gabel reported she has seen gabapentin, antiepileptic drugs, and atypical antipsychotic drugs used to treat anxiety. But, she commented, "Off-label use is not necessarily unusual in psychiatry. We're very fond of labeled uses, but we are not afraid to go beyond that because there's not a lot out there for mental illnesses."

And, for thousands of years, herbs have been used to treat anxiety. Recently, kava has come under close scrutiny because of reports of idiosyncratic liver failure in individuals taking relatively normal doses, short-term. In March 2002, the Food & Drug Administration issued a consumer advisory for kava, warning of the potential risk of severe liver injury. Consequently, many pharmacists are steering patients away from use of kava.

For individuals who want to use herbal therapy, Gabel commented, "I usually tell them to look for chamomile tea and valerian. I had a patient who had a type A personality disorder who couldn't take any kind of prescription drug because it just [didn't work for] him—but he has done great on chamomile tea." Lemon, balm, lavender, and even peppermint tea have also been used.

Cognitive behavioral therapy can also play an important role in helping individuals with anxiety disorders, either in conjunction with medication or alone. Ninan remarked, "The evidence would suggest there are certain conditions for which the combination is better than a single treatment, but not uniformly." He explained, "Every treatment has a proportion of patients who respond, a proportion who achieve remission, and a proportion of less-than-responders. We have people who are intolerant on medications or intolerant of cognitive behavior therapy, because cognitive behavioral therapy requires, for example, that you do things to induce anxiety as a way of getting over it. And in clinical studies, about 25% of patients refuse to do those things."

Although cognitive therapy can be very beneficial, one of the concerns is its lack of uniformity and the shortage of people available to provide competent cognitive behavioral therapy. "There's considerable distance between recommending it and being able to deliver it," Ninan commented.

Nonpharmacological therapy also benefits individuals with anxiety disorders. Gabel explained, "Exercise is a wonderful way of dealing with mild anxiety, and it supports the treatment that you use for the severe anxiety—get those endorphins working for us. Massage—what a great way to relax when you're stressed."

The pharmacist's role

Regardless of their practice settings, pharmacists are involved with patients who have anxiety problems. Kirkwood considers it vital that pharmacists know what their patients are being treated for so they can adequately counsel them. "When you get a prescription for a drug like Paxil or Zoloft, I think that's an important question to ask because you're talking about social phobia, PTSD, GAD, OCD. If you're talking about OCD, the patient may not have a full response for 10-12 weeks."

Gabel feels it is important to remember that patients don't choose to have anxiety disorders. "It's an illness. Some of it can be managed with nondrug therapy, and nondrug therapy can help when we manage it with medication." She also believes it is important that pharmacists validate to patients that anxiety disorders are bona fide illnesses "because [healthcare professionals] are not going to be able to get them to do any kind of therapy if the patient doesn't feel accepted."

Rickels sees "the role of the pharmacist as providing consistent and sufficient education that will improve patient comprehension." He explained that comprehension is related to adherence, "but we also want to cause more positive beliefs about using the medication and help the patient feel better about taking it because that's also a predictor of outcome."

Ninan noted that pharmacists "should consider anxiety to be a serious, potentially life-threatening illness." He believes pharmacists should counsel about side effects and encourage patients who are not responding to therapy to return to their physicians for additional treatment.

Ross summed up her view of anxiety disorders with the mantra, "They are real, they're serious, and they're treatable." She urged her colleagues to be alert to opportunities to help patients with these problems.

Kathy Hitchens, Pharm.D.

The Author is a clinical writer based in Indiana.

Web resources on anxiety disorders

• Anxiety Disorders Association of America
(brochures, referral network, self-help tools, book catalogue)

• American Psychiatric Association
(educational materials, guidelines)

• National Center for PTSD
(fact sheets, assessment, information)

• National Institute of Mental Health
(public information about coping with anxiety disorders)


Kathy Hitchens. Cover Story: HIGH ANXIETY. Drug Topics Aug. 4, 2003;147:41.

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