Developing Novel Treatments for Mood Disorders: Accelerating

Developing Novel Treatments for Mood Disorders:Accelerating Discovery

Carol A. Tamminga, Charles B. Nemeroff, Randy D. Blakely, Linda Brady,Cameron S. Carter, Kenneth L. Davis, Raymond Dingledine, Jack M. Gorman,Dimitri E. Grigoriadis, David C. Henderson, Robert B. Innis, John Killen,Thomas P. Laughren, William M. McDonald, Greer M. Murphy, Jr.,Steven M. Paul, Matthew V. Rudorfer, Edward Sausville, Alan F. Schatzberg,Edward M. Scolnick, and Trisha Suppes

This review was generated from discussions by the Phar-macologic and Somatic Treatments Section of the NationalInstitute of Mental Health Strategic Plan for Mood Dis-orders Committee on advancing novel pharmacologic andsomatic treatments for mood disorders. The openingsection of the article summarizes in broad strokes, currentpharmacologic treatments, and new directions in the field.Thereafter the topics focus on specific research initiativesthat could advance the current therapeutics for mooddisorders including new basic and clinical research invivo human imaging procedures, somatic therapeutics,and the vast new area of pharmacogenetics. New scientificand technical opportunities exist today based on advancesin basic neuroscience, opportunities in clinical testing,industry interest in advancing central nervous systemtherapeutics, and on active consumer advocacy groups.The question of how to bring all of these positive forcestogether to accelerate discovery in mood disorder thera-

peutics is the topic of this article. Biol Psychiatry 2002;52:589–609 © 2002 Society of Biological Psychiatry

Key Words: Depression bipolar disorder research re-sources, government/industry collaboration

Introduction

Depression is one of the most pervasive and costlybrain diseases. It affects more than 20 million Amer-

icans, significantly more women than men; it shows anoverall lifetime prevalence rate in the United States of17.1% and comparable figures worldwide. It not onlyaccounts for much pain and suffering but also significantdays of lost work; it is associated with several comorbidpsychiatric disorders and often goes undetected, especiallyin children and adolescents. The illness has 10% mortalitydue to suicide and a presumption of increased rates ofserious accidents among persons with active mood disor-ders. It is a major risk factor for the development ofcoronary artery disease and stroke and possibly othermajor medical disorders. Although neither the neurobio-logical mechanisms of mood-related illnesses nor even anunderstanding of normal mood regulation are known,elucidation of the biological contributors to normal andpathologic mood is progressively accumulating. Suchconstituents of mood include not only the putativelyinvolved neurotransmitter systems of serotonin, norepi-nephrine, dopamine, and acetylcholine, but also the influ-ence of two endocrine axes, the hypothalamic-pituitary-adrenal (HPA) and hypothalamic pituitary-thyroid (HPT)axes, as well as alterations in immune function. Treat-ments exist, but response to medication is not inevitable, isfrequently incomplete, and is often accompanied by lim-iting side effects. The two major classes of antidepressantsdeveloped have been the tricyclic antidepressants (TCAs)and the selective serotonin reuptake inhibitors (SSRIs).

From the Maryland Psychiatric Research Center, Department of Psychiatry,University of Maryland School of Medicine (CAT), Baltimore, Maryland;Emory University School of Medicine, Department of Psychiatry and Behav-ioral Sciences (CBN) and Departments of Pharmacology (RD) and Psychiatry(WMM), Emory University, Atlanta, Georgia; Department of Pharmacology,Vanderbilt University School of Medicine (RDB), Nashville, Tennessee;Neuropharmacology and Drug Discovery and Clinical Therapeutics Programs,Molecular and Cellular Neuroscience Research Branch (LB) and MolecularImaging Branch (RBI) National Institute of Mental Health (MVR), Bethesda,Maryland; Western Psychiatric Institute, Department of Psychiatry, Universityof Pittsburgh (CSC), Pittsburgh, Pennsylvania; Department of Psychiatry, Mt.Sinai School of Medicine (KLD), New York, New York; Department ofPsychiatry, New York State Psychiatric Institute, Columbia University Collegeof Physicians and Surgeons (JMG), New York, New York; NeurocrineBiosciences, Inc. (DEG), San Diego, California; Department of Psychiatry,Harvard Medical School and Massachusetts General Hospital (DCH), Boston,Massachusetts; Division of AIDS, National Institutes of Health/NationalInstitute of Allergy and Infectious Diseases (JK), Bethesda, Maryland; Foodand Drug Administration (TPL), Rockville, Maryland; Psychiatry Neuro-science (GMM) and Department of Psychiatry and Behavioral Sciences (AFS),Stanford University School of Medicine, Stanford, California; Lilly ResearchLaboratories, Eli Lilly and Company (SMP), Indianapolis, Indiana; Develop-mental Therapeutics Program, Division of Cancer Treatment and Diagnosis,National Cancer Institute (ES), Rockville, Maryland; Merck Research Labora-tories (EMS), West Point, Pennsylvania; Department of Psychiatry, TheUniversity of Texas Southwestern Medical Center (TS), Dallas, Texas.

Address reprint requests to: Carol A. Tamminga, M.D., Maryland PsychiatricResearch Center, University of Maryland School of Medicine, Department ofPsychiatry, P.O. Box 21247, Baltimore MD 21228.

Received October 18, 2001; revised May 14, 2002; accepted May 23, 2002.

© 2002 Society of Biological Psychiatry 0006-3223/02/$22.00PII S0006-3223(02)01470-1

Monoamine oxidase inhibitors (MAOI) also have played atheoretical and practical role in therapeutics. A richpharmacopeia for the treatment of depression has beendeveloped in only 40 years; however, it is startling that,with the exception of modifications to the existing mono-amine-based strategies, the last true innovation in the areaof antidepressant treatment occurred decades ago.

Advances in basic neuroscience have provided a richand increasingly mature knowledge base for understand-ing pathophysiology and developing rational pharmaco-therapy in brain diseases. New discoveries based on novelexperimental techniques have repeatedly provided humanbrain research with emerging models of neural mecha-nisms that will potentially contribute to disease under-standing, as well as a more comprehensive understandingof current drug action. Progress in the Human GenomeProject has actually been faster than predicted and willcontribute exponentially to identification of pathology inmood disorders. Brain regions involved in the modulationof mood are being delineated with considerable precisionand cross-laboratory consistency. Several neurotransmittersystems and their metabolic pathways have been eluci-dated, including glutamate, �-aminobutyric acid (GABA),serotonin, norepinephrine, and dopamine, as have themembrane-bound signal transduction elements and theintracellular signaling systems, which modulate gene tran-scription and protein synthesis. Clues to mechanisms fornovel selective pharmacologic manipulation are increas-ingly evident. Studies of the mechanisms of action ofeffective antidepressant drugs are converging around spec-ulations of a common set of intracellular actions. Thisconcatenation of new knowledge will progressively con-tribute to new therapeutics and allow scientists interestedin mood disorders to think differently about drug targets.

The major question addressed in this article is how toaccelerate the process of discovery in mood disordertreatments so as to make quantum leaps toward noveltreatment techniques. What needs to be done, and wherecan the elements of discovery be carried out most effi-ciently? What roles should government, patient advocacygroups, academia, and industry play? A rational plan thatis compelling enough to engender widespread supportfrom all stakeholders, cooperation among scientists, andinterest from funding sources would be ideal. Even fo-cused funding initiatives in a critical area can shape thedirection of the field. If cooperation is maximized, newdiscoveries and treatments will result.

Fortunately, the National Institute of Mental Health(NIMH) is able to take advantage of the experience ofother groups within the National Institutes of Health thathave posed similar questions of how to develop novel andbetter therapeutics. For example, the National CancerInstitute (NCI) has had a drug development program for

anticancer drugs for more than 20 years that was started inan era when pharmaceutical companies were not aggres-sively pursuing treatments for cancer. The NCI has re-cently articulated the goal of encouraging mechanisticallynovel drug development for cancer treatments. It currentlysupports a complex set of modular mechanisms, includingrepositories of drugs, natural products, research tools, andinformation, as well as preclinical and clinical drugdevelopment services all available to NCI grantees andsmall business contractors (http://dtp.nci.nih.gov). TheNational Institute of Allergy and Infectious Diseases(NIAID) has developed a program for drug developmentin AIDS to facilitate new therapies and, when necessary,support preclinical and clinical development. NIAID alsohas a modular, flexible but integrated preclinical/clinicalgrant program for academia and a contract program forsmall business researchers to facilitate drug developmentnot only for AIDS but also for its accompanying oppor-tunistic infections; they aim to target research to gapsin treatment knowledge (http://www.niaid.nih.gov/aidstherapeutics). In the process of these efforts, NCI in cancertherapeutics and NIAID in target infectious diseases, haveboth developed a clinical trials networks with well-trainedclinical scientists who not only conduct scientific trials,but also develop improved rating scales for specifiedclinical end points and focus on identifying biomarkers fordrug action. These institutes use grant and contract mech-anisms for these programs, they collaborate on researchand development projects of mutual interest with for-profitcompanies, and they have publicly accessible databases ofcompounds and substantial compound repositories forpublic use. The National Institute on Aging (NIA) also hasa drug development program in Alzheimer’s disease (AD)that is predominantly grant based with respect to itsresearch but also includes a clinical trials network. Thisgroup of clinical investigators works together to test newdrug strategies for AD and, in parallel, develops newdiagnostic and dimensional rating scales; it also seeksbiomarkers to identify successful treatment response.These potential models, already active in other branches ofthe NIH, have as their goal to encourage and facilitateinnovative drug development based on rational pathophys-iology. They include successful clinical trial networks, andsome have suggested that these are one of the most criticalcontributions of NIH institutes in attaining the goal of newtreatment development.

Current Status of Drug Treatments forMood Disorders and Directions for theFuture

Medications for the treatment of depression and bipolardisease were introduced in the late 1950s and early 1960s

590 C.A. Tamminga et alBIOL PSYCHIATRY2002;52:589–609

as part of what is commonly referred to as the psycho-pharmacology revolution. Two classes of antidepressantmedications were originally identified, TCAs and MAOIs. Asecond major wave of new antidepressants occurred in 1988when the first SSRI, fluoxetine, was introduced. More re-cently venlafaxine, nefazodone, and mirtazepine have beenintroduced in the United States and reboxetine, milnacepan,moclobamide, and tianeptine in Europe, Asia, or Canada.

Antidepressant Medications Currently Used for theTreatment of Depression

OLDER LINE AGENTS: TCAs AND MAOIs. The TCAswere the first line medication therapy for depression fornearly 30 years, until the introduction of the SSRIs. Thesemedications can be further divided into two main classes(Potter et al 1998). The tertiary amines (e.g., amitriptylineand imipramine) are drugs that are generally dual (i.e.,serotonin [5HT] and norepinephrine [NE]) reuptake inhib-itors, are metabolized to secondary amines, and have ahigh burden of anticholinergic side effects. The secondaryamines (e.g., nortriptyline and desipramine) are generallymore selective at blocking NE reuptake with somewhatreduced anticholinergic side effects. The TCAs havewell-documented efficacy in the treatment of major de-pression, with some still equivocal evidence that thetertiary amines are more effective than secondary aminesfor severe depression (Anderson 2000). These agents arelethal in overdose, however; in fact, they remain thenumber one cause of overdose death among prescriptiondrugs in the United States and worldwide. They alsoproduce a range of potentially serious side effects, some ofwhich involve the cardiovascular system.

Three MAOIs are now available in the United States,phenelzine, tranylcypromine, and isocarboxazide. Theseare irreversible MAOIs that inhibit the enzymatic degra-dation of both MAO-A and MAO-B. They are best usedby titrating dose to approximately � 80% inhibition ofMAO-B. Strict dietary restrictions must be observed whentaking MAOIs because there are potentially life-threaten-ing drug–food interactions. There is evidence that MAOIsare more effective than TCAs (and perhaps SSRIs) foratypical depression (characterized by hypersomnia, hy-perphagia, reverse diurnal mood variation, and prominentfatigue), as well as in persons who do not respond to otherantidepressants (McGrath et al 1993; Stewart et al 1997);however, because of the adverse side effect profile, theyare at present generally reserved for patients who arerefractory to other medications.

FREQUENTLY USED DRUGS. The SSRIs are clearly thedrug treatment of choice for all forms of depression in theUnited States. Five are now available: fluoxetine, sertra-line, paroxetine, fluvoxamine (which is not approved for

depression by the Food and Drug Administration [FDA]),and citalopram (Charney et al 1998). These drugs areapproximately equivalent to each other and to TCAs inefficacy, although some evidence suggests that the tertiaryamines may be more effective than SSRIs for severedepression (Anderson 2000). The SSRIs have a muchmore benign side effect profile than TCAs and, largely forthis reason, have replaced TCAs as first line therapy. TheSSRIs are structurally distinct and, although they share thecommon property of 5HT reuptake blockade, each pro-duces additional effects that render them different fromeach other (Owens et al 2000). Indeed, paroxetine is a dual5HT/NE reuptake inhibitor, and sertraline is a dual 5HT/dopamine reuptake inhibitor (Tatsumi et al 1997). A majorproblem of the SSRIs (and indeed of all drugs that blockthe reuptake of serotonin) is sexual dysfunction (Rosen etal 1999). A serotonin reuptake inhibitor that shared thegood efficacy and side effect profile of available SSRIsbut lacked the propensity to cause sexual dysfunctionwould represent a significant therapeutic advance.

There are several other effective antidepressants thathave been introduced since the TCAs that are frequentlyused but do not fall conveniently into any single catego-rization. Trazodone is a weak serotonin reuptake inhibitorand a potent 5HT2 receptor antagonist, which possessesantidepressant activity at high doses but is usually used asa hypnotic (Haria et al 1994). Nefazodone is a potent 5HT2

antagonist and also a NE and 5HT receptor inhibitor(Owens et al 1995). Venlafaxine is a dual (serotonin andnorepinephrine) reuptake inhibitor but is not a tricyclicdrug (Andrews et al 1996). Mirtazapine is a �2-receptorantagonist that increases presynaptic release of both sero-tonin and norepinephrine (de Boer 1996) and is also a5HT2 and 5HT3 antagonist. Because of advantages in theside effect profile and possibly in efficacy, these drugs areoften used as first-line agents.

MEDICATIONS USED FOR THE TREATMENT OF BIPO-

LAR DISORDER. The treatment of depression in patientswith bipolar disorder remains inadequately researched andconsequently a source of confusion for clinicians. It isgenerally agreed that all bipolar patients should be main-tained on a mood stabilizer. Of these, the most commonlyprescribed are lithium and the anticonvulsant valproate.When patients with bipolar illness become depressed, thefirst step is to initiate mood stabilizer therapy. If thepatient is already on a mood stabilizer at the time ofdepression onset, there are data to suggest that maximizingthe dose may effectively treat the depression (Nemeroff, inpress); however, when this fails, it is often necessary toadd an antidepressant. The risk of placing a bipolar patienton an antidepressant is the induction of a switch in moodto hypomania or mania or the induction of rapid cycling,but estimates on how commonly these occur vary (Alt-

Novel Treatments for Mood Disorders 591BIOL PSYCHIATRY2002;52:589–609

shuler et al 1995). Some data suggest that TCAs are morelikely than MAOIs or SSRIs to cause mania in bipolarpatients (Kalin 1996). It is commonly believed that theantidepressant bupropion is the least likely of all antide-pressants to produce manic shift, although the databasesupporting this contention is meager (Sachs et al 1994).Recently, it has been shown that the anticonvulsant lam-otrigine, which acts in part by modulating glutamatergicneurotransmission, may be particularly effective in treat-ing depression in the bipolar patient without inducingmania (Calabrese et al 1999). Major research tasks are todetermine whether these differences in propensity toinduce manic shifts are real and then to define uniqueaspects of the mechanism of action of agents that are lesslikely to cause manic shift but are still effective in treatingbipolar depression.

MEDICATIONS USED FOR TREATMENT REFRAC-

TORY PATIENTS. About 30% of patients with depressiondo not respond (i.e., exhibit a 50% or greater reduction insymptom severity) to an initial course of a single antide-pressant agent (Fava and Davidson 1996). A higherpercentage, perhaps 70%, is not brought into completeremission by antidepressant monotherapy. Some of thesenonresponders, after the monotherapy is maximized, areswitched to another antidepressant, usually from anotherclass. Another approach is to attempt to “potentiate” theeffect of the prescribed antidepressant by adding anotheragent that is not itself an antidepressant. There is along-list of such adjuncts, but among them are psycho-stimulants and dopamine agonists, (e.g., methylphenidate,amphetamine, modafenil, pramipexole), anticonvulsants(e.g., valproate, lamotrigine, gabapentin, topiramate), lith-ium, triidothyronine (T3), gonadal steroids (e.g., estrogen,testosterone), or atypical antipsychotics (Nemeroff 1996).The best-controlled data for efficacy as augmenting agentsis for T3 and for lithium, although the recent atypicalantipsychotic data are impressive.

DRUGS USED TO SPEED THE ONSET OF ACTION OF

ANTIDEPRESSANTS. Most patients with depression do notexhibit a therapeutic response until they have taken thedrug for at least 3 to 5 weeks. A number of agents havebeen used as add-ons to established antidepressants in anattempt to reduce this latency to response. So far, system-atic evidence that any such agent is effective in this regardis lacking. There are some data, however, that the additionof benzodiazepines (Smith et al 1998), 5HT1A antagonists(e.g., pindolol; Blier and Bergeron 1998), or �2-antago-nists (e.g., yohimbine; Cappiello et al 1995) may speed theonset of antidepressant action.

HERBAL REMEDIES. “Off the shelf” herbal remediesare self-prescribed by many individuals for the relief ofdepression, but they are not regulated by the FDA (Ernst

et al 1998). Therefore, there is virtually no information onefficacy, adverse events, or drug–drug interactions ofthese agents, nor is there any regulation of drug compo-sition. Moreover, in most cases the possible mechanism(s)of action of these compounds is obscure. Nevertheless,some studies, however flawed, have suggested that sub-stances such as St. John’s Wort (hypericum) or S-adenosylmethionine may have antidepressant properties; however,recently, two controlled studies failed to demonstrate thatSt. John’s Wort is more effective than placebo in thetreatment of depression (Davidson et al, in press; Sheltonet al 2001).

Medications Currently under Development

SELECTIVE NOREPINEPHRINE REUPTAKE INHIBI-

TORS. Although medications that are believed to actprimarily as selective NE reuptake inhibitors are effectivein treating depression, the only ones available in theUnited States are heterocyclics. One selective NE reuptakeinhibitor, reboxetine, is available in several Europeancountries and Canada but has not been approved in theUnited States. As expected, it has a more distinct adverseside effect profile than the SSRIs (Kasper et al 2000), withurinary and cardiovscular side effects of greatest concern.

DUAL REUPTAKE INHIBITORS. There is some evi-dence, although it is not universally accepted, that dualreuptake inhibitors work more quickly or are more effica-cious than single monoamine reuptake inhibitors (Ander-son 2000; Thase et al 2001), although at least one studydid not confirm these findings. Available dual reuptakeinhibitors include the tertiary TCAs and venlafaxine.Other dual reuptake blockers, such as duloxetine, andmilnacepran, are under development in the United States,although the latter is available in several countries includ-ing Japan and France (Sharma et al 2000).

DRUGS THAT INVOLVE DIRECT OR INDIRECT DOPA-

MINE RECEPTOR AGONISM. There is some limited evi-dence that drugs that enhance dopaminergic neurotrans-mission may have antidepressant properties. This is notsurprising in view of the fact that there is growingevidence for a reduction in the activity of certain dopa-mine (DA)-containing circuits in depressed patients. Thus,pramipexole, a DA receptor agonist, has been reported tobe as effective as fluoxetine in treating depression. Apreviously available medication, nomifensine, which is apotent DA reuptake inhibitor and an effective antidepres-sant, was withdrawn from the market because of adverseevents (rare hemolytic anemia). Therefore, novel DAreuptake inhibitors, including some that are also 5HT orNE reuptake inhibitors, are currently under development.As noted earlier, sertraline is the only SSRI with potentDA reuptake antagonist properties.


DRUGS THAT COMBINE SEROTONIN REUPTAKE IN-

HIBITION WITH 5HT2/5HT3 ANTAGONISM. Several cur-rently available antidepressants are antagonists of postsyn-aptic serotonin receptors. This is thought to change theadverse side effect profile that is associated with enhanc-ing serotonin neurotransmission. For example, nefazodoneclearly has reduced sexual side effects compared withSSRIs, and this may be due to its potent 5HT2A antago-nism (Ferguson et al 2001); mirtazapine shares this ab-sence of sexual dysfunction as well as reduced incidenceof nausea mostly due to 5HT2A and 5HT3 receptorantagonism (Gelenberg et al 2000). Antianxiety and hyp-notic effects have also been associated with antagonism ofthe 5HT2 receptor. Nevertheless, evidence proving thatthere is a link between postsynaptic receptor effects andthese adverse events remains incomplete. Nevertheless,drugs that combine serotonin reuptake antagonism with5HT2 and/or 5HT3 antagonism are being developed.

CORTICOTROPIN-RELEASING FACTOR (CRF) RECEP-

TOR ANTAGONISTS. Abundant evidence suggests thatincreased production and/or release of CRF within thecentral nervous system (CNS) occurs in patients withposttraumatic stress disorder (PTSD) and major depres-sion (Heim and Nemeroff 1999). Preclinical studies haverevealed that CRF receptor antagonists have anxiolyticand antidepressant properties. Hence, there is a solidrationale to support CRF receptor antagonists as a novelclass of antidepressants and anxiolytics. At least one CRFantagonist has been studied in an open-label design,suggesting antidepressant efficacy (Zobel et al 2000);however, a multisite placebo-controlled, double-blind,randomized clinical trial with a CRF receptor antagonisthas yet to be completed for the outcome of this strategy tobe evaluated.

Two compounds that act as antagonists for the lowaffinity glucocorticoid receptor (GR) are currently beingstudied in patients with severe major depression withoutpsychotic features (ORG 34517) or with psychotic fea-tures (mifepristone or C-1073). A recent preliminaryreport indicates that mifepristone can produce a very rapidreduction in psychotic symptoms in patients with majordepression (Belanoff et al 2001) in keeping with the earlierhypothesis that excessive HPA axis activity plays a keyrole in the development of cognitive impairment or psy-chosis in depressed patients (Schatzberg et al 1985).

SUBSTANCE P (NEUROKININ) RECEPTOR ANTAGO-

NISTS. Based on preclinical evidence suggesting anxio-lytic properties of inhibitors of the Substance P receptor,also known as the neurokinin I (NK1) receptor, selectivecompounds have been tested. Several NK1 antagonistshave been tested in rigorous designs, and in one studySubstance P was found to be superior to placebo and equal

to active comparators in treating depression (Kramer et al1998; Stout et al 2001). There are a number of ongoing trialsof novel NK1 antagonists in a variety of disorders rangingfrom depression to generalized anxiety disorder and panicdisorder. Indeed, several candidate NK1 receptor antagonists,and some antagonists of other NK receptors, are currentlyunder development for the treatment of depression.

DRUGS THAT MODULATE GLUTAMATERGIC NEURO-

TRANSMISSION. The excitatory amino acid glutamate hasbeen linked to a variety of psychiatric disorders, includinganxiety and depression, and in inhibition of neurogenesisor contribution to neurodegeneration. Glutamate neuro-transmission involves several distinct types of receptor,generally categorized as ionic or metabotropic. Antago-nists of postsynaptic glutamate receptors (e.g., NMDAantagonists) and medications that reduce presynaptic re-lease of glutamate (e.g., mGluR agonists) are among thecandidate medications under development as potentialantidepressants (Mathew et al, in press).

Targets for Future Antidepressant Research

DRUGS THAT INTERACT WITH SECOND MESSENGER

SYSTEMS. After binding to postsynaptic receptors, mono-amines and other neurotransmitters initiate a cascade ofintraneuronal events that include effects on a variety ofsecond messenger systems including cAMP and PIP (Hy-man and Nestler 1996). Evidence suggests that, in general,activation of certain of these pathways is necessary for theaction of currently available antidepressants. Conse-quently, medications that act directly on second messengersystems, such as rolipram, may be effective antidepres-sants.

DRUGS THAT INTERACT WITH RESPONSE ELE-

MENTS AND TRANSCRIPTION FACTORS. There is alsoevidence that antidepressants stimulate the expression ofearly immediate genes, phosphorylation of protein ki-nases, activity of response elements such as cAMP re-sponse element binding protein, and the activity of tran-scription factors (Duman et al 1997). Each of theseelements is a potential target for antidepressant drugdevelopment. For example, there is reason to believe thatphosphorylation inhibitors active in the CNS may possessantidepressant activity.

DRUGS THAT ENHANCE NEUROPROTECTIVE AND

NEUROGENIC FACTORS. In recent years, it has beenunequivocally demonstrated that, in contrast to previousnotions, neurogenesis occurs in the adult brain particularlyin the dentate gyrus of the hippocampus. Moreover, thereis evidence that depression and stress may interfere withneurogenesis, perhaps in part by inhibiting the activity ofneurogenic factors such as brain-derived neurotrophic


factor (BDNF) or of antiapoptotic genes such as bcl2.Thus far, all somatic treatments known to be effective intreating depression, including electroconvulsive therapy(ECT), have in common the property of stimulating theexpression of BDNF (Duman et al 1997), and those testedalso enhance neurogenesis (Duman et al 1997). At leastone validated animal model of depression, maternal depri-vation, is associated with reduced hippocampal neurogen-esis (Plotsky et al, unpublished data). Hence, moleculesthat enhance neurogenesis, including neurogenic and neu-roprotective factors, could function as antidepressants.

DRUGS THAT MANIPULATE CYTOKINE RECEPTORS

AND ACTIVITY. There is limited and controversial evi-dence that changes in the expression of cytokines andother molecules usually associated with immune functionmay be involved in the pathogenesis of depression. Cyto-kines are expressed in the brain, and during developmentthey play important roles in normal brain embryogenesis.A recent study revealed that induction of increased cyto-kine activity was associated with depressed mood innormal volunteers (Duman et al 1997). Elevated IL-6concentrations in plasma have been reported in depressedpatients (Musselman et al 2001). Should further workconfirm a relationship between cytokines and depression,medications directed at cytokines might represent novelantidepressants.

DRUGS THAT MODULATE NEUROTRANSMITTER

TRANSPORTER TRAFFICKING. Because drugs that inhibit5HT and NE transporters are mainstays in our currentarsenal of antidepressant medications, it is reasonable toconsider that drugs that alter the surface expression ofthese proteins might possess clinical utility. Recent studieshave revealed that the 5HT and NE transporters areregulated by intracellular kinase and phosphatase-depen-dent trafficking pathways that ultimately alter the densityof transporters on cell membranes (Bauman et al 2000;Blakely et al 1998; Ramamoorthy and Blakely 1999).Whether current antidepressants influence the traffickingof transporter proteins in vivo remains unknown. Never-theless, as the signal transduction pathways underlyingphosphorylation-based changes in transporter surface ex-pression are unraveled, new targets for pharmacologicintervention may be uncovered.

How Does Mood Disorder ResearchAdvance Novel Treatments?

The pathophysiology underlying mood disorders remainsobscure. Consequently, there are few primary biologicaltargets toward which to direct new therapeutics develop-ment. Current treatments for mood disorders have beenlargely developed based on serendipitous clinical observa-

tion. These were critical observations—not of mechanism,but of clinical response. The ability first of clinical and thenof pharmaceutical scientists to move basic and clinicalobservations into effective clinical treatments represent ad-vances that, in their time, made a difference in many lives andcannot be overlooked. Furthermore, these observations pro-vided clues for mechanistically oriented basic scientists todevelop even newer treatments. Nevertheless, it is now timeto forge ahead with new clinical research based on thenumerable advances in neuroscience.

Scientists agree that finding the critical pathophysiolo-gies in mood disorders will facilitate movement towardtreatment, leading more quickly than any other pathway tonovel therapeutic candidates. This rapid movement, basedon known pathophysiology, has taken place in almostevery medical discipline and is perhaps best exemplifiedin recent years in Alzheimer’s disease research. Clearly,the first answer to the question of how to move novel drugdiscovery ahead is to facilitate basic discovery. This is notas simple as merely increasing basic research support; inaddition, funding mechanisms must be specifically tar-geted so as to direct relevant basic ideas and projectstoward application in the areas of disease pathophysiologyand drug target development. Indeed, the NIMH and othermental health funding entities already support these direc-tions. Within NIMH, movement toward consolidatingdisparate programs each having a goal of novel treatmentdevelopment, would facilitate this process. The commonproblems of rigidity in pharmacologic ideas and clinicalconcepts, both for investigators and grant reviewers, fail-ure to incorporate the newest technologies into appliedapproaches, and utilizing the same old research method-ologies, still serve as obstacles to new drug discovery inthe R-O1 grant mechanism for basic research. Innovativethinking in basic research and incentivizing its appliedaspects from the best laboratories could advance innova-tions through federally funded initiatives.

Many of our best treatments for mood disorders have beenused as pharmacologic models for further discovery. Al-though there have been few other options in therapeuticsresearch to date, this strategy has had both advantages anddisadvantages. On the one hand, it has provided new treat-ments with marginally improved therapeutic action, butconsiderably improved side effect profiles. On the otherhand, when used as a direct template without the benefit ofnew basic research, it has not provided the field withsubstantially innovative treatments. In contrast, when cre-ative basic scientists directly study common antidepressant orantimanic drug action at cellular and molecular level, newobservations have emerged which may underlie new thera-peutic directions. For example, the actions of lithium andother mood stabilizers on intracellular signaling cascadesmay redirect treatment targets in these areas.


One of the critical elements of successful drug discov-ery is the involvement of astute, well-trained clinicians indesigning clinical methodologies, defining outcome crite-ria in validated disease entities, and developing suitablesurrogate measures that track drug response. Such aprogram requires a network of sites and scientists. Thedays of the isolated clinical experimentalist making criti-cal contributions are largely past. Networks of trained,observant clinicians with “real-world” patient volunteers,representative of actual treatment populations, are neededto service the promise of basic discovery. Problems withclinical trials in psychiatry, particularly in mood andanxiety disorder, are so severe that industry enthusiasm fordrug discovery waxes and wanes with virtually eachclinical trial. All clinical investigators in industry andacademia alike are painfully aware of these problems: highplacebo response rates that compromise the identificationof drug–placebo differences; clinical trials that garnerdropout rates higher than 50%; poor patient volunteerscreening criteria allowing patients with poor or compro-mised response rates into the test populations; and the lackof outcomes other than clinical response, namely, theabsence of one or more critical neurophysiologic re-sponses corresponding to the drug’s therapeutic action. Inother NIH branches, successful programs responsible forbringing new treatments to development, do so withexperienced, well-developed clinical networks, and newclinical methodologies are created in the process.

An additional benefit of such a multisite clinical network isto provide the practitioners pool with knowledge and tech-niques garnered from research, which are then extended intoclinical practice. Such a cadre of scientists will infiltrate notonly clinical practice but industry to improve clinical testingthere, and into governmental offices (FDA, NIH, CDC) toaffect applied research endeavors.

What Is the NIMH Already Doing to FacilitateDrug Development?

BASIC RESEARCH FUNDING. The NIMH funds basicneuroscience research pertinent to depression and maniamechanisms, particularly the R-O1 grants. Much of thiswork focuses on disease target identification. Currently,the NIMH provides support for the identification of noveltargets through the Brain Molecular Anatomy Project(BMAP). The goal of BMAP is the discovery of novelgenes expressed in the developing mouse nervous systemand the development of resources for the neurosciencecommunity. The genetic resources made available throughBMAP include: the identification of 3�- and 5�-expressedsequence tags (ESTs) from adult mouse brain; the gener-ation of cDNA libraries from 10 brain regions (hippocam-pus, striatum, basal ganglia, amygdala, frontal cortex,

hypothalamus, pineal gland, olfactory bulb, brain stem,cerebellum), the spinal cord, and the retina in the adultmouse using strain C57BL6/J; and a nonredundant arrayedset of more than 20,000 mouse brain cDNA clones(http://www.resgen.com/products/BMAP.php3). In addi-tion, because the primary targets of many clinicallyimportant medications are membrane receptors, new ini-tiatives in the Intramural Research Program at NIMHinclude the isolation, cloning, and characterization ofnovel human G-protein coupled receptors and orphanreceptors (http://intramural.nimh.nih.gov/research/log/).

NOVEL COMPOUND SCREENING. The NIMH Psycho-active Drug Screening Program (PDSP) was instituted toaid investigators in the design and development of newchemical entities and small molecules to be used asresearch tools, probes, drug delivery vehicles, potentialtherapeutic agents, and positron emission spectrometry(PET) or single photon emission tomography (SPECT)ligands for brain imaging. New chemical entities andnatural products can be screened for pharmacologic andfunctional activity at a large number of cloned human orrodent CNS receptors, channels, and transporters throughthe NIMH PDSP program (http://pdsp.cwru.edu/pd-sp.htm). Services include: receptor binding assays, devel-opment of assays for molecular targets, and functionalassays to determine effects on second messengers, chan-nels, and transporters. A new addition to the program is asearchable database that provides affinity constants atvarious receptors for nearly two thousand compounds(http://pdsp.cwru.edu/pdsp.asp).

CONTRACT CHEMICAL SYNTHESIS. The NIMH cur-rently synthesizes certain novel or difficult-to-obtain psy-choactive compounds, maintains a repository, and distrib-utes compounds and reagents for use in basic and clinicalresearch relevant to mental health through the ChemicalSynthesis and Drug Supply Program (http://www.sri.com/pharmdisc/NIMH.program.html). The repository containsligands for CNS receptors, radiolabeled compounds forautoradiography, unlabeled precursors for PET andSPECT radiotracers, biochemical markers, drug analogsand metabolites, and reference standards. Compounds areavailable through an online searchable catalog.

The Chemical Synthesis and Drug Supply Program alsohas the capability to provide bulk manufacturing (GLP andGMP synthesis) of promising compounds, especiallynovel PET and SPECT ligands, for toxicology and safetystudies.

MOUSE BEHAVIORAL PHENOTYPING. The NIMH cur-rently supports efforts to generate mutant mouse strains(through ENU mutagenesis) and distributes these strains tothe scientific community through the Mouse NeurosciencePhenotyping and Distribution Center. This resource serves


to enhance the identification of novel drug targets and thetesting of novel compounds. The program could alsopermit the development of new assays for testing noveltherapeutics through the exploratory and developmentgrant mechanism (R21).

BIOLOGICAL MARKERS. The NIMH has initiated ac-tivities to foster the identification and validation of bio-logical markers in multiple domains (e.g., imaging, cog-nitive, behavioral, and genetic) in mechanistic studies ofdisease pathogenesis and treatment. Several recent pro-gram announcements have called for ancillary mechanisticstudies of novel biological markers for diagnosis, progno-sis, disease activity, or treatment response using patients,patient materials, or information from multisite clinicaltrials in pediatric and adult populations (http://grants.nih.gov/grants/guide/pa-files/PA-01–043.html; http://grants.nih.gov/grants/guide/pa-files/PAR-00–095.html).

CLINICAL EFFECTIVENESS TRIALS. The NIMH cur-rently supports several large-scale clinical trials to assessthe effectiveness of marketed drugs for the treatment ofmental disorders. Three ongoing trials for the treatment ofmood disorders include 1) the Treatment for Adolescentswith Depression Study (TADS) (http://www.nimh.nih-.gov/studies/tads.cfm), 2) Sequenced Treatment Alterna-tives to Relieve Depression (STAR*D; http://www.edc.gsph.pitt.edu/stard/), and 3) the Systematic TreatmentEnhancement Program for Bipolar Disorder (STEP-BD;http://www.nimh.nih.gov/studies/stepbd.cfm). This initia-tive will serve to develop a clinical trial network in mooddisorders.

Specific Suggestions for NIMH Efforts in DrugDiscovery and Development

The limiting factor in drug discovery globally in all areasis the available knowledge base. Basic research focused onan understanding of the biology of severe mental illnessesis pivotal to advances in therapeutics. Effective drugdiscovery requires knowledge of drug targets that arerelevant to the underlying pathophysiology. The develop-ment of protease inhibitors for HIV/AIDS, gamma secre-tase inhibitors for Alzheimer’s disease, and tyrosine kinaseinhibitors for chronic myelocytic leukemia were derivedfrom the elucidation of fundamental pathophysiologicmechanisms that could be targeted for drug therapy. Thesubstantial speed with which these areas of medicine wereable to translate basic advances to the clinic demonstrateswhat is possible for the treatment of major depressivedisorder, bipolar disorder, and other mood disorders, if andwhen their pathophysiologic mechanisms are well definedand rational therapeutic targets follow. As noted earlier, todate the discovery of drugs for mood disorders has itsroots in basic research on novel mechanisms of action,

careful clinical observations of the effects of psychoactivecompounds, and serendipity (Vetulani and Nalepa 2000).

How Can Basic Research Be Optimized for DrugDiscovery by NIMH Initiatives?

PROJECT FUNDING FOR BASIC NEUROSCIENCE RE-

SEARCH. Basic research aimed at understanding diseasebiology and the discovery of “drugable” targets needs tobe promoted through increasing R-O1 funding in this area,using RFAs for this goal, and perhaps most importantlyfunding riskier research. Incorporation of creative andnovel disease models needs emphasis in the RFAs. Inno-vative formulations of mechanisms as models to explorenovel disease targets need a forum. An articulated focus oninnovation, in both R-O1-type and SBIR-type mecha-nisms, in the models being tested and in the methodologiesincorporated are equally important. This will involve anemphasis on the development of new and pathophysiolo-gy-based animal models for mood disorders, especiallymouse models, because these will most easily be able tocapture an advantage from modern genomics. Behavioralcharacterization of genetically altered mice is essential.

Incentivizing the use of modern molecular tools, manyof which are now or will be developed by NIMH, maybring faster progress. Capitalizing on public drug reposi-tories, drug databases, advancing behavioral characteriza-tion of genetically altered mice, application of powerfulDNA array, and proteomic techniques are all likely toadvantage discovery. Strategies to prioritize these newdirections within NIMH should be considered.

Of some importance would be a central NIMH office toadminister and coordinate these activities to fully deliver aprogrammatic advantage. Drug development has been anundervalued area of mood disorder research for so longthat a “remedial” focus may be helpful.

CENTER FUNDING FOR DRUG DEVELOPMENT. Acomplementary mechanism to stimulate innovation in thedrug discovery process is not only to invest in R-O1research, but also to emphasize multidisciplinary centersthat have the dual goal of elucidating pathophysiologicmechanisms of mood disorders and developing targets fordrug discovery. Such centers might be based on the Contemodel, but also have their success ultimately based on thedegree to which proposed studies clearly articulate hy-potheses about disease pathophysiology and propose andtest targets for drug discovery. These model centers,directed toward discovery in drug targets and treatmentmechanisms, would need to facilitate the application ofnew insights from basic neuroscience to innovative treat-ment discovery. As such, successful centers would includebasic and clinical scientists working interactively to bringclinical observations to the bench and basic insight to the


clinic. Innovation and risks should not only not be penal-ized, but should be considered essential for such centers.

The current model for a center needs to address manyinterwoven needs ranging from training of basic andclinical researchers, technology development, and infra-structure investments to targeted research. Single hypoth-eses are most appropriate for program project applications,whereas centers should support and stabilize a cadre ofinteractive investigators whose research includes basic andclinical dimensions and may in many cases take the formof “discovery-based” research as opposed to “hypothesistesting.” This is particularly true in stimulating the flow ofideas between branches of neuroscience that can beartificially segregated by department rather than funda-mental brain mechanisms. Other institutes such as NCIand National Institute of Diabetes and Digestive andKidney Diseases have made strategic use of general centermechanisms to develop promising research areas, recruitinvestigators by supporting intensive core facility devel-opment, and encourage local investments in basic andpreclinical model investigation. The perception of manyoutside the NIMH is that the center mechanism currentlyin place at the NIMH is too narrow in its mission.

SMALL BUSINESS GRANT FUNDING FOR DRUG DE-

VELOPMENT. The NIMH has a successful SBIR/STTRprogram. This program has been particularly valuable tomany start-up biotechnology companies. With the currentfunding available, the greatest strength of the SBIR/STTRprogram is to provide support for pilot proof-of-concept(Phase 2) studies. To increase the level of interaction orinvolvement of the NIMH with industry, the amount ofSBIR funding should be increased. This can be achievedby an increase in the funds available for Phase I and PhaseII SBIR grants or by the institution of a Phase III grant forthe continuation of successful programs.

Other vehicles of funding should be examined asalternatives to the SBIR/STTR program and used to fostercloser collaboration between NIMH and industry. Thegoal is a true collaboration in which scientific expertisefrom each group, contributes to projects of mutual interest.One representative mechanism may be to institute a modelsimilar to the National Cooperative Drug DiscoveryGroups (NCDDG) that exist within NCI. These programshave at their core substantial funding available for acollaboration between government, an academic institu-tion, and industry. At funding levels of $1 million per yearfor up to 5 years, these programs provide realistic levels ofsupport to advance drug discovery substantially.

At the moment, in addition to the financial gain, SBIRand STTR funding have an important qualitative benefit toindustry. Projects that successfully go through NIMH peerreview and achieve funding receive credibility both withscientists and investors alike. This validation of a research

project, the proof of concept of a novel mechanism, or theintroduction of a novel yet risky technology greatlybenefits the reputation of a small company. With avalidated proof of concept behind a drug discovery pro-gram, partnership with major pharmaceutical companiesbecomes easier, allowing novel ideas and mechanisms tobe explored in the development of novel therapy.

How Can Clinical Research Be Optimized forNovel Drug Development?

EARLY CONCEPT TESTING OF PROBES USING NOVEL

DRUG PROBES. The NIMH should establish a program ofearly drug development that conducts proof of conceptstudies of innovative agents in mood disorder treatment.Drugs and strategies exist that have been hypothesized topossess a therapeutic benefit in a variety of psychiatricdisorders but that have been inadequately tested. Many ofthese agents are actually used in clinical practice in theabsence of compelling clinical data (e.g., the use ofpsychotomimetics to augment SSRI response in depressedpatients). For those drugs, a definitive concept-testingstudy would provide the needed evidence to appropriatelyinfluence clinical practice. In testing other putative anti-depressants or antimanic drugs, important hypothesesregarding the role of a particular neurotransmitter orneuromodulatory system can be tested. It is expected thatpositive results from NIMH-sponsored proof-of-conceptstudies would encourage industry to invest in Phase II/IIIprograms. Concomitantly, negative results would have thebenefit of ruling out hypotheses that have lingered in thefield for decades.

The identification of putative therapeutic candidates isan initial challenge. Sources of drugs can include 1) drugsapproved for another indication, 2) off-patent genericdrugs, 3) new compounds developed by biotech pharma-ceutical companies, 4) new compounds available throughlarge pharmaceutical companies for other indications, and5) drug probes, developed for concept testing throughsmall academic or government programs. Some of thesecategories are far fuller and easier to bring forward thanothers, especially given issues of intellectual propertyrights. In the case of generic drugs, clinical testing isstraightforward. Collaboration with small companies whopossess interesting compounds is done in other NIHinstitutes. Hence, legal and financial precedents exist forsuch partnerships. In fact, there are substantial advantagesto companies who partner with the government for proof-of-concept studies rather than large pharmaceutical com-panies in that a positive trial can substantially increase theasset value of their product before they have to partnerwith a major pharmaceutical company. Direct collabora-tion between the NIMH and large pharmaceutical compa-


nies to facilitate the development of new compounds orseek new indications for approved compounds can provemore problematic, yet such relationships are far fromimpossible.

TRAINING AND SUPPORT OF CLINICAL SCIENTISTS.

Programs attempting to attract competent and well-trainedphysicians to enter mental health research have thus farnot been successful. Disappointingly, the numbers ofcommitted physicians entering research in brain diseaseshave been shrinking. The shortage of bright and motivatedyoung physicians in the field of clinical research isremarkable. Just at the point when basic neuroscience iscreating opportunity in mood disorders, it seems that thebrightest and best young physicians elect other medicaldisciplines. Consequently, the creative translation of basicneuroscience into clinically feasible treatment regimens,let alone their competent testing, is sorely compromised.

The NIMH needs to address this shortage of clinicalresearch scientists in an effective manner. One couldspeculate that funded training programs, educational loanreimbursement programs, effective advertisement of clin-ical roles, and an enhanced “reputation” for clinician-scientists might all be effective. Indeed, an NIMH-spon-sored special panel to articulate the issues and to proposespecific and feasible remedies was held recently. Already,the loss of a generation of clinical scientists can be seenand felt in academic psychiatry and neurology depart-ments around the country, as well as in industry.

CLINICAL TRIAL NETWORKS. With the identification ofdrug candidates and concept testing, a need will arise foreffective and efficient clinical trial networks, capable of largemultisite clinical trials. Such networks will be most valuableif they are composed of optimal trial sites with trained andexperienced staff at those sites. The current structures of theNIMH Effectiveness Trials Networks in Depression andBipolar Disorder will surely be the nidus for broader NIMH-sponsored Clinical Trial Networks.

The goals, resources, administration, and focus of aClinical Trials Network in Mood Disorder Therapeuticsneed careful consideration. Experience from other insti-tutes and from current NIMH initiatives can be examined,along with the unique requirements of mood disorders asa disease focus. Techniques to attract the best clinicalscientists in the field without jeopardizing other NIMH-funded projects needs to be considered. This topic mayalso be a part of a special panel work group to drawtogether models for such networks in the area of mentalhealth research.

RESEARCH-RELATED BENEFITS OF A CLINICAL TRI-

ALS NETWORK. Although the need for new therapeuticagents to treat affective disease would be the driving force

behind clinical trial networks, fostering such networks bythe NIMH would inevitably yield additional benefits. Thequestion of the appropriate diagnostic or symptom-con-stellation criteria for a particular treatment would certainlybe addressed. The identification of effective drug treat-ments for symptomatic subgroups of depressive syn-dromes could prove an important impetus to new method-ologic approaches to clinical trials. The putativemultigenic etiologies of neuropsychiatric diseases and theincreasing likelihood of linking particular genetic, molec-ular, and cellular pathways with specific behavioral orneurochemical phenotypes encourage this approach al-ready. Clinical phenotypes (rather than diagnostic catego-ries) may prove targets for drug development in the future.Moreover, the more technical but important aspects ofclinical trial design would necessarily receive attention,including appropriate subject populations to answer aclinical question, optimal length of trials, optimal use ofplacebo designs, and evaluation of surrogate markers fordrug action or optimal drug dose to advance new drugdevelopment.

The generation of new, more precise psychometricmeasures would be another benefit to the field. Thedevelopment of new rating scales could be encouraged,and their validity and reliability could initially be tested assecondary measures in other trials. Importantly, biologicalmeasures that could serve as surrogate markers for clinicalresponse could be introduced. Obviously the developmentof new scales, more sensitive ones, or biological markersof clinical response would have the long-term conse-quence of improving the efficiency of subsequent drugdevelopment.

Clinical trial networks would necessarily have to ad-dress directly the myriad problems in clinical trials notedhere, including but not limited to high placebo responserate, optimal illness populations, high subject dropoutrates, and imprecise symptomatic outcome measures, per-haps with a series of focused methodologic experiments.Because these problems surely contribute to the unaccept-ably high rate of failed trials and imprecise outcomes inmood disorders, the problems need effective and timelysolutions. Solutions to these critical clinical trial problemswould be a service not only to government and academicresearch but to industry-based drug development efforts aswell.

EMPHASIZING SPECIAL POPULATIONS. The evalua-tion of drugs for mood disorders in all populations of use,especially children and adolescents, is a recommendationof the FDA and universally espoused. The ethical issues ofsuch trials have been debated and a consensus has beenreached; however, because pediatric drug trials in mooddisorders have not been widely implemented, the clinicalmethodology for multicenter trials in children requires


attention. Differential diagnosis of mood disorders inchildren can be challenging; outcome measures, evensymptomatic ones, need evaluation; likewise, simple de-sign features such as subject number and study duration,concomitant medications, and diagnostic diversity all needdefining. In addition, a focus on other special age groups,including the elderly and their special treatment require-ments, is needed.

Mood disorder diagnosis and treatment studies in ethnicsubpopulations in the United States and worldwide is ofgreat importance. An abundance of methodologic issues,many of which are ill defined, plague these studies. Moresignificantly, these kinds of studies are done far tooinfrequently. Moreover, actual therapeutic trials in racialpopulations are also lacking, even though their importancecan be predicted from known racial differences. Metabolicdifferences lead to pharmacokinetic differences acrosspopulations and probably to neurochemical changes aswell, both of which are likely to affect treatment response.Pharmacogenetic markers of response also differ acrossethnic groups as well. In today’s push toward globaliza-tion, this area of pharmacology is a critical one.

What Are the Optimal Tools to Stimulate DrugDiscovery?

FACILITATING ACCESS TO DRUG REPOSITORIES

AND PUBLIC DRUG LIBRARIES. Despite the paucity ofrational drug discovery targets in mood disorders, goodhypotheses exist. An obstacle to testing many hypotheses,basic and clinical alike, derives from the absence of“probe” molecules to interact with target brain proteins.Chemical libraries consisting of synthetic and naturalproducts are valuable assets for drug discovery programs.Ultimately, the library could serve as a source of com-pounds deliverable or available to investigators. An addi-tional consideration is to have the NIMH fund effortsusing medicinal chemistry resources already developedwithin the institute to generate libraries of compoundsdirected at examining known pharmacophores; these canbe made available through the NIMH Chemical Synthesisand Drug Supply Program. If a library of “CNS-active”molecules could be collected, cataloged, and made avail-able for funded science, this would allow a concentratedeffort on generating interesting diverse molecules that mayhave utility as starting points for drug discovery programs.

ASSIMILATING A DRUG DATABASE. Similarly, theNIMH could maintain a database of information on newcompounds and reagents that can be made available tofacilitate drug discovery. This reagent database woulddirect investigators to laboratories where they could obtainnew antibodies or ligands, well before they are commer-cially available. This proposed repository of information

could be an add-on to the existing NIMH ChemicalSynthesis and Drug Supply Program repository. TheWeb-based database of reagents for the current NIMHsynthesis program needs to be integrated with otherdatabases, perhaps that at Case Western Reserve Univer-sity (CWRU), to provide relevant information about bio-logical activity in a searchable manner. It would be helpfulto identify existing data on the selectivity and specificityof the compounds in the library through hyperlinks eitherto references or contract databases. The goal should be tohave a single user interface that would allow investigatorsto identify either a target such as “5HT7 receptor” or aligand class such as “phenothiazine” and then obtain allthe information as to compound availability, activity, orstructural variants.

FACILITATING AVAILABILITY OF DISEASE TISSUE

FOR STUDY OF DRUG TARGETS. Promoting the availabil-ity of high-quality human postmortem tissue for the fieldfrom carefully diagnosed cases of mood disorders andmatched healthy control subjects would provide a substan-tial contribution to pathophysiology studies. This could beaccomplished either with or without a further NIMHinvestment into federally funded collections. An ongoinginventory of available tissue, with tissue characteristics,diagnosis, source, and supervising scientists would be anobvious start. Common standards for collection and diag-nosis could be developed by a group of experts. Afacilitation of high-quality scientific collaborations acrosslaboratories with the application of cutting-edge technol-ogies to well-collected and characterized human tissuewould be the hope. If the NIMH had its own tissue source,then it could direct collection characteristics and providethat tissue to new investigators with cutting-edge technol-ogies, potentially contributing to new information aboutdisease mechanism and drug targets.

For example, the application of regional expressionprofiling to human postmortem mood disorder tissue forthe purpose of drug target development could be advancedby the NIMH. DNA microarray technology enables thegeneration of large data sets contrasting gene expressionfrom disease with nondisease brain tissue on a regionalbasis; the NIMH could produce publicly available regionalexpression libraries for mood disorder investigators. Theopportunity to develop and make these data sets publiccould enable a broad cadre of investigators to use thecomplex experimental results for subsequent hypothesistesting toward the goal of developing drug targets. If theNIMH would sponsor this work, it could ensure optimalstarting material, consistent methodology, and broad ap-plication of data-analytic and mining techniques to maxi-mize information yield. One could predict an optimalscenario: first an effort in new treatment developmentcould begin based on data from a regional expression


library to formulate a novel hypothesis of mood disorders;investigators could test the hypothesis in appropriatepostmortem tissue itself, then launch a novel developmentplan for a mood disorder diagnosis. One could conceive ofthis as being completed under grant or contract mecha-nisms. The related task of developing high-quality re-gional cDNA expression libraries could also be similarlyaccomplished, with equivalent advantage to the field.

What Is the State of Somatic Treatments forMood Disorders?

In many respects the study of somatic treatments iscomparable to that of other interventions for mentaldisorders using clinical trials methodology, includingspecified treatment parameters, duration, and standardoutcome measures; however, certain characteristics ofsomatic treatments distinguish them, to varying degrees,from standard pharmaco- and psychotherapeutic interven-tions and present special challenges to the performance ofscientific research.

Because of the relatively invasive nature of somesomatic therapies, their use is skewed toward a moreseverely ill mood disorder population. For example, ECTis specifically indicated in cases of severe depressionaccompanied by psychosis or catatonia. This also meansthat a disproportionate number of individuals available forstudy or clinical treatment using electroconvulsive therapyor another relatively invasive treatment modality, such asvagal nerve stimulation (VNS), will be treatment refrac-tory at presentation. This can work against the develop-ment of new somatic treatments, in which the classicalactive versus control condition paradigm may fail to showsufficiently robust efficacy for a new treatment whentypical, moderately ill patients may not be available forstudy with a novel but invasive treatment modality.

The need to study very ill patients also means that it isdifficult to establish a medication-free baseline, whichwould be ideal to study the true effects of a somaticintervention and essential for meaningful mechanism ofaction research. This has been less of an obstacle topharmacotherapy research, for which the use of multiplemedications has become the norm in severe mood disor-ders. The only controlled trial of ECT in mania, forexample, was published more than a dozen years ago(Rudorfer 1989). Some investigators have moved insteadtoward combined treatment studies of somatic treatmentsplus drug treatment.

Indeed, in some cases there is no agreement, scientifi-cally or ethically, on an appropriate control or placebocondition for somatic treatment research. A sham ECTcondition, involving the induction of general anesthesiawith no electrical stimulation, was used in more than a

dozen studies in the United Kingdom during the late 1970sand 1980s but has never been used in the United States dueto the unacceptable risk of anesthesia in the absence ofpossible benefit to the individual patient. Much of the lighttreatment literature is clouded by questions about theunpersuasive (e.g., dim red light) nature of the putativecontrol condition. More recent research (e.g., by Eastman)using sham negative ion generators as a more plausiblecontrol condition have helped establish the efficacy oflight treatment in winter depression.

Current Research and Future Directions

ECT. Electroconvulsive therapy continues to be theprimary treatment for medication-resistant depression de-spite developments in new medications and other somatictreatments including vagal nerve stimulation (VNS) andtranscranial magnetic stimulation (TMS). Although ECTis associated with significant side effects and other draw-backs such as social stigma, ECT use in the United Stateshas increased and, with the pressure of containing costs byshortening hospital stays, the use of ECT in generalpsychiatry will probably continue to increase over the nextdecade. The following four major areas of research in ECTand other somatic treatments should be supported.

Developing a scientific understanding of the mecha-nisms of action of ECT. Understanding the mechanism bywhich an electrical convulsion can exert a therapeuticbenefit in depression can support depression research bothby decreasing the stigma of ECT and by encouraging thedevelopment of new somatic treatments. The NIMH ispromoting ECT research (Salzman 1998), but more basicscience research is needed. Theories such as the dience-phalic hypothesis (Abrams and Taylor 1976; Fink andOttosson 1980) have been challenged by recent datasupporting the anticonvulsant hypothesis (Sackeim 1999).The anticonvulsant hypothesis proposes that the therapeu-tic effect of ECT is due to the release of endogenousneuropeptides and neurotransmitters that decrease theexcitability of the brain. This hypothesis is supportedprimarily by clinical research and intriguing but sparsepreclinical data (Tortella and Long 1985) supporting thetheory that when ECT is effective, there is an activeinhibitory process shown by an increase in the seizurethreshold (Sackeim et al 1986), and electroencephalo-graphic (Krystal and Weiner 1994) and regional cerebralblood flow changes (Nobler et al 1994).

Funding for clinical research should continue to con-centrate on developing algorithms to determine the rela-tionship of ECT treatment variables (e.g., seizure thresh-old) to ECT response or the loss of seizure efficacy duringa course of ECT. These algorithms can test theories such


as the anticonvulsant hypothesis and guide clinicians inadministering effective treatments. Changes in treatmentvariables related to response (e.g., diminished CBF in theanterior frontal lobes or an increase in the seizure thresh-old) may also be investigated to predict relapse.

Optimization of the efficacy of an acute course of ECT.This area has been a focus of NIMH research on ECT, butthe results have had a minimal impact on clinical practice,perhaps because there is no currently standardized certifi-cation for ECT practitioners. Moreover, much of the datacomparing uni- and bilateral ECT has been limited tomajor depression, and there is a need for data in othertreatment groups particularly in acute mania (Black et al1989; Mukherjee and Debsikdar 1994). Others have alsoargued for the support of ECT research in special popu-lations including adolescents and individuals with neuro-logic diseases such as Parkinson’s disease, agitation indementia, and developmental disabilities.

The debate, which has been focused on the efficacy ofunilateral versus bilateral treatments, should shift to otherareas including electrode placement and ultrabrief pulsefrequencies. These treatment modifications have the po-tential advantage of decreasing ECT-related cognitive sideeffects, although controlled clinical trials have not beencompleted (Sackeim et al 1994). These ultrabrief pulsewidths (compared with the .5–2 msec used by mostpractitioners) have the potential advantage of producing aseizure using decreased energy and causing fewer cogni-tive side effects.

Although the d’Elia is the accepted electrode positionfor right unilateral ECT, recent trials have supported theuse of novel bilateral electrode placements to replace thetraditional bifrontotemporal position. There is evidencethat bifrontal placement may increase efficacy and de-crease cognitive side effects (Bailine et al 2000; Lawson etal 1990; Letemendia et al 1993). Further research isneeded to test these electrode placements as well as othernovel placements such as the combination of a rightfrontal placement and a left frontotemporal placement(Swartz 1994).

Minimizing the cognitive side effects from ECT. Re-search into alternative stimulus electrode placements,stimulus waveforms, and pharmacologic agents (e.g., nal-oxone, physostigmine, and thyrotropin-releasing factor) todecrease the cognitive side effects of ECT should beencouraged. Clinical studies of acute and maintenanceECT should be carefully designed to examine the effectson cognition.

Optimizing long-term outcome. The NIMH support forstudies in continuation and maintenance pharmacotherapy

and ECT after an acute course of ECT that will provideimportant clinical guidelines for clinicians who are in-creasingly using maintenance ECT. These studies shouldinclude measures to predict relapse in vulnerable popula-tions. Previous studies have shown that medication resis-tance before ECT is an important predisposing factor inrelapse after ECT (Prudic et al 1996). There is preliminaryevidence that electroencephalographic morphology andcerebral blood flow may also predict response to ECT andrelapse after a course of ECT. Research into the clinicaland biological markers of relapse after ECT can haveimportant clinical implications.

REPETITIVE TMS. In contrast to the application of anelectrical stimulus to the scalp, as in ECT, a moreprecisely localized electrical current can be producedwithin the brain by pulsing a magnetic wave (generatedthrough a coil on the head), which passes undistortedthrough the skull. The resulting cortical stimulation hasbeen used as a neurophysiologic probe to assess motorfunction within the cortex.

Over the past decade devices have been developedcapable of delivering repeated TMS pulses. A train ofTMS pulses, delivered to the left prefrontal cortex repeat-edly but at a subconvulsive rate over time daily to anawake and alert patient, has demonstrated antidepressantefficacy in several small open and sham-controlled trials.To date, antidepressant effects have been relatively mod-est, and few patients have been medication free or fol-lowed systematically beyond a 1- or 2-week rTMS treat-ment trial. Thus, the role of this new modality in thetreatment armamentarium remains uncertain. Encouragingfurther research is a critical need for this noninvasiveprocedure, which does not require anesthesia and hasrarely been associated with adverse effects beyond mildheadache.

The growth in TMS research has increased dramaticallyin the last decade. Most of the studies have included smallsample sizes, patients on antidepressant medications, andvarying treatment parameters and machinery. There havebeen a number of obstacles to TMS research including theinfinite number of variables (pulse duration, intertrainintervals, stimulation frequency, days treated, site oftreatment), difficulties in establishing a true placebo con-dition, and restrictions on the use of TMS in only the mostseverely treatment resistant patients. Perhaps the mostdifficult obstacle has been the lack of funding. Companiesmanufacturing the TMS machinery are small and havelimited resources for the type of multicenter, placebo-controlled studies needed to definitely test TMS.

Despite these difficulties, there is preliminary evidenceof an antidepressant effect when TMS is applied to thearea of the prefrontal cortex and additional evidence forpossible efficacy in mania, anxiety disorders, and schizo-


phrenia. The promise of an alternative treatment forpatients who have failed medication that has fewer sideeffects, is easier to administer and is not associated withthe social stigma of ECT is encouraging. Research onTMS has not progressed to the point at which a definitivelarge-scale trial is warranted. Research should be focusedon small grant proposals to determine which technical,clinical, and biological factors predict who will respond toTMS.

There is initial evidence supporting a number of factorsthat may improve treatment response. Clinical factors thatpredict improved response include younger age and lackof psychosis. Technical factors influencing outcome in-clude increased number of total stimulations and increasedintensity of stimulations relative to the motor threshold. Abiological factor predicting outcome includes patterns ofglucose uptake on PET scanning. Once these variableshave been further clarified, then support for a large-scaleclinical trial, using the most efficient technical parametersin a patient population that is designed to benefit from theprocedure, will be clearly warranted.

VAGUS NERVE STIMULATION. Vagus nerve stimula-tion is an effective treatment of refractory seizure disor-ders that has shown some promise as an antidepressantintervention. It was approved by the FDA in 1997 forselected cases of epilepsy. VNS was first reported to beassociated with improved mood in neurology patients andmore recently has shown partial efficacy in refractorymood disorders. Although, recently the results of a largemulticenter trial has been disappointing. The afferentconnections of the left vagus nerve with locus ceruleus,dorsal raphe, and limbic structures are implicated in theputative antidepressant effect of this intervention.

A small, pacemaker-like device is implanted beneaththe clavicle, with an attached lead wrapped around the leftvagus nerve in the neck. Safety experience with seizuredisorder patients has been satisfactory; stimulation of theleft vagus nerve has no cardiac effects. In addition, VNSholds promise for the treatment of resistant patients, withthe added benefit of improvement that persists over timeand may actually show increased benefit during mainte-nance treatment.

A recent interesting finding on the development ofdepression in an individual with Parkinson’s disease afterimplantation of a deep brain stimulator in the area of thesubthalamic nucleus (Bejjani et al 1999) raises anotherpossible use of somatic treatments in understanding andtreating depression. This subject had no history of depres-sion, yet stimulation through specific electrodes precipi-tated depressive symptoms. This suggests that depressionmay be hard wired in the brain (Yudofsky 1999). There-fore, in the future, it may be possible to use high-frequency stimulation to modulate circuits involved in

depression; however, deep brain stimulation (DBS) is aninvasive procedure, and its use in treating psychiatricdisorders is highly speculative. Research in this areashould focus on psychiatric symptoms developing inpatients with DBS implanted to treat PD and otherneurologic disorders.

OTHER MODALITIES. Early observations that manydepressed patients with repeated fall and winter depres-sions benefited from light therapy introduced the idea thatthe melatonin system is involved in affect modulation.Considerable work has been done in studying diurnalrhythms of melatonin in winter depressions and in phasedisorders. Now melatonin and its agonists are beingapplied not only in sleep-phase disorders but also inseasonal depression and in depression of the elderly.Considerable research is ongoing in this area, covering thebasic as well as applied effects of light.

Several small studies have reported antidepressant ef-fects of acupuncture in unipolar major depression. Indeed,a controlled pilot study reported a full remission in 64% ofdepressed patients treated over 8 weeks with acupuncture(Allen et al 1997). These data formed the critical back-ground for a study of medication-resistant bipolar subjectsusing acupuncture (Trisha Suppes, personal communica-tion) now in progress.

The Contribution of Human Brain ImagingTechniques to Disease Mechanism Study,Drug Target Identification, and DrugDevelopment

Overview

Biomarkers are commonly used in fields of medicine otherthan psychiatry to aid in diagnosis, to determine treatment,and to monitor the efficacy of therapy. A commonexample of a biomarker is the cholesterol test, which isused as an indirect or sometimes called “surrogate” mea-sure of increased risk for future cardiovascular disease.Thus, measurement of serum cholesterol is recommendedin some subjects (including middle-aged individuals andthose at increased genetic risk) who are completelyasymptomatic. Elevated cholesterol levels, even in theabsence of signs or symptoms of disease, are justificationfor preventive treatment. Furthermore, cholesterol levelsare repeated during treatment to ensure an adequate andsustained response. The field of psychiatry lacks any suchcomparable biomarker to measure mood disorders. Inanalogy to the cholesterol test, an ideal biomarker inpsychiatry would detect abnormalities before the manifes-tations of a depressive or manic episode (i.e., before thephysician or even the subject could predict the onset ofsymptoms). It also should provide critical information to


direct specifically targeted therapies, including psychoso-cial as well as pharmacotherapies, and it should be used tomonitor the efficacy and sustained effect of those inter-ventions. Such a biomarker would not supplant currentpsychiatric evaluation and direct patient contact. Instead,similar to the cholesterol test, a psychiatric biomarkerwould be used in conjunction with direct patient contact inmultiple roles of education, prevention, and therapy.

Current Status

Biomarkers for mood disorders can be roughly dividedinto four groups, with examples and a representativereview article provided for each.

PERIPHERAL. Examples: urinary and plasma levels ofcatecholamines, plasma cortisol level, densities of seroto-nin transporters on platelets (Review: Holsboer 2000).

CNS NEUROCHEMICAL. Examples: PET and SPECTmeasurements of receptors or magnetic resonance spec-troscopy (MRS) measurements of GABA and glutamate.(Review: Fujita et al 2000).

CNS FUNCTIONAL. Examples: measures of local neu-ronal activity determined from EEG, ERP, magnetoen-cephalogram, and functional magnetic resonance imaging.(Review: Drevets 2000).

GENETIC. Examples: DNA markers of risk factors orindividual genes that cause mood disorders. (Review:Sanders and Detera-Wadleigh 1999).

The succinct summary of the current status of biomar-kers in the field of mood disorders is that no stronglypredictive measure is currently available; however, recentdevelopments in neuroimaging (especially neurochemicalimaging with PET and functional imaging with functionalmagnetic resonance imaging [fMRI]) offer great promiseboth to gain better understanding of the underlying patho-physiology of mood disorders and to develop usefulbiomarkers to evaluate drug response (Innis et al 2001).

Biochemical Markers

The majority of work to date on biomarkers has examinedperipheral markers, including catecholamine levels inplasma and urine, platelet markers such as the serotonintransporter, and plasma measures of HPA axis activity(e.g., cortisol and adrenocorticotropic hormone). The stud-ies on peripheral biomarkers in mood disorders wereinitially quite popular and well received by the researchcommunity; however, a strong counterreaction to thecatecholamine and platelet measures subsequently devel-oped, in large part because they did not clearly reflect CNS

activity or function. In contrast, studies of the HPA axis(including plasma cortisol) have continuously flourished,showing the role of extra-hypothalamic areas in regulatingand being affected by cortisol. Neurochemical imaging inthe brain with ligands (i.e., PET and SPECT) and withspectroscopy (MRS) will almost certainly overcome lim-itations of the peripheral chemical biomarkers by examin-ing chemical activity directly in the brain. For example,promising preliminary studies suggest that depression maybe associated with altered levels of several serotoninergicmarkers, including reduced density of the serotonin trans-porter, 5-HT1A receptors, and 5-HT2A receptors. Most ofthe ligand neuroimaging studies in mood disorders havebeen limited to the serotonin system and have usedrelatively small sample sizes. Two major ways to expandthese techniques in the future would be to examine a muchwider number of targets and to use much larger samplesizes to accurately capture the diversity of subsyndromesand components of illness reflected in patients with mooddisorders.

Functional Markers

New methods from cognitive and affective neuroscienceprovide an unprecedented opportunity to use noninvasivetechniques to examine the function of brain circuitryunderlying disturbances of cognitive and affective pro-cessing in affective disorders. These methods take thegeneral approach of defining behavioral constructs anddeveloping valid behavioral probes that are incorporatedinto neuroscientific studies to reveal activity in the rele-vant brain networks. Reliable methods now exist toexamine the brain circuitry associated with attentional andexecutive functions and to define the abnormal cerebralactivation patterns in unipolar depression and bipolardisorder. Conceivably, a “normalization” of these abnor-mal cerebral activation patterns could define drug activity.Similarly, reliable paradigms have been developed toexamine activity in subcortical and limbic circuits associ-ated with processing reward, threat, and other kinds ofemotionally relevant information. Deficits in these func-tional domains are widely reported to be present inindividuals with affective disorders.

Despite the dramatic increase in research into the neuralbasis of normal cognitive and emotional processes, notenough has been done to apply these methods to theinvestigation of affective disorders. However, the potentialfor these tools to provide insights into pathophysiologyand mechanisms of action of treatment, as well as to serveas predictors of outcome, is considerable, and the nonin-vasiveness and potential wide availability of methods suchas fMRI and high-density ERP make these tools especiallyattractive. Facilitating the application of cognitive and


affective neuroscience based imaging methods for use aspotential biomarkers could lead to significant progress inthe diagnosis and treatment of affective disorders.

Target Goals and New Initiatives

NEW LIGAND DEVELOPMENT. Tremendous opportuni-ties exist for the application of PET and SPECT imagingin studies of the pathophysiology and treatment of CNSdisorders, but relatively few radioligands are currentlyavailable for functional imaging of target molecules im-plicated within normal brain function and in CNS disor-ders. Thus, we recommend that the NIMH work within itsintramural and extramural programs to develop new li-gands but then facilitate their dissemination for use by allresearchers in the field. These ligands are likely to beuseful for several purposes: 1) to better understand theabnormal chemical processes that underlie mood disor-ders; 2) to be used in conjunction with the development ofnew therapeutic agents to determine where they work inthe brain and to guide initial dosing of such agents; and 3)to be used as central biomarkers of the illness, potentiallyto predict onset of symptoms, to monitor the progressionof the disease, and to assess the efficacy of therapy.

Effective partnering with industry for ligand develop-ment will be immensely valuable. The pharmaceuticalindustry has valuable chemical expertise and an array ofwell-characterized molecules that are the products of alarge investment in research and development of medica-tions for CNS disorders. These molecules (marketed andnonmarketed) could be adapted as PET or SPECT ligandsto visualize brain targets (e.g., receptors, intracellularmessengers, disease-related proteins) of mutually benefi-cial interest to pharmaceutical companies, academic inves-tigators, and the NIH.

The NIMH has already begun to assess the need for, andits potential role in, the development of new ligands. A1-day panel on this topic was convened in January 2001and included representatives from academic sites, theFDA, pharmaceutical companies, and representatives fromseveral NIH branches (http://www.nimh.nih.gov/research/confsummaries.cfm). This panel recommended severalexcellent ways in which NIMH could foster ligand devel-opment, including the following: 1) partnering with indus-try, including possible means to address intellectual prop-erty rights issues so that they do not impede the process(Innis et al 2001); 2) issuance of an radio frequencyablation (RFA) specifically for the development of radio-ligands; 3) establishment of an annual meeting of aneuroimaging consortium (industry, academia, NIH, andthe FDA) to continue the exploration of means to stimulateligand development.

Certainly, ligand imaging need not completely supplantall other peripheral biomarkers. Rather, useful peripheral

measures such as cortisol should be obtained in conjunc-tion with the imaging studies. This combined analysis willbetter help to understand the significance of each andpotentially help to dissect subsyndromes or aspects of theillness such as cognitive dysfunction and mood dysregu-lation.

FUNCTIONAL BIOMARKER DEVELOPMENT. The non-invasiveness of fMRI, its wide availability, and its abilityto engage specific brain circuitry associated with discrete,functionally relevant aspects of affective disorders make ita particularly promising tool for biomarker development.For some functional measures (e.g., attention and execu-tive functions), paradigms already exist for which validityand reliability have been established. In other areas,particularly the affective domain, further development andvalidation are needed. A consensus conference sponsoredby the NIMH and focused on the development of behav-ioral measures of affective processing and their integrationinto functional imaging studies could facilitate this pro-cess. The rapid validation of these methods would also beenhanced if incentives were offered to “add on” thesemeasures to ongoing multicenter treatment studies. AnRFA could facilitate this process.

Pharmacogenetics and Its Contributions toDrug Discovery and Drug Utilization

Current Status of the Field

Pharmacogenetics seeks to find DNA markers for medi-cation treatment outcome (Roses 2000). The current statusof pharmacogenetics in mood disorders is relatively lim-ited. There are three published reports in the United Statesand Europe indicating that the allele for the short form ofthe serotonin transporter promotor is associated with poorresponse to SSRIs (Pollock et al 2000; Smeraldi et al1998; Zanardi et al 2000). Homozygotes for this allele arefound at a frequency of approximately 25% in Caucasianpopulations. There is also one report from Korea that thelong form of the transporter promoter, which is lesscommon in that population, is associated with poorerresponses to SSRIs (Kim et al 2000). In another study(presented by Murphy et al at ACNP 2000 and NCDEU2001), the APOE ε4 allele was associated with rapidresponse to mirtazapine but not paroxetine in elderlypatients. All of these studies have used conventionalpolymerase chain reaction (PCR)–based genotyping forsingle polymorphisms. In the Murphy et al mirtazapine-paroxetine study, a commercially available microarraywas used to query for 16 CYP2D6 alleles that affectantidepressant metabolism. The results showed very mod-est effects of intermediate and poor metabolic alleles onability to tolerate mirtazapine and paroxetine during long


term treatment. In another study, Murphy et al (2001) usedCYP2D6 oligonucleotide microarrays to predict nortripty-line drug levels at steady state in patients with geriatricdepression. To our knowledge, these are the only pre-sented or published data on pharmacogenetics in depres-sion. In bipolar disorder, the short form of the serotonintransporter protein promotor has been associated withmania induced by proserotonergic medications (Mundo etal 2001). There are no studies relevant to mood disordersin which large numbers of single nucleotide polymor-phisms (SNPs) are queried to identify chromosomal re-gions potentially harboring new antidepressant pharmaco-genes.

Goals

IDENTIFICATION OF POLYMORPHISMS ASSOCIATED

WITH TREATMENT RESPONSE. One goal for pharmaco-genetics is to have a set of polymorphisms that predictrelative response and tolerability to specific classes ofantidepressants or to specific members of classes. Thesuite of genetic variants could also help predict whichpatients need longer term maintenance treatment. Identi-fication of polymorphisms predicting medication intoler-ance could help avoid unnecessary exposure to variousdrugs. Pharmacogenetics could also stimulate the devel-opment of new agents with even more specific or targetedmodes of action. Many polymorphisms could be identifiedin public databases using candidate loci chosen based oncurrent understanding of antidepressant mechanisms ofaction.

GENOTYPING MECHANISMS. A secondary goal wouldbe identification of a high-throughput platform for deter-mining genotypes economically in large numbers of pa-tients (Jain 2000). This could lead to screening of a largenumber of SNPs throughout the genome to identify phar-macogenetic markers not previously associated withknown antidepressant mechanisms.

NIH ROLE. There is a potential downside risk for somepharmaceutical companies in that they could potentiallylose market share if markers are identified that predictnonresponse or intolerance to a product. Therefore, it is aunique opportunity and likely essential for the NIH to takea lead role in this area. Partnerships with industry will bepredictably easier to effect when possible predictor genesfor specific drugs are already identified.

There are a number of timely questions that should beconsidered:

● Should all treatment studies funded by NIMH rou-tinely collect blood for DNA?

● Should pharmacogenetics be routinely added only tolarge-scale studies (e.g., to Star-D, CATIE)?

● What types of funding mechanisms should be used tosupport such research?

● Should DNA extraction or genotype analysis be donecentrally? Distributed across sites?

● How should the possibly differing views regardingissues of ethics or informed consent be resolved?

● What platform(s) should be supported for high-throughput genotyping efforts?

● How should data involving hundreds or thousands ofpolymorphisms in thousands of patients be analyzed?

● How can the impact of ethnicity on pharmacogeneticoutcome be addressed in current clinical trial de-signs? Are new designs needed?

Recommendations for Facilitating Research inPharmacogenetics

EDUCATION. First, there is a need to educate the fieldon pharmacogenetic studies, including optimal study de-signs, identification of candidate genes relevant to psychi-atry, statistical strategies to analyze data at multiple loci;the field should also be informed about which studies arecurrently funded. Although the technology exists to deter-mine thousands of SNPs rapidly in large numbers ofpatients, there are no established statistical techniques foranalysis of massive data sets in which issues of multiplestatistical testing become of paramount importance. Aneffort should be led by the NIMH to advance pharmaco-genetic methodology and analysis and should include aseries of workshops as well as a possible Web site.Specific guidelines for how to design and conduct phar-macogenetic studies should also be developed by theNIMH and included on the Web site.

The NIMH can play a role in deciding on those genesthat should first be explored in pharmacogenetic studies.This could initially include several hundred candidategenes, and an interdisciplinary conference format could beorganized to develop the candidates. Current lists ofcandidate loci and polymorphisms (Cravchik and Gold-man 2000) need to be regularly updated due to theconstant influx of new information on genetic variabilityin public databases. Consideration should be given tointeracting with groups—public and private, contractingwhen necessary—who may have important data on DNAsequence variants in the genes of interest and allelefrequencies in various ethnic populations. This informa-tion should be made available to interested scientistsworking in the field.

DATA-MINING OF EXISTING DATABASES. The NIMHshould support efforts to mine existing DNA sequencedatabases for polymorphisms already identified in genesof interest (Pfost et al 2000). Databases such as thoseestablished by the SNP Consortium, HGBASE, the


NIGMS Pharmacogenetics Research Network, and NCBIdbSNP contain thousands of SNPs that could be immedi-ately used for pharmacogenetics studies in mood disor-ders. The NIMH should support the development ofpoint-and-click software tools designed to provide easyaccess to SNP sequences at individual loci, as well asavailable information on PCR primers, amplification pro-tocols, and allele frequencies. Collaborations with existingbioinformatics companies in the process developing data-base mining tools should be supported. Efficient mining ofexisting SNP databases could result in tremendous savingsof time and money otherwise spent in redundant DNAsequencing, assay development, and population geneticstudies.

TECHNOLOGY DEVELOPMENT OF PHARMACOGE-

NETICS. Haplotype analysis is likely to become importantin pharmacogenetic prediction (Judson et al 2000). BothDNA database mining and de novo sequencing effortsshould be directed toward identifying sets of allelesforming common haplotypes (alleles inherited as a unit) atimportant candidate loci. This may substantially increasepharmacogenetic predictive power because multiple SNPsthat occur together in most individuals may have anadditive effect on phenotype (Drysdale et al 2000).

The NIMH should support the development of technol-ogy to speed genotyping at specific loci relevant topsychiatry, including microarray technology and otherhigh-throughput platforms (Jain 2000). This could be thenmade available to investigators, possibly through NIMHcenters designed to provide this core service, or industrysubcontractors. At present, there are variety of competingplatforms for high-throughput genotyping, and it is unclearwhich, if any, will emerge as the dominant technology. Itis likely technologies will be identified that are best suitedfor a particular pharmacogenetic application. For example,microarray platforms may be best suited for scoring largenumbers of SNPs on a relatively small number of patients(Fan et al 2000), whereas other techniques with lower perpatient costs may be suitable for scoring a few SNPs onvery large numbers of patients. The NIMH should supportstudies to define the application of these emerging tech-nologies.

Large-scale clinical trials supported by the NIMHshould be encouraged to develop and include pharmaco-genetic protocols. Specific polymorphisms should betested across studies. Efforts should be made to encouragecollaboration and reduce duplication. Current NIMH trialssuch as CATIE and Star-D have a naturalistic design thatis well-suited to testing treatment algorithms in real-worldclinical settings; however, these designs involving largenumbers of clinicians, study sites, variability in actualtreatment regimen among patients, and population strati-fication may lack the necessary homogeneity necessary to

detect subtle pharmacogenetic effects. During the planningstages future algorithm-based clinical trials should con-sider study design features specific to pharmacogenetics.

Strategies are needed to incorporate more ethnic minor-ities in pharmacogenetic trials. Allele frequencies varyacross populations, and identical polymorphisms mayhave different effects depending on genetic background;however, haphazard inclusion of minorities in samplepopulations is likely to confound results due to populationstratification and yield insufficient numbers of minoritiesfor meaningful statistical analysis. In the planning stages,future pharmacogenetics studies should specifically targetethnic recruitment with statistical power considerationstaken into account. The NIMH should provide specificfunding for recruitment of minorities into pharmacoge-netic trials. This should include support for recruitmentspecialists who are skilled in outreach to minority com-munities where traditional attitudes toward blood samples,heritability, and mental illness may be at variance withparticipation in clinical pharmacogenetic studies.

Ethical Guidelines Leadership

The NIMH and other institutes should support efforts todevelop uniform standards for informed consent andguidelines for utilization of DNA samples in multiplepharmacogenetic studies. At present, there are no stan-dards for informed consent for pharmacogenetic studies,and the nature of consent in pharmacogenetics may differfrom that for studies of disease-risk genes (Robertson2001). Standards are also lacking as to how to consent forfuture studies with stored DNA samples. Standards shouldbe devised that facilitate genetic research in this area whilerespecting individual privacy. Subcontracts with estab-lished clinical research organizations (CRO) to developuniform informed consent forms and to manage storedDNA data may be a way of rapidly implementing newstandards; however, at present most CRO lack experiencein pharmacogenetic studies. The NIMH should supportinteraction of pharmacogenetic researchers with the CROindustry to facilitate this process.

Conclusion

We have attempted to comprehensively review the state ofcurrent treatments, and the development of novel treat-ments, for mood disorders. We have made myriad recom-mendations, ranging from strategies to increase the dis-covery of novel molecules to those that will enhance thelikelihood of detecting a therapeutic signal in large-scaleclinical trials. The leadership of the NIMH must decidewhich of these many recommendations can be imple-mented.


This manuscript is one of ten prepared by workgroups under the auspicesof the National Institute of Mental Health (NIMH) strategic planninginitiative for mood disorders research. Each of the workgroups was giventhe specific charge to 1) review the state of their assigned area; 2) identifygaps and state a vision of where the field should be going and why; and3) make general recommendations for NIMH to consider regardingresearch initiatives that would advance and improve the knowledge andtreatment of mood disorders. This document reflects the opinions of theauthors and not those of NIMH, but was used in an advisory capacitywhile the actual strategic plan was developed by NIMH staff. Overallguidance was provided by the National Advisory Mental Health Council.

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