PHILADELPHIA— The science of anxiety is entering a complex new phase in which more and more patients appear to have comorbidities, resulting in hybrid disorders that defy traditional diagnostic categories. At the same time, the absence of comparative clinical data for the growing number of available pharmacologic agents poses an added challenge for the treatment of such compound disorders.

That is the assessment of Philip T. Ninan, MD, Professor of Psychiatry and Behavioral Sciences at Emory University School of Medicine in Atlanta. Speaking at the 2002 Annual Meeting of the American Psychiatric Association, he delivered a wide-ranging lecture on the role non-benzodiazepine anxiolytics can play in ameliorating the sometimes devastating effects of anxiety disorders.

Dr. Ninan likened the situation to a dance between two facets of the brain: the emotional and the cognitive or, using his term, the executive. “Normalcy is the flexibility to decide whether we want to respond emotionally or in an executive/cognitive manner, and that choice is ours,” he said. “In anxiety disorders, the pathology is that the control has shifted down to the emotional system. You can then look at the presentations of these anxiety disorders as what occurs when that emotional responsiveness has, in a sense, hijacked the brain.”

From this perspective, Dr. Ninan focused on what clinicians can do psychotherapeutically or pharmacologically to bring about clinical benefit, particularly when the first treatment fails. Much of his talk centered on selective serotonin reuptake inhibitors (SSRIs) and how they can be used effectively to treat some of these more complex anxiety disorders.

A LOOK BACK, A LOOK AHEAD

Originally marketed as antidepressants, SSRIs and other non-benzodiazepine agents came to the fore in treating anxiety in the past decade or so—in part because of their favorable benefit-to-side-effect profile compared to that for benzodiazepines. The 1970s and early 1980s constituted the “Valium (diazepam) era,” when benzodiazepines were the focus in managing anxiety disorders, according to Dr. Ninan. “The idea was that the level of symptoms crossed all psychiatric disorders as well as medical disorders, so if you had a heart problem and you were anxious, they would give you Valium,” he said.

In the 1980s, studies showed such high-potency benzodiazepines as alprazolam to be effective in panic attacks and other disorders. By then, however, the concern over adverse effects and the disadvantages of extended use with these drugs was mounting. Drawbacks of benzodiazepines include sedation, decreased reaction time, cognitive impairment, discontinuation difficulties, and potential for abuse. Their side-effect profile created an opening for a new class of drugs, and the SSRIs—which include fluoxetine, paroxetine, and sertraline—initially filled the bill.

The SSRIs have been shown to be highly effective as well as safe in the treatment of anxiety, and their efficacy has been demonstrated systematically in studies conducted during the past decade in each of the major anxiety disorders. These include obsessive-compulsive disorder, social phobia, posttraumatic stress disorder, generalized anxiety disorder, and panic disorder.

EXPECT COMORBIDITIES AND TAKE A NUANCED APPROACH

In Dr. Ninan’s view, the challenge for clinicians is to understand the different nuances of pharmacologic management in patients who are treatment-resistant to the initial use of an SSRI. He pointed out the limitations of the current system of diagnostic categories that imply there are very clear boundaries and no overlap among disorders, when the reality is that comorbidity is the rule rather than the exception. “If you look at it on the basis of the way the brain functions,” he explained, “you are able to recognize that, yes, you would expect these kinds of comorbidities and that the treatments might be fairly nonspecific and have benefits in certain symptom dimensions but not necessarily for the whole illness.”

Dr. Ninan cited data from the 1996 National Comorbidity Survey showing, for example, that about three quarters of the patients who were agoraphobic met the criteria for another anxiety disorder, half met the criteria for any affective disorder, and one third met the criteria for any substance disorder. “Comorbidity is the rule, and these are the patients US clinicians are struggling with,” he said.

COMPARISONS LACKING BETWEEN SSRIs AND SNRIs

The complexity involved in treating anxiety disorders today was further illustrated by an analysis of the comparative efficacy of SSRIs and another class of non-benzodiazepine antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs). The issue of SSRI versus SNRI efficacy in depression and anxiety disorders is an interesting one, not only for clinical reasons but because it provides a window into neurochemistry.

“There is persuasive evidence but not compelling evidence—researchers make these subtle distinctions—that the SNRIs are more effective in depression than the SSRIs,” he said. “The question is, ‘Is there any comparable evidence in the anxiety disorders?’ and I would say no.”

Furthermore, Dr. Ninan maintained, the lack of comparative data renders any assessment of the relative efficacy of these two classes highly subjective. “We can have our own expectations and hopes and biases, but in the absence of any data, it’s just a belief system,” he said.

He was unaware of any major ongoing study addressing the issue. Part of the problem may be the lack of tools necessary to effectively do so. With an SNRI such as venlafaxine, investigators need to push the dosage up in clinical trials, something that is not being done in current studies in anxiety disorders, according to Dr. Ninan. “If you find that the SNRIs are as effective as the SSRIs, that’s not surprising, because they have as much of a serotonin effect as the SSRIs,” he said. “If you fail to find superior efficacy, it’s because you haven’t asked the question the right way in order to demonstrate that.”

Take the case of a patient who has both obsessive-compulsive disorder and major depressive disorder, he suggested. A few years ago, a clinician might have appropriately prescribed one of the SNRIs—shown to be effective in depression, although not in obsessive-compulsive disorder—to first treat the patient’s major depressive disorder. Research has shown, however, that a drug that works just for depression does not help patients with this combined disorder, and the opposite approach is the correct strategy. “You really need to have the obsessive-compulsive disorder under control before the depression would respond to treatment, and you see that with the SSRIs,” he observed.

IMMUNOLOGICALLY BASED TREATMENTS MAY BE ON THE HORIZON

Dr. Ninan concluded his lecture with the “intriguing story” of an infectious agent, streptococcus, initiating an immune process that has been correlated with the onset of obsessive-compulsive disorder in children. The resulting disorders have been termed PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus). A group at the National Institute for Mental Health has enumerated the criteria for this diagnosis, including a sudden surge of obsessive-compulsive symptoms that occurs following streptococcal infection.

The recognition of these disorders opens up a new avenue of potential treatments for anxiety disorders—one that would be immunologically based or would include antibiotics for the prevention of the initial infection, said Dr. Ninan. “It points out that anxiety disorders can be ‘no-fault’ illnesses that result from genetic or environmental factors,” he added. “You just happen by an accident of nature to have a particular structure that is similar to a structure that is found in streptococcus.”

When asked if he was optimistic about this line of research, Dr. Ninan answered that, as with so many things, the devil is in the details. “We don’t have the technology or the knowledge base at this point to be definite about it,” he concluded. “Yet it might prove to be an important component in the practice of psychiatry.”

—Fred Balzac

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