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Comorbid Mood Disorders and Medical Illness: A Foodand Drug Administration Perspective
Comorbidity is more the rule than the exception inpsychiatry. Comorbid mood disorders and medical ill-nesses are an important subset of overall comorbidity.Thus, there is interest in understanding how comorbidmood disorders and medical illnesses might affect oneanother and how the treatments of each might be compli-cated by this comorbidity and the co-administration of multiple medications to treat the comorbid disorders.There are many possibilities for interactions betweenmood disorders and comorbid medical illnesses and theirrespective treatments, and all are worthy of exploration.This article will focus more narrowly on a subset of thesepotentially complex interactions (i.e., those between co-morbid mood disorders and medical illnesses) and thedrug treatments for these comorbid conditions, since theseinteractions have regulatory interest. In particular, thediscussion will focus on claims that may arise from drugstudies of the population of patients with comorbid mooddisorders and medical illnesses. A regulatory perspectivewill be provided for such claims.
Potential Interactions Arising in the Contextof Comorbid Mood Disorders and MedicalIllnesses That Are of Regulatory Interest
In general, there are six types of potential interactions thatare of regulatory interest when considering a population of patients that is being treated simultaneously with a psych-otropic drug for a psychiatric illness and a medical drugfor a comorbid medical illness. These potential interac-tions can be summarized as follows:1. Influence of psychotropic drug on co-administeredmedical drug and/or its actions.2. Influence of medical drug on co-administered psy-chotropic drug and/or its actions.3. Influence of medical drug on comorbid psychiatricillness.4. Influence of comorbid psychiatric illness on themedical drug and/or its actions.5. Influence of psychotropic drug on comorbid medicalillness.6. Influence of comorbid medical illness on the psych-otropic drug and/or its actions.The two domains of influence in these various potentialinteractions that are of interest from a regulatory stand-point are efficacy and safety. The possible mechanismsunderlying such influences fall broadly into pharmacody-namic or pharmacokinetic and, of course, could involveboth. Finally, the direction of influence for each possibleinteraction could be to enhance, diminish, or have nomeaningful effect on either efficacy or safety.While in general terms there are numerous possibilitiesfor complex interactions, even when the focus is limited tothose interactions of regulatory interest, from a practicalstandpoint, a comorbid medical illness and its drug treat-ment are considered two of many possible covariates indesigning a psychotropic drug trial. While comorbidity isvery common in psychiatric practice, including both co-morbid psychiatric disorders and comorbid medical ill-nesses, there is a tension between recruiting a homoge-neous population without comorbidity and a moreheterogeneous population with comorbidity. Recruiting ahomogeneous population may increase the efficiency of the trial, but clearly the trial with a more heterogeneouspopulation would have greater generalizability and rele-vance to typical clinical practice. Generally, a comorbidmedical illness and its drug treatment would not beexpected to have an important influence on a psychotropicdrug’s action or on the psychiatric disorder being treatedand would not be considered in the design or analysis of apsychotropic drug trial, except for exploratory purposes. If there were a basis for expecting an important influence of a comorbid medical illness or its drug treatment on thetrial outcome, stratification on one of these covariatesmight be included or one or more of these covariates mightbe included in the statistical model.It is unusual for psychotropic drug development pro-grams to have included much exploration for interactionswith comorbid medical illnesses or coadministered medi-cal drugs. This is true despite the fact that the Food andDrug Administration (FDA) strongly recommends thatsponsors increase the heterogeneity of studied populationsas they move into phase 3, in the interest of increasing therelevance of the premarketing database to typical clinicalpractice. Unfortunately, the exploration of potential inter-actions is usually limited to a few formal drug interactionstudies with commonly co-administered drugs and topharmacokinetic studies of the new drug in hepatic and
© 2003 Society of Biological Psychiatry 0006-3223/03/$30.00doi:10.1016/S0006-3223(03)00529-8
 
renal compromised patients. Most interactions based oncomorbid medical illnesses or co-administered drugs totreat those comorbid conditions are discovered postap-proval.
Pseudospecific Claims
Before addressing the issue of potential claims that mayarise from studies of psychotropic drugs in patients havingcomorbid mood disorders and medical illness, it is neces-sary to introduce the concept of pseudospecificity. Aproposed claim for a drug in a psychiatric illness would beconsidered pseudospecific if it was found to be artificiallynarrow (i.e., focusing on a subgroup within the ill popu-lation or on a particular aspect of the illness, such as aparticular symptom) in the absence of any empiricalevidence to support such a restricted focus. Such claimsserve only to permit a promotional advantage for the drug,since they imply an advantage of that drug over otherdrugs in the class for the subgroup or symptom of interest.Since no such advantage has been demonstrated, suchclaims would be misleading. Of course, if superiority overother drugs in the class with regard to the subgroup orsymptom of interest could be demonstrated, the claimwould no longer be considered pseudospecific. Legitimacyof a claim in a subgroup or for a particular symptom couldalso be established by showing that the drug works only inthat subgroup or only for that particular symptom. Whiledemonstrations of superior efficacy for a drug are difficultto accomplish, they are most likely to be feasible insituations where a particular subgroup of an ill populationor a particular symptom of an illness are not well treatedwith existing therapies. The bottom line is FDA considersnarrow claims in subgroups of an ill population or forparticular symptoms of that illness as pseudospecific untilproven otherwise.It is easiest to illustrate pseudospecificity with exam-ples. One type of pseudospecificity would be to focus ona demographic subgroup of a recognized entity (e.g.,major depressive disorder [MDD] in women). A relatedtype of pseudospecificity would be to focus on a recog-nized entity in the context of a comorbid illness (e.g.,MDD in patients with coexisting hypertension). Anothertype of pseudospecificity would be to focus on a specificsymptom of a recognized entity (e.g., targeting hallucina-tions in schizophrenia). Similarly, focusing on psychiatricsymptoms that occur as a normal accompaniment tomedical illness and that improve with the effective treat-ment of the underlying medical illness (e.g., targetinganxiety that occurs in patients with herpes simplex andthat improves as the herpes infection clears) would beconsidered pseudospecific. Finally, claiming an effect in asingle disease model of a recognized nonspecific symptom(e.g., a specific claim for dental pain rather than a moregeneral analgesic claim) would be considered pseudospe-cific. The FDA would consider all of these claims to bepseudospecific in the absence of evidence to show they arelegitimate. While there is the potential for any of theseclaims to be shown to be legitimate, the burden falls to thesponsor of a drug to show that any particular claim is justified.
Claims Arising in the Context of ComorbidMood Disorders and Medical Illnesses
It is easiest to illustrate the regulatory issues that arise inconsidering claims based on studies of psychiatric drugs totreat mood disorders in patients having comorbid medicalillnesses by providing examples. Several possible scenar-ios will be proposed, each involving the psychiatric drugtreatment of mood symptoms or other psychiatric symp-toms occurring in patients having comorbid medical ill-nesses.
Scenario 1
Major depressive disorder occurs in patients with seriouscardiovascular disease, and a psychiatric drug is shown tobe superior to placebo in treating the MDD in thispopulation.
DISCUSSION.
The important observation in this exam-ple is that the MDD seen is identical to MDD seenindependently of this medical illness (i.e., it just happensto coexist with this medical illness). Thus, a claim forMDD in serious cardiovascular disease would be consid-ered pseudospecific. Theoretically, it would be possible togain a claim in this very narrow context (e.g., if it could beshown that this drug were effective in treating MDD onlyin the presence of serious cardiovascular disease and nototherwise). Alternatively, if it were possible to show thatthis drug had superior efficacy compared to other drugs inthe class in treating MDD in the presence of seriouscardiovascular disease and not more general superiority toother drugs in the class, a narrow claim might be sup-ported. As noted earlier, it is this kind of superiority that isimplied by such a narrow claim. While such demonstra-tions of differential efficacy are theoretically possible,they are difficult to accomplish.
Scenario 2
A depressive syndrome that can be well characterized(phenomenology, course, etc.) and is phenomenologicallydistinct from MDD occurs in patients with Alzheimer
’
sdisease (AD), and a psychiatric drug is shown to be
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superior to placebo in treating this unique depressivesyndrome.
DISCUSSION.
The important assumption in this hypo-thetical example is that the depressive syndrome is char-acterized well enough to be considered a unique syndromeof AD, distinct from MDD, and occurring in parallel withthe dementia of AD. It should be noted that there is aprecedent for establishing a unique psychosis of AD as anacceptable target for a drug claim(Laughren 2001).Thus,if a unique syndrome of depression in AD could beestablished, it could be considered a reasonable clinicaltarget for a new claim. It would, however, require sub-stantial work to establish depression of Alzheimer diseaseas a distinct entity from MDD (Lyketsos and Olin 2002).There is no precise formula for deciding whether or nota particular cluster of signs and symptoms should beconsidered a unique entity and therefore a reasonableclinical target for a drug claim; however, there are ques-tions that may help in addressing this issue: 1) Are thephenomenology and course of this entity distinguishablefrom related disorders (e.g., MDD)? 2) Is the entityalready recognized in the diagnostic nomenclature (e.g.,DSM-IV)? 3) Do experts in the relevant academic/clinicalcommunity recognize the entity as unique? 4) Does theentity respond differently to certain treatments comparedto related disorders? and 5) Is the entity understood at amechanistic level, and does it have a unique pathophysi-ology? None of these principles is definitive, and in theend, making a determination of uniqueness for a proposedsyndrome is a judgment. In the case of psychosis of AD,FDA
’
s decision to endorse this entity was made afterbringing the issue to a meeting of the Psychopharmaco-logical Drugs Advisory Committee(Laughren 2001).
Scenario 3
Depressive symptoms that are significant but not wellcharacterized occur in patients with Parkinson
’
s disease(PD), and a psychiatric drug is shown to be superior toplacebo in treating these poorly characterized symptoms.
DISCUSSION.
The important observation in this exam-ple is that the depressive symptoms are not sufficientlycharacterized to be identified as a unique clinical targetand could therefore not be adequately described in label-ing. The alternative would be to better characterize them.If it turned out that these patients could be best character-ized as having MDD, there would be no basis for a newclaim (see Scenario 1). On the other hand, if a case couldbe made for a depressive syndrome that is unique to PD,occurring in parallel with the motor symptoms of PD anddistinct from MDD, it might be considered a reasonableclinical target for a new claim(Gareri et al 2002).As witha unique depression of AD (see Scenario 2), it wouldrequire substantial work to establish depression of PD as adistinct entity from MDD.Alternatively, it might be possible to establish that thedepressive symptoms seen with PD meet diagnostic crite-ria for the DSM-IV entity known as Adjustment Disorderwith Depressed Mood(American Psychiatric Association1994).This diagnosis (DSM-IV, 309.0) implies the fol-lowing: 1) an identifiable stress, in this case, the PD; 2)depressive symptoms in excess of what would be ex-pected; 3) significant impairment of social or occupationalfunction; and 4) does not meet diagnostic criteria foranother more specific depressive syndrome(AmericanPsychiatric Association 1994).Admittedly, it is difficult toknow what an expected reaction would be for a givenpatient, and it may be difficult to distinguish impairment infunctioning due to a mood disturbance from that due to thePD itself. This alternative is raised only as a possibility toconsider, since there is no precedent for FDA approvingdrugs for any of the adjustment disorders. If FDA were toendorse this new claim, it would likely not be sufficient tohave only one model of adjustment disorder. As for drugsconsidered for treating pain, the FDA would likely want tosee data from more than one model of Adjustment Disor-der with Depressed Mood (i.e., its occurrence in thecontext of other stressful circumstances as well).
Scenario 4
Mood symptoms occur in association with a medicalillness but are not sufficient to meet diagnostic criteria forany depressive syndrome or for adjustment disorder withdepressed mood. Rather, the symptoms are best viewed asa normal accompaniment to significant medical illness,and they improve with effective treatment of the medicalillness.
DISCUSSION.
The regulatory question in this scenario iswhether or not there is justification for a claim forimprovement in minor mood symptoms that can be con-sidered to be a normal accompaniment to any significantmedical illness and that improve with the effective treat-ment of that illness. This example may seem out of placein this discussion, since there is no specific drug treatmentof the mood symptoms. It is relevant, however, sincesponsors have at times sought specific claims for improve-ment of associated psychiatric symptoms for drugs knownto be effective in treating certain medical illnesses (e.g.,one sponsor sought a claim for improvement in the
“
anxiety of herpes
”
as a result of effective antiviral controlof the herpes infection). Another recent example was aclaim for improvement in the
“
insomnia of gastroesopha-
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