Chairs of two APA councils and several other well-known geriatric psychiatrists are urging the Food and Drug Administration (FDA) to adopt labeling for three new drug indications for treatment of conditions due to Alzheimer’s disease: psychosis, alteration in circadian rhythms, and depression.
Doing so, they believe, will open up development of drugs to treat these specific disorders.

Christopher C. Colenda, M.D., M.P.H., chair of APA’s Council on Aging, and Jacobo Mintzer, M.D., chair of APA’s Committee on Ethnic Minority Elderly, provided testimony in March to the Division of Neuropharmacological Drug Products (DNDP) of the FDA at a meeting of its Psychopharmacological Drugs Advisory Committee.

The DNDP had solicited input from medical experts and industry on legitimate targets for development of new drugs and indications for psychiatric and behavioral disturbances associated with dementia. In a position paper prepared for the meeting, the DNDP states that "one obstacle has been the difficulty in identifying, defining, and naming the different clinical entities that fall under this broad umbrella."

Because pharmacological approaches are among the various treatments that are being developed to treat the psychiatric and behavioral disturbances associated with dementia, the FDA is playing a role in that development. The FDA requires that for a drug to be approved for the treatment of a condition, the condition must be identified and defined unambiguously, that appropriate methods be used in assessment and measurement of the condition, and that appropriate clinical trials show efficacy and safety.

"Labeling recommending a drug as a treatment for a clinical entity that is poorly defined is potentially misleading," states the DNDP position paper, "since it would not be possible to adequately inform clinicians through labeling as to the appropriate use of the proposed drug treatment."

In general, drug claims are focused on a clinical entity that is either a specific disease or syndrome (for example, congestive heart failure) or nonspecific signs or symptoms associated with many diseases or syndromes (for example, pain or fever).

Either way, the FDA looks at three basic criteria to determine whether the clinical entity is a valid target for drug therapy: the proposed clinical entity must be accepted by the relevant clinical and academic community, it must be operationally definable, and it must identify a reasonably
homogenous patient group.

Current labeling of psychotropic medications is, by the FDA’s own admission, misleading. For example, current labeling for antipsychotics medications states that they are indicated "for the management of manifestations of psychotic disorders." This indication is at best vague and too general for the FDA’s rules. However, this general statement is then followed by identification of the population in which the claim was established, in every antipsychotic case so far, schizophrenia. And, in fact, according to the DNDP position paper, all antipsychotics are approved specifically for schizophrenia, not "psychosis." Any attempt to market a drug for psychotic symptoms in the context of another disease state, for example Alzheimer’s disease, would be subject to regulatory action.

Over the last 10 years, the FDA has attempted to approve psychotropic drugs for more specific indications. For example, drugs are no longer approved to treat "anxiety"; they are specifically approved for the treatment of panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, and posttraumatic stress disorder.

The FDA’s stated intention with new approvals of psychiatric disease indications, such as psychosis and depression, is to focus the indications on the specific clinical entities studied, "rather than perpetuating the impression of general claims."

Recognizing that patients with dementia have a number of associated signs and symptoms that represent important areas for drug development, the DNDP position paper suggests two approaches to address the problem: that the clinical and academic community attempt to identify unique psychiatric and behavioral syndromes that exist in this population, or pursue clinical entities that are nonspecific signs or symptoms, such as "agitation." The DNDP convened the Advisory Committee meeting to gather input on both of these approaches.

APA’s Colenda, professor and chair of psychiatry and acting dean of the College of Human Medicine at Michigan State University, and Mintzer, a professor of psychiatry at the Medical University of South Carolina, joined with other noted geriatric psychiatrists to provide compelling evidence for establishment of new indications.

"The ‘who’s who’ of geriatric psychiatry was at that meeting," said Colenda, "and what that demonstrated was the maturation of the subspecialty."

Colenda thought both the written and oral testimony provided to the FDA was well received.

"There was a general consensus that you can achieve increased specificity," Colenda told Psychiatric News. "Specifically, there is a preponderance of scientific and clinical evidence that psychosis is part and parcel of the disease process [of Alzheimer’s] and a legitimate target for drug development."

Colenda also said there is increasing evidence that circadian rhythm disturbances associated with Alzheimer’s are part of the evolution of the disease and that they considerably increase morbidity for both the patient and the caregivers.

"Depression is more complicated, in the sense that depression itself in late life may cause a cognitive impairment," said Colenda. "Depression may also be one of the early manifestations of a dementia syndrome."

Among others testifying in support of the new indications was Eric D. Caine, M.D., professor and chair of psychiatry at the University of Rochester Medical Center, who provided testimony regarding the reclassification of the manifestations of Alzheimer’s in DSM-IV-TR. Caine, who headed the revision of DSM-IV Alzheimer’s entries, testified that in anticipation of ICD-10, the DSM-IV-TR , for example, prefers that Axis I be used to code for "Dementia in Diseases Classified Elsewhere" (294.1), along with Alzheimer’s being recorded on Axis III (331.0). The same would be true for psychosis due to Alzheimer’s (293.81). The change in coding reflects strong evidence supporting the clinical occurrence of important symptoms in patients with Alzheimer’s disease. It also satisfies the FDA’s requirement that a clinical entity must be recognized in the appropriate clinical and academic setting.

Colenda believes that the likelihood of the FDA’s adopting new indications for psychosis and circadian rhythm disturbances due to Alzheimer’s is good. However, adoption of the indication of depression due to Alzheimer’s has not yet been solidified.