A Publication of the Stanley Foundation Bipolar Network

Bipo

lar

Net

wor

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ews Clinical Trials Update

The Year in Review

Antidepressant TrialSeventy-three patients with bipolar disor-der have been randomized to bupropion(Wellbutrin), sertraline (Zoloft), orvenlafaxine (Effexor) in the Network’s on-going controlled trial of three different an-tidepressants for the treatment of break-through depression. Forty-three (59%) ofthese 73 patients have acutely responded toone of these drugs and elected to enter a 1-year phase of continued prophylaxis. Thirty-three (77%) of these 43 patients respondedto the first drug in the 10-week trial, 8(18%) responded in the second crossoverphase, and 2 responded in the third phase.The remaining 30 (41%) of the 73 patientsfinished or are still in the 1 year prophy-laxis trial and we hope to ascertain whichof the 3 drugs is the most effective in pre-venting depression without inducing ma-nia.

New Drug EvaluationsOpen clinical trials have been performedwith 4 new drugs to gain information abouttheir potential range of efficacy in patientswith bipolar disorder. These new drugs are:(1) the atypical neuroleptic olanzapine(Zyprexa), and the new anticonvulsants (2)lamotrigine (Lamictal), (3) gabapentin(Neurontin), and (4) topiramate(Topamax). Olanzapine has a positive side-effects profile and a recent double-blind ran-domized comparison with placebo indicatesit has acute efficacy in mania. As reviewedin BNN Vol. 4, Iss. 2, considerable evidencesupports the use of the new (atypical)neuroleptics such as clozapine (Clozaril),risperidone (Risperdal), olanzapine,quetiapine (Seroquel), and ziprasidone(Zeldox, soon to be approved) in the acuteand long-term treatment of psychosis in pa-tients with schizophrenia and schizoaffectiveillness. There are many benefits to usingthese atypical neuroleptics instead of the

(Continued on page 2)

Volume 4, Issue 4

December 1998

typical neuroleptics whenever possible fortreating bipolar illness. The older (or typi-cal) neuroleptics are liable to induce acuteextrapyramidal side effects as well as long-term difficulties, such as tardive dyskinesiain 10-40% of bipolar patients treated withthese neuroleptics. Intermittent treatmentdoes not appear to lessen the risk of tardivedyskinesia, and may even enhance it.

(1) In our Network trial, 8 (57%) of 14patients responded to olanzapine, at a meandosage of 15 mg/day for an average trial du-ration of 117 days (see p. 6). The most prob-lematic side effects of olanzapine appear tobe weight gain and sedation (despite night-time dosing). Use of this and the relatedatypical agents in bipolar illness (noted above)and in affective illness with psychotic depres-sion would appear warranted based on thecurrent preliminary data.

(2) The Network open trial of lamotrigineindicated moderate or marked response onthe Clinical Global Impressions scale in 11(65%) of 17 patients at a mean dosage of187 mg/day for an average trial duration of159 days (Suppes et al., 1999; in press). Theseresults are highly convergent with data from2 unpublished, double-blind, controlled

In This Issue:

Clinical Trials Update:The Year in Review..................1

Meeting Highlight:Neurobiology of Psychiatry.....3

Life Chart Highlight:Childhood Bipolar Disorder.....4

Around the Network:Affiliated Site in Germany.......7

BNN Vol. 4, Iss. 4

Page 2

Bipolar Network News

Editors-in-Chief:Robert M. Post, MDGabriele S. Leverich, MSW

Production & Design:Chris Gavin

The BNN is published 4 times a yearby the Stanley Foundation BipolarNetwork, an international group ofinvestigators who, together with pa-tients with bipolar disorder whoparticipate in research studies, in-vestigate the long-term course andtreatment of bipolar disorder. Thegoal of the Network is to improvethe understanding of bipolar illnessand develop better strategies fortreatment.

We welcome any comments or sug-gestions you may have. Forcommunication or to be placed onthe mailing list, please contact usat:

Bipolar Network Newsc/o Stanley Foundation Bipolar Net-work5430 Grosvenor Lane, Suite 200Bethesda, MD 20814

Telephone: (800) 518-SFBN (7326)Fax: (301) 571-0768Website: www.bipolarnetwork.orgE-mail: stanley@sparky.nimh.

nih.gov

J Clin Psychiatry 60: 79–88), treatmentwith lamotrigine (50 mg/day or 200mg/day) was more effective than pla-cebo in depressed patients with bipolardisorder. Lamotrigine was well-toleratedand effective in approximately 50% ofpatients in that study as well.

Based on these data from controlledtrials, in conjunction with our Networkdata from an open trial, and the opentrial data from a variety of other inves-tigators including Dr. Calabrese and as-sociates, it is likely that lamotrigine willplay an important role in treatment ofdepression in bipolar disorder. An im-portant precaution in using this drug isto begin with a low dose (12.5 to 25mg/day) and increase the dose veryslowly to lower the incidence of a po-tentially serious rash (see BNN Vol. 4,Iss. 1). A benign rash occurs in approxi-mately 10% of individuals, and a se-vere rash in approximately 1 in 500.

(3) In contrast to the low responserate for gabapentin in our double-blind,monotherapy study in treatment refrac-tory inpatients at the NIMH (seeabove), adjunctive gabapentin therapywas effective in 20 (72%) of 28 outpa-tients in the Bipolar Network. Typicaldosages ranged from 1200 to 1800 mg/day (Altshuler et al., 1999; in press).These data parallel a number of openadd-on studies and suggest thatgabapentin may have an adjunctive rolein the treatment of patients with bipo-lar disorder. Gabapentin’s target symp-toms may include helping sleep, decreas-ing anxiety, improving mood, and treat-ing paroxysmal and chronic pain syn-dromes. A double-blind trial ofgabapentin in social phobia was posi-tive, but another in acute mania wasnot. Given the benign side-effects pro-file of this agent and a lack of interac-tions with other psychotropic medica-tions, gabapentin may come to play arole in the pharmacotherapeutics of pa-tients with bipolar disorder despitenegative results in double-blind

monotherapy studies. In the NIMHstudy, younger patients with shorter ill-ness durations were among those whoresponded best to the drug. Studies inearly onset patients would thus appearindicated.

(4) Forty-eight patients have beenstudied on topiramate, the most effec-tive of the newly approved add-onanticonvulsants. Topiramate has uniquemechanisms of action that may be im-portant to its spectrum of therapeuticand side effects. It is a direct blocker ofglutamate AMPA/kainate receptors, andthus has the ability to decreaseglutamatergic tone selectively throughthis receptor system, while at the sametime enhancing GABAA mechanismsthrough an indirect (nonreceptor me-diated) mechanism. In addition, itblocks influx of sodium through thesodium channel and thus may decreaseglutamate release. Its actions as a car-bonic anhydrase inhibitor may be asso-ciated with the side effects of renal stonesin 1% of individuals and paresthesiasin a larger group.

Preliminary evidence suggeststopiramate may have positive effects onmanic mood in bipolar patients. A sig-nificant degree of dose-related weightloss was also evident, which appearedto occur both as a function of decreasedappetite or craving, and perhaps alteredmetabolism as well; the weight loss(which averaged about 10 pounds) wassustained during treatment with thisagent. The side effect of weight loss con-trasts with many other of the commonlyused psychotropic agents such aslithium, valproate, many antidepres-sants, and atypical neuroleptics. Muchfurther work is needed to better delin-eate the potential role of this agent withits helpful side effect profile in bipolarillness.

Thus, each of the drugs (notedabove) approved for other indications(one atypical neuroleptic for schizophre-

Clinical Trials Update(Continued from page 1)

(Continued on page 11)

clinical trials. The first trial, a random-ized, crossover study at the National In-stitute of Mental Health (Frye et al.,1998) indicated a 52% response rate to6 weeks of lamotrigine monotherapycompared with 27% response to 6 weeksof gabapentin monotherapy and 23%response to 6 weeks of placebo.Lamotrigine was significantly more ef-fective than either gabapentin or pla-cebo (using Cochran’s Q statistic). Thedrug was well-tolerated, although oneindividual experienced a severe rash thatprogressed to exfoliative dermatitis, re-quiring hospitalization. In a secondmulticenter trial (Calabrese et al., 1999;

BNN Vol. 4, Iss. 4

Page 3

Meeting Highlights

�The Neurobiology of Psychiatry�

Association for Research in Nervous and Mental DiseaseDecember 4-5, 1998, New York City, New York

The Association for Research inNervous and Mental Disease(ARNMD), in conjunction with

the New York Academy of Medicine,held its 78th Annual Conference fromDecember 4th-5th, 1998, on the topic,“The Neurobiology of Psychiatry.” Lead-ing researchers from around the UnitedStates and Canada presented excitingand groundbreaking work on this im-portant topic. Among the presenterswere the following:

Dr. Joseph LeDoux, PhD, “Emo-tion, Memory, and the Brain.” Dr.LeDoux began the meeting with an ex-citing presentation on dissecting the roleof the amygdala and related circuits inconditioned fear, and how this informa-tion may lead to new targets of thera-peutics in psychiatry.

Dr. Bruce McEwen, PhD, “Stress,Sex, and Hippocampus: From Seren-dipity to Velerance.” Dr. McEwen re-viewed his work on the effects of sexhormones on morphology and functionof the hippocampus, indicating thatstructural changes may occur in this cru-cial structure (for cognition) in a varietyof stress-related animal models, and inhumans with Cushing’s disease, recur-rent depression, post-traumatic stress dis-order, schizophrenia, normal aging, anddementia.

Dr. Steven Hyman, MD, (Director,National Institute of Mental Health)“Molecular Neurobiology and Genet-ics.” Dr. Hyman presented his view ofthe potential for molecular neurobiol-ogy and genetics of psychiatric disordersin the next century, outlining the tech-nical revolution that has occurred in our

ability to identify alterations in gene ex-pression with gene chips and rapidly re-late these to specific alterations in thebrain. Dr. Hyman indicated that a ma-jor focus of the NIMH will be on thesekinds of new molecular approaches topsychiatry.

Dr. Solomon Snyder, MD, “NovelNeural Messengers.” Dr. Snyder re-viewed the novel class of neuronal mes-sengers that turn out to be gases—nitricoxide and most surprisingly, carbonmonoxide. Neurotoxicity of glutamateand other insults can be largely blockedby blocking the enzyme that synthesizesnitric oxide—nitric oxide synthase(NOS). Moreover, NOS inhibitors blockstroke damage in animals even when thedrugs are given after tying off the middlecerebral artery. These drugs are thus im-portant targets for clinical therapeuticsin a variety of degenerative disorders andmore subtle alterations involving toxic-ity, i.e., perhaps in the psychiatric ill-nesses as well.

Dr. Huda Akil, PhD, “Molecular,Anatomical and Functional Studies ofStress: Implications for UnderstandingMood Disorders.” Dr. Akil presentedelegant data indicating that the mean-ing or significance of the stressor to ananimal can be associated with very dif-ferent changes in its neurobiology. Thesestudies are revealing much informationabout the neuroendocrine and neuro-chemical dysregulation of depression andpost-traumatic stress disorder at the levelof environmentally-induced changes ingene expression.

Dr. Eric Nestler, MD, PhD, “Mo-lecular Basis of Addictive States.” Dr.Nestler spoke on the molecular basis of

addictive states, indicating a new under-standing of how many of the drugs ofabuse also induce long-lasting alterationsin neurochemistry at the level of geneexpression and how some of this newunderstanding may be translated intotherapeutic approaches in the future.

Dr. Philip Seeman, MD, PhD,“Dopamine Receptors, AntipsychoticDrugs and Psychosis.” Dr. Seeman re-viewed the relationship of dopamine re-ceptor blockade to the antipsychotic ef-fects of the major neuroleptic drugs.

Dr. Patricia Goldman-Rakic, PhD,“Salmon Lecture: The Dopmine D1

Receptor in Cortical Structure andCognitive Function.” Dr. Goldman-Rakic’s lecture indicated an importantrole for dopamine D

1 receptors in pre-

frontal cortical structures and cognitivefunction. Her integrative work is a para-digm for examining the biochemistryand physiology of a brain area that hasbeen closely linked to pathology in bothaffective disorders and schizophrenia.

Dr. Sue Swedo, MD, “The NeuralBasis of Psychiatric Disorders: OCDand Autoimmunity.” Dr. Swedo pre-sented her new data on how childhoodobsessive-compulsive disorder (OCD)can be associated with an infectious au-toimmune illness, in the same waySydenham’s chorea or rheumatic fevercan occur with postgroup A Streptococ-cal (strep) infections. She terms these ill-nesses “Pediatric Autoimmune Neurop-sychiatric Disorders Associated withStreptococcal Infections,” or PANDAS,in which patients often present with ob-sessive-compulsive disorder, tic disorders,prepubertal onset and episodic course,

(Continued on page 10)

78th Annual ConferenceDecember 4-5, 1998

A RNMD

BNN Vol. 4, Iss. 4

Page 4

Life Chart Highlight

Lithium and valproate combination therapyin a 9 year-old with bipolar disorder

Nora K. McNamara, MD, Robert L. Findling, MD,Tricia E. Robben, Kwang-Hie Park, MD, Joseph R. Calabrese, MD

It is an extraordinary opportunity tobe involved with the Stanley EarlyIntervention Initiative. As part of

our work at Case Western Reserve Uni-versity/University Hospitals of Cleve-land, we have begun enrolling young-sters with bipolar disorder in a 2-yearstudy that will compare the efficacy andsafety of lithium carbonate to divalproexdodium (Depakote, or valproate for restof article). This trial is one of only a fewrandomized clinical trials in pediatric bi-polar disorder (see BNN Vol. 4, Iss. 2,for an update on the comparison oflithium (Eskalith, Lithobid)carbamazepine (Tegretol), and val-proate in early onset mania by Dr.Kowatch of the Dallas Center). Theproject is also unique in that this studyis more than just a few weeks long. Inthe first phase of the study, youngsters(ages 5 to 17) with bipolar disorder (typeI or II) are stabilized on lithium andvalproate combination therapy. Aftermood stabilization, they are transitionedinto the second phase of the study, dur-ing which only 1 of the mood stabilizers(lithium or valproate) is continued.

Having begun this study, we haveseen several consistent patterns in ourpatients with pediatric bipolar illness.First, we have observed that most of ourpatients have been extremely symptom-atic for years with their mood disorderadversely affecting their development,peer relations, functioning at school, andfunctioning within their family. In ad-dition, families often report that the chil-dren have received treatment from nu-merous other professionals prior to com-ing to the Stanley Center. Generally, par-ents also note that their children with

bipolar disorder have previously receivedmany inaccurate diagnoses and ineffec-tive treatments. By the time we have seenthe child/adolescent, families often ex-press concern that “nothing would everhelp.”

In this report, we tell the story of onepatient and his family to illustrate howaccurate diagnosis and appropriate treat-ment can change the course of a child’slife. This child’s name and identifyingcharacteristics have been changed to pro-tect his right to confidentiality.

Case Report: Mood HistoryRichie is a 9 year-old boy who was evalu-ated in September 1998 at the CaseWestern Reserve Stanley Center. Priorto our seeing him, Richie’s mother esti-mated that her son had been seen by atleast 10 specialists and treated with nu-merous psychotropic medications in avariety of combinations.

Richie’s mother provided additionalhistory. Richie was born at term. He wasvery colicky until he was a toddler, atwhich time he was noted to be moodyand prone to extensive and frequent tem-per tantrums. He reached all of his de-velopmental milestones early, and despitehis failure to outgrow his moodiness andhis tantrums, was considered to be verybright and verbal. Richie had been ex-tremely hyperactive since toddlerhood,and was diagnosed in kindergarten ashaving attention-deficit hyperactivitydisorder (ADHD) (see Figure 1).

While Richie was in kindergarten, hewas referred for art therapy. His symp-toms did not improve, and he began toexhibit periods of very aggressive behav-ior that would last for days. Periods of

extreme irritability, low self-esteem, andsocial isolation soon became pervasive(Figure 1). He was then referred to a psy-chiatrist who prescribed methylpheni-date (Ritalin) which, in Richie’s words,did “nothing.” He was then prescribeddextroamphetamine (Dexedrine) withthe same result. During this time, he en-gaged in some sexual play with older fe-male children, and began smearing fe-ces on the bedroom wall on a regularbasis.

Initial Medication TrialsRichie’s mother then took him to a sec-ond psychiatrist. Over the next twoyears, Richie would have trials ofsertraline (Zoloft), carbamazepine(Tegretol), and one brief trial of valproicacid (valproate). Despite these interven-tions, his symptoms continued to getworse. He began to have recurrentthoughts of hurting himself, and madefrequent suicidal gestures when over-whelmed. His mood symptoms becamemore distinct, with depressed periodslasting up to a month and manic epi-sodes lasting 7 to 10 days (see Figure 2).He would have 8 to 10 mood switchesper year. He also had many mixed epi-sodes. His clinical deterioration contin-ued despite aggressive case management,school interventions, respite care, and aday treatment program. Prior to com-ing to the Case Western Reserve StanleyCenter, Richie’s last psychiatrist told hismother that if Richie did not improveon carbamazepine and sertraline, hewould never get any better and wouldbe a chronic mental patient.

(Continued on page 6)

BNN Vol. 4, Iss. 4

Page 5

Figure 1: Richie�s life chart showing moodiness, hyperactivity, inattention, aggressiveness, andinappropriate behavior prior to medication treatment.

Figure 2: After several failed medication trials, Richie�s treatment with lithium and valproate (1998) aspart of an E.I.I. study, together with methylphenidate, stabilized his mood for the first time.

Clinical effectiveness of lithium and valproate combinationtherapy in a nine year-old child with bipolar disorder

BNN Vol. 4, Iss. 4

Page 6

Study EntryAfter a diagnosis of bipolar disorder wasestablished, Richie was enrolled in ourstudy. Richie’s medications were taperedand then discontinued. He continued tomeet diagnostic criteria for bipolar dis-order type I, most recent episode manic.He began combination lithium and val-proate treatment as per study protocol(Figure 2). Within 4 weeks, Richie’smood was stable. Richie’s mother re-ported that for the first time, Richieseemed happy. Despite Richie’s stablemood, he was still having difficulties atschool and in social situations due tocontinued impulsivity, hyperactivity, andinability to concentrate. Because thesewere residual symptoms of ADHD,Richie was offered a therapeutic trial ofadjunctive methylphenidate. Initially,Richie and his mother were both reluc-tant to try a stimulant again due to his

Life Chart Highlight(Continued from page 4)

poor response in the past. We informedhim and his mother that it was our ex-perience that few patients derive robustbenefit from treatment with stimulantsbefore mood stabilization, and that al-most every one of our patients with bi-polar disorder and ADHD have ben-efited from stimulant treatment aftermood stabilization. With this informa-tion, Richie and his mother agreed to amethylphenidate trial. It was subse-quently found that 10 mg doses of me-thylphenidate were very helpful (Figure2).

Exactly 8 weeks had passed since wehad first seen Richie. His mother wasecstatic. She told the Center staff thatshe had never been so happy with herson before. For the first time in his life,Richie was doing well at home and atschool.

Richie had some trouble acceptingthe need for medication. We workedwith his mother on the importance ofmedication compliance. We also pro-vided developmental guidance for hismother regarding the impact of a psy-chiatric illness on his view of himself.Richie’s mother developed increased con-fidence in her parenting skills.

At present, Richie is doing well andis back on his normal developmentaltrack. His mother states that he is likeany other boy now. She feels that hisimprovement is nothing short of amiracle. Our greatest hope is thatthrough the information learnedthrough all of the activities of the StanleyFoundation Early Intervention Initiative(E.I.I.), more children like Richie willone day be able to get the assessmentand treatment they deserve. ■

Publication Update:Olanzapine in Treatment-Resistant Bipolar Disorder

Susan L. McElroy, Mark Frye, Kirk Denicoff, Lori Altshuler, Willem Nolen, Ralph Kupka, Trisha Suppes, Paul E.Keck, Jr., Gabriele S. Leverich, Geri F. Kmetz, Robert M. Post

Journal of Affective Disorders 49: 119�122, 1998

Introduction: Substantial clinical data suggest that the atypical antipsychotic clozapine may be effective inthe acute and prophylactic treatment of some patients with bipolar disorder, including some patients inad-equately responsive to treatment with mood stabilizers, electroconvulsive therapy (ECT), and conventionalantipsychotics. The new atypical antipsychotic olanzapine has a pharmacologic and electrophysiologic profilesimilar to that of clozapine. To investigate the efficacy, tolerability, and safety of olanzapine in bipolar disor-der, we reviewed the response of patients with bipolar disorder who received treatment with olanzapine atour centers for persistent affective symptoms inadequately responsive to standard psychotropic agents.

Methods: Patients with bipolar I disorder who were participating in the Stanley Foundation Bipolar Networknaturalistic follow-up study and who received treatment with olanzapine for at least 1 week were included inthe study. Patients were excluded if olanzapine was begun when they were euthymic or within 2 weeksbefore or after any other major changes in their medication regimens. Response to olanzapine was rated withthe Clinical Global Impression Scale modified for bipolar disorder at two points in time: response of affectivestate at time of olanzapine initiation was assessed after 1 month of treatment with olanzapine; and overallresponse of illness was assessed at the patient�s last evaluation while receiving olanzapine.

(Continued on page 10)

BNN Vol. 4, Iss. 4

Page 7

Around the Network

The Munich/Freiburg Site in Germany

Heinz Grunze, MD, Jörg Walden, MD, PhDSandra Schlösser, MA

Prof. Heinz Grunze

Professor Heinz Grunze at the Uni-versity of Munich and ProfessorJörg Walden at the University of

Freiburg in Germany have entered theNetwork as an affiliated Site via theirfunding as a freestanding EuropeanStanley Center. They are an ideal groupto join the Network from a number ofperspectives. They are extremely experi-

enced in thepsychophar-m a c o l o g y(both clinicaland basic) ofthe routineand novelmood stabiliz-ers and haveexamined theunique mecha-

nisms of action of nimodipine and re-lated calcium channel blockers on cal-cium dependent models of seizures aswell as their clinical efficacy in bipolarillness. Additionally, they are studyingthe newer anticonvulsants and have con-ducted trials of the GABA-active agentsgabapentin (Neurontin) and gabatril(Tiagabine).

Dr. Grunze received his medical de-gree in 1986 after studying in Aachen,Germany, as well as in England at Ox-ford and London. After a research fel-lowship in psychiatry at the Max PlanckInstitute in Germany he was a researchfellow from 1993 to 1995 in the De-partment of Psychiatry at Harvard Medi-cal School in Cambridge, Massachusetts.His major research interests include neu-roendocrinological changes in depressionand schizophrenia, electrophysiologicalinvestigations of the effects of

antiepileptic drugs in vitro as well asclinical studies of the neurobiology ofschizophrenia and bipolar disorder. Oneof the clinical studies was done in col-laboration with Professor Walden, look-ing at prophy-lactic efficacyof nimodipine(Nimotop),carbamazepine,( Te g r e t o l )and lithium.

Dr. Waldenstudied medi-cine and psy-chology at uni-versities in Germany as well as in En-gland. He received his M.D. degree in1984, his doctoral degree in physiologyin 1989, and his doctoral degree in psy-chology in 1994. He completed residen-cies at the universities of Essen andFreiburg, with a specialty in psychiatryin 1994, and received his professorshipin psychiatry at the University ofFreiburg in 1995. He and Dr. Grunzehave won several awards for their re-search and clinical work and both shareda Stanley Foundation research award forstudies on the clinical efficacy of calciumagonists in psychiatry.

Sandra Schlösser, who had previouslybeen working with both doctors as a re-search assistant, joined them as a master’sdegree psychologist in their longitudi-nal studies in bipolar disorder followingtheir appointment as a free standing Eu-ropean Stanley Center in 1998. In herrole as coordinator of the Stanley Foun-dation studies in the affective disordersat the Ludwig-Maximilians-Universityof Munich, Ms. Schlösser recently spent

2 weeks at the Bethesda Site to be trainedin Network methodology. She receivedcertification as a highly reliable rater onall Network assessment tools, includingthe life chart method, and will be in-strumental in implementing some of ourNetwork protocols at the Munich/Freiburg Site in Germany. She has takenthe lead in a collaborative effort to trans-late all Network forms into German andis in the process of submitting the AD-1 Network protocol for a blind random-ized comparison of sertraline (Zoloft)and venlafaxine (Effexor) (bupropionis not yet available in Germany). Theyare also interested in participating in the

double-blindevaluation ofomega-3 fattyacids, a Net-work protocolabout to belaunched.

We verymuch lookforward to this

and other European Stanley Centers fill-ing an increasingly important role in theacquisition of new patients for morerapid completion of Network protocols.In this fashion, critical information froma large number of patients can be col-lected on the relative acute and long-termefficacy of medications so that a betterclinical knowledge base can be createdfor more effective treatment of bipolardisorder. ■

GERMANY

Prof. Jörg Walden

Sandra Schlösser

BNN Vol. 4, Iss. 4

Page 8

Network News Briefs

As illustrated in the flow chart on page 9, the 8 randomized clini- cal trials currently available in

the Network are designed to answer anumber of clinically important ques-tions. If patients are starting lithium pro-phylaxis they will be offered the oppor-tunity to be randomized to augmenta-tion with levothyroxine sodium (T

4) to

see if this will improve outcome overlithium alone. If they enter a depressiveepisode they are eligible for the double-blind antidepressant trial-1 (AD-1) com-paring bupropion (Wellbutrin),sertraline (Zoloft), and venlafaxine(Effexor)(see p. 1). Partial but inad-equate responders to any antidepressantare offered a randomized comparison oftriiodothyronine (T

3) augmentation ver-

sus the psychomotor stimulant meth-ylphenidate (Ritalin) in AD-2 (bottomleft, p. 9).

Those failing to respond to AD-2 areoffered a randomized comparison (AD-3) of the putative mood stabilizerlamotrigine (Lamictal) versus themonoamine oxidase inhibitor tranyl-cypromine (Parnate), which has an ex-cellent record of response in bipolar de-pression (Himmelhoch et al., 1991; AmJ Psychiatry 148: 910-916). Those de-pressed patients (as well as those in amanic episode or those who are cycling)who fail to respond adequately will beoffered the blind, randomized evaluationof augmentation with omega-3 fatty ac-ids (6 grams) compared to placebo for 4months, with all patients offered an ad-ditional 8 months of open treatmentwith omega-3 fatty acids if so desired(bottom right, p. 9).

If patients require a major tranquil-izer, we will compare the atypicalneuroleptics olanzapine (Zyprexa) andquetiapine (Seroquel) for efficacy andside effects. If cycling patients require theaddition of a new putative mood stabi-lizer, gabapentin (Neurontin) will becompared to topiramate (Topamax)(bottom right, p. 9). If patients are notsymptomatic but are struggling withdrug-induced weight gain, we will com-pare sibutramine (Meridia) with

The Bipolar Network Protocol Flow Chart

topiramate (top left, p. 9). Sibutramineis a recently approved dietary aid thatblocks the re-uptake of all three majorneurotransmitter amines (serotonin,norepinephrine, and dopamine). Its ef-ficacy and tolerability in bipolar patientshas not previously been studied. ■

BethesdaNIMHBiological Psychiatry Branch10/3N21210 Center Drive MSC 1272Bethesda, MD 20892(301) 496-7180

CincinnatiUniversity of CincinnatiCollege of MedicineBiological Psychiatry ProgramML 0559231 Bethesda Ave, Suite 7005Cincinnati, OH 45267-0559(513) 558-5117

DallasUT Southwestern Medical CenterBipolar Disorder Clinic8267 Elmbrook, Suite 250Dallas, TX 75247(214) 689-3765

Los Angeles/UCLAUCLA Ambulatory ClinicalResearch CenterMood Disorders Research Program300 UCLA Medical PlazaSuite 1544, Box 957057Los Angeles, CA 90095-7057(310) 794-9912

Los Angeles/VAVA Medical Center, West LAB116AA, Bldg 158, Room 10411301 Wilshire BlvdLos Angeles, CA 90073(310) 478-3711 (ext. 44198)

UtrechtHC Rümke GroepWillem Arntsz HuisVrouwjuttenhof 183512 PZ UtrechtNetherlands(31) 30-2308 828

Stanley Foundation Bipolar Network Site Addresses:

BNN Vol. 4, Iss. 4

Page 9

NFS

Put on Lithium

NO

Li + T4 vs.

Li + placebo*NO

(If 1st Li Trial)

Is patient currentlysymptomatic?

<4 cycles/year

Omega-3 fatty acidsvs. placebo*

Olanzapine vs.Quetiapine*

Topiramate vs.Gabapentin*

Depression protocols

Venlafaxine vs.Bupropion vs.

Sertraline (AD-1)*

Response?

Mania protocols

PartialYes No

AD-1(above) (AD-2) T3 vs.

Methylphenidate*(AD-3) Lamotrigine vs.

Tranylcypromine*

Bipolar Network Protocol Flow Chart

Does patient have aWEIGHT problem?

YES

Sibutramine vs. Topiramate*

YES

YES

Abbreviations: NFS = naturalistic follow-up study;T4 = thyroxine; T3 = triiodothyronine;* = indicates randomized trial

On a mood stabilizer?

Cycling frequency?

(Clinician’s Discretion)

Continuation Augmentation Substitution

Episode Protocols

Rapid cycling

Cycling Protocols

Ultra-rapid orultradian cycling

Atypicalantipsychotics

Newanticonvulsants

BNN Vol. 4, Iss. 4

Page 10

temporal association of symptom exac-erbation to strep infections, and associ-ated neurological abnormalities. Prom-ising new data on therapeutics suggeststhat both antibiotic treatment and im-munoglobulin treatment may be help-ful in patients with PANDAS.

Dr. Robert Post, MD, “Bipolar Dis-order/Kindling and Pharmacologic Im-plications.” Dr. Post presented new datafrom the Stanley Network on how earlylife experiences impact the unfolding ofbipolar disorder, including data thatshow that patients with physical abusehave a higher incidence of worseningmania, and patients with sexual abusehave increased suicidality. These severeearly stressors (physical/sexual abuse)were associated with an earlier onset ofbipolar illness and a higher incidence ofultra-rapid and ultra ultra-rapid(ultradian) cycling. Preclinical data in arodent model of maternal separation sug-gest that some of these effects may beassociated with stress-induced alterationsin neurotrophic factor gene expressionand subsequent long-term changes in theregulation of endocrine and stress-reac-

tive behavior.Dr. Carol Tamminga, MD, “Neu-

robiology of Schizophrenia.” Dr.Tamminga reviewed new evidence ofglutamate involvement in schizophrenia,using glutamate blockers (such as theanaesthetic ketamine) as probes of thisillness. This work and the work of oth-ers in this area has led to possible thera-peutic approaches to psychosis by facili-tating a glycine modulatory site of theglutamate receptor.

Dr. William Bunney, MD, “Neuro-pathological Abnormalities in Schizo-phrenia.” Dr Bunney reported that inthe dorsolateral prefrontal cortex ofschizophrenic patients, 3 neuronal mark-ers of the neural subplate show signifi-cant alterations in their anatomy. Hesuggested that schizophrenia may be as-sociated with several factors related tofaulty neuronal migration.

Dr. Jack Gorman, MD, “Neurobi-ology of Anxiety Disorders.” Dr.Gorman presented exciting new data onthe neurobiology of the anxiety disor-ders, indicating important roles for se-rotonergic transmission and the possible

Meeting Highlight: ARNMD(Continued from page 3)

involvement of corticotropin-releasinghormone (CRH) in stress sensitivity andfear conditioning. CRH receptor antago-nists will be available for clinical studiesin the near future and all are anticipat-ing their potential therapeutic applica-tion in a variety of syndromes.

Dr. Steve Goldman, MD, PhD,“Neural Progenitor Cells of the AdultHuman Brain: Their Identification,Isolation and Use.” Dr. Goldman re-ported on the culturing ofneuroprogenitor cells from thesubependymal zone of the ventricularlining. These cells are pluri-potent andcan develop into either neurons or glia,and hold promise for the ultimate abil-ity to repair brain dysfunction.

Thus a tremendous body of knowl-edge was reviewed in the two days of theARNMD meeting, leaving one with theimpression of considerable progress inunderstanding some of the neural path-ways to the major psychiatric illnessesand many avenues of exploration for newapproaches to therapeutics. ■

Results: Fourteen consecutive patients with bipolar I disorder treated with olanzapine and meeting theinclusion criteria were identified. Eight (57%) patients were evaluated prospectively and six (43%) wereevaluated retrospectively. Thirteen patients had received prior treatment with an antipsychotic other thanolanzapine. Olanzapine was added to pre-existing psychotropic regimens in all but one patient. Olanzapinewas begun in all patients at 5�10 mg/day, usually given all at one dose at night. Olanzapine doses weresubsequently increased by 5�10 mg/day every 7�14 days according to patient response and side effects toa maximum dose of 30 mg/day. At their last evaluation, 8 (57%) of the 14 patients were rated as much (n=6)or very much (N=2) improved, after a mean ± S.D. (range) of 117.4 ± 46.8 (57�217) days of treatment witha mean ± S.D. (range) olanzapine dose of 15.2 ± 6.7 (7.5�30) mg/day. Olanzapine was generally well toler-ated; one patient discontinued the drug due to bad dreams. No patients developed extrapyramidal symp-toms or required concomitant anti-parkinsonian agents.

Conclusion: These preliminary observations are limited by several methodologic shortcomings: (1) datawere obtained nonblindly and without a randomized control group; (2) in all but one patient, olanzapine wasadded to ongoing psychotropic regimens; and (3) formal rating scales for extrapyramidal side effects werenot used. However, even when these limitations are considered, the response observed in 57% of patientswith treatment-refractory bipolar disorder is promising. ■

Publication Update: Olanzapine(Continued from page 6)

BNN Vol. 4, Iss. 4

Page 11

DISCLAIMER:

Although the editors of the BNN havemade every effort to report accurateinformation, much of the work detailedhere is in summary or prepublicationform, and therefore cannot be taken asverified data. The BNN can thus assumeno liability for errors of fact, omission, orlack of balance. Patients should consultwith their physicians, and physicianswith the published literature, beforemaking any treatment decisions based oninformation given in this issue or in anyissue of the BNN.

Clinical Trials Update(Continued from page 2)

nia and three anticonvulsants for epi-lepsy) preliminarily explored in openNetwork trials appears to have prom-ising utility in different aspects of bi-polar disorder. We are very pleased thata range of options beyond lithium,valproate, and carbamazepine are nowbeing studied, potentially allowing forbetter differential targeting of symp-toms and side effects in bipolar illness.

Omega-3 Fatty AcidsThe double-blind, randomized evalu-ation of omega-3 fatty acids (6 grams)versus placebo will be a leading proto-col effort for 1999. The initial phaseof the trial is 4 months of adjunctivedouble-blind treatment with eitheromega-3 fatty acids or placebo.Nonresponders will be offered an open8-month extension of the trial so thatall patients will have the opportunityto be on active drug treatment for atleast 8 months. ■

NIMH RecruitmentRepeated Transcranial Magnetic Stimulation (rTMS) and Patientswith Depression

The NIMH Site continues to need volunteers (18 years or older) with a diagnosisof unipolar or bipolar depression who wish to participate in studies evaluating thecomparative efficacy of high (20 Hz) and low (1 Hz) rTMS vs. sham rTMS (allpatients will receive both active forms of rTMS [20HZ and 1 Hz] during thestudy). We continue to observe differential effects on mood and brain activity withlow versus high frequencies of rTMS, and are attempting to ascertain which pa-tients respond best to which frequencies. A new study at a higher intensity ofstimulation (110% of motor threshold as compared to the current study set at100%) will test 3 weeks of 1 Hz vs. 20 Hz rTMS vs. sham over the left frontalcortex in the future. Each patient will have an opportunity for another 3 weeks ofcontinued rTMS if they respond, or they can cross over to the other frequencyshould they fail to respond in the first phase. If you are interested in the rTMSstudy, please call Nadine Khoury or Dr. Andy Speer at (301) 402-2294.

Six-Week Comparison of Lamotrigine, Gabapentin and PlaceboThe NIMH Site also continues to recruit bipolar patients with affective disorderswho have not been treated with gabapentin or lamotrigine so that we can continueto examine the efficacy of these agents compared with placebo, and establish po-tential clinical and biological predictors and correlates of response. Currently, thedata suggest that lamotrigine monotherapy is more effective than that of gabapentinor placebo. However, many of the add-on trials in bipolar illness with gabapentinshow it to be effective, and the overall clinical utility of this agent remains to befurther delineated. If you are interested in pharmacological intervention withlamotrigine and gabapentin, please call Dr. Robert Dunn at (301) 402-2293 orGabriele Leverich, MSW, at (301) 496-7180.

Parents whose children ages 4–16 have been diagnosed with (1) bipolar disorder,(2) unipolar depression, or (3) no psychiatric diagnosis (children doing well inschool, social, and family environments) are encouraged to participate in a retro-spective survey to better define the earliest symptoms of these affective illnesses (1and 2) compared with non-ill controls (3). This survey, which would be mailed toyou, will take approximately an hour or more to complete—depending on yourchild’s age and symptoms experienced—and will provide the Network with veryimportant preliminary data about the early presentation of childhood affectivedisorders, which can then be further validated and pursued in more detail in pro-spective studies.

We thank all those who have already contributed to this study, the results ofwhich will be reported. However, it now appears that we will need a substantiallylarger number of parents who have children with major depression in order todraw more definitive conclusions about what early behaviors are most typical ofchildhood onset bipolar versus unipolar illness. We hope you can contribute tothis effort. Please contact Emily Fergus at the following address or phone numberto participate: 5430 Grosvenor Lane, Suite 200, Bethesda, Maryland 20814 (phone:(301) 496-6827; fax: (301) 402-0052; e-mail: emily.fergus@nih.gov).

Survey: Early Symptoms Preceding A Diagnosis Of ChildhoodAffective Illness

Visit the StanleyFoundation

Bipolar NetworkWorld Wide Web Site

at:

www.bipolarnetwork.org

Bipolar Network NewsStanley Foundation Bipolar NetworkA Program of the NAMI Research Institute5430 Grosvenor Lane, Suite 200Bethesda, Maryland 20814www.bipolarnetwork.org

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In This Issue:1998: The Year in Review

Treating Childhood Bipolar DisorderARNMD Meeting Highlights

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BNN Vol. 4, Iss. 4