The Increasing Use of Polypharmacotherapy
`for Refractory Mood Disorders: 22 Years of Study
`
`Mark A. Frye, M.D.; Terence A. Ketter, M.D.;
`Gabriele S. Leverich, L.C.S.W.; Teresa Huggins, Ph.D.;
`Caprice Lantz, M.A.; Kirk D. Denicoff, M.D.; and Robert M. Post, M.D.
`
`Background.‘ Few studies have approached
`the subject of polypharmacotherapy systemati-
`cally. This retrospective review of 178 patients
`with refractory bipolar disorder or unipolar de-
`pression {Research Diagnostic Criteria or DSM—
`Ill-R criteria) discharged from the National Insti-
`tute of Mental Health (NIMH) Biological
`Psychiatry Branch between I974 and 1996 was
`conducted to assess the degree and efficacy of
`“add-on“ pharmacotherapy.
`Metlrod: Following completion of formal
`structured blinded research protocols, patients
`entered a treatment phase [often again on a blind
`basis) in which all agents available in the commu-
`nity could be utilized. Each patient's retrospective
`life chart and all prospective double—blind nurse-
`and self-rated N IMH data were reviewed. The
`
`overall degree of improvement at discharge was
`assessed by rating on the Clinical Global Impres-
`sions scale {CG|) as modified for bipolar illness
`(CGI-BPJ.
`Results: A 78% improvement rate (moderate
`or marked on the CGI) was achieved at the time
`of discharge. There was a significant relationship
`between number of medications utilized at disw
`charge as a function of discharge date (r = 0.45.
`p -c .000| ). The percentages of patients dis-
`charged on treatment with 3 or more medications
`were 3.3% ( |974—l9'l9), 9.3% (1980-1984),
`34.9% (1935-I989). and 43.8% (1990-1995). No
`correlation was found between polypharmacy and
`age (r = -0.03, p = .66). Patients more recently
`discharged from the NIMH had an earlier age at
`illness onset. more lifetime weeks depressed. and
`a higher rate of rapid cycling than patients in the
`earlier cohorts.
`Conclusion.‘ Increasing numbers of medica-
`tions in more recent NIMH cohorts were required
`to achieve the same degree of improvement at
`hospital discharge. More systematic approaches
`to the complex regimens required for treatment of
`patients with refractory mood disorder are clearly
`needed.
`
`l.l Cliri Psy£‘l1itttr'_v 2000,'6l.'9—l5)
`
`1‘ 998; accepted July 28. l 999. Front tlie Biological
`Received May 28.
`P.r_-rclriatry Brancli. National lnstitutc ofMental Health, Betlicscla. Md. (all
`arrrltors,J.'
`the Department of P.i_l’(‘ltlfllt'_‘.‘ and Biolreltavioral Scieiicer.
`UCIA Srlrool ofMe'cliciue. Los Angcles (Dr: Fr_vel.' and the Department of
`P.r_vcl1iutr_1' and Behavioral Sciences. Stanford Um'i-'ersr'ty School of
`Mea‘icim:. Srunfoml. Calif (Dr: Ketter).
`Presenretl
`in part at
`the l49tl1 arimruz‘ nreeting of the Aniericrur
`P.ry('l1t'a'.rrit' A.r.wciatiorr. May I5. l99(i. New lriorlr, N. K
`Reprint re'qi:e.rts to: Robert M. Post. M.D.. Chief; 3l()l(Jglt'fll P.v_vclrirrtr_i;
`Brrmcli. Nllrll-l. Bldg.
`l0. Room 3N2l‘2, 10 Center Dr: MSC l272.
`Betlicszla. MD 20892- l 272.
`
`"The true pol_vplmrmac_v is the skillful combination of
`remedies.“
`—Sir William Osler'
`
`Patients with refractory mood disorder. particularly
`
`manic-depressive illness. are commonly treated
`with multiple medications. Circa 1996. these medications
`primarily included lithium and the anticonvulsants carba—
`mazepine and divalproex sodium, as supplemented by cal-
`cium channel blockers. conventional antidepressants. ben-
`zodiazepines. antipsychotics. and thyroid hormone.
`Lithium carbonate has clearly been the gold standard
`for treatment of acute mania and bipolar depression and
`for long-term maintenance treatment} However, the fail-
`ure rate for lithium in acute mania has been reported in rev
`cent reviews to be 50% or higher.“ For example, in the
`largest double-blind. randomized study of lithium and val-
`proate to date.‘ the response rate (defined as a 50% reduc-
`tion in manic severity) to either of these agents at the end
`of the 3-week study period was only 50%. Furthermore,
`patients who have some bipolar subtypes have particularly
`poor responses to lithium, including those with mixed or
`dysphoric mania.“ rapid cycling,7 :1 depressiomrnania-well
`interval sequence,‘ and substance abuse cornorbidity.“"”
`Although the mood-stabilizing anticonvulsants provide
`treatment alternatives. some patients fail to respond acutely
`or prophylactically to carbamazepine and divalproex so-
`dium, and others can gradually develop loss of efficacy or
`tolerances‘ Although early observations of the acute effi-
`cacy of a new generation of potential mood—stabi|izing
`anticonvulsants (gabapentin and lamotrigine) look prom-
`ising,”"5 further controlled studies are encouraged.
`Often, polypharmacotherapy is needed for maximal sta-
`bilization. This is not infrequent clinical practice in the
`
`J Clin Psychiatry 61:1, January 2000
`
`Alkermes Ex. 1
`
`1 of 7
`
`Alkermes, Ex. 1029
`
`

`
`Frye et al.
`
`tnedical management of tuberculosis.“ congestive heart
`failure,” autoimmune disorders,” multiple sclerosis,” ac-
`quired immunodeficiency syndrome,” immunosuppres-
`sion in transplantation.“ and refractory epilepsy." In fact,
`iamotrigine and gabapentin received their recent U.S. Food
`and Drug Administration (FDA) approval utilizing "add-
`on” design:-:.3"'3“ Furthermore.
`lamotrigine and valproate
`have what appears to be pharmacodynamic synergy with
`anticonvulsant effectsfi and enhanced efficacy for mood
`stabilization.1“‘" However. few clinical studies in affective
`
`disorder have incorporated this design. and no FDA ap-
`provals have been based on such adjunctive clinical trials.
`The most common mode of polypharmaeotherapy (or
`complex combination therapy} utilized in psychiatry is
`“add-on" or adjunctive pharmacotherapy. The prevalence
`of this practice has been reported to exist in 28% to 795%
`of diverse patient populations and study designs and is re-
`viewed extensively by Rapp and Kaplan” and Gardos et
`al.“ More recent reviews, both in bipolar illness"’°‘3' and
`unipolar depression."“" continue to suggest that this is a
`very common practice.
`In the National Ambulatory Medical Care survey. psy-
`chiatric practice. compared with other medical specialties.
`was predictive of greater use of polypharmacotherapy. and
`manic patients were 4 times more likely to receive mul-
`tiple medications than nonpsychiatrie patients.” When
`lithium is prescribed. greater than ?0% ofthe time it is uti-
`lized in combination strategies."“"" This polypharmaeo-
`therapy has been reported to be more prevalent in women
`and to increase with age.“ Furthermore. some point preva-
`lence studies have noted an increasing rate of poly-
`pharmacotherapy in more recent study cohorts."“"“’ The
`study by Hallin et al.” noted single-agent therapy (48%
`lithium) in 57% of 240 bipolar patients in I939; in con-
`trast. single-agent therapy (26% lithium) was used in only
`3?% of 190 patients 5 years later in 1994. Neither of these
`studies assessed baseline severity of illness or the degree
`of improvement on combination treatment.
`Peselow et aI..‘“’ in a large naturalistic study of lithium
`prophylaxis for patients with bipolar illness (N = 305), re-
`ported that the probability of remaining euthymic was
`85%. 52%. and 37% after 1. 3, and 5 years of lithium
`monotherapy. respectively. For an affective relapse, pa-
`tients were treated with lithium plus an adjunctive mood
`stabilizer. antidepressant, neuroleptic. or benzodiazepine;
`70% of these patients did better on combination treatment
`and obtained greater protection against subsequent relapse
`when compared with the initiai course of lithium mono-
`therapy.
`Few studies have approached the subject of poly-
`pharmacotherapy systematically, and it is the purpose of
`this article to initiate such a discussion. This retrospective
`review of 178 patients with refractory mood disorder dis-
`charged from the 3-West Clinical Center Research Unit of
`the Biological Psychiatry Branch (BPB). National Institute
`
`of Mental Health (NIMH), between l9?4 and 1995 was
`conducted to assess the degree and eflieaey of "add-on“
`polypharmacotherapy utilized on a double—blind basis.
`
`METHOD
`
`The referral base for the BPB. NIMH, is t'eft'aetot'y uni-
`polar and bipolar patients (meeting Research Diagnostic
`Criteria or, more recently. DSM-lll-R criteria) who have
`failed usual therapies in the community and who wish to
`participate in intensive neurobiological evalttation and
`clinical treatment utilizing double-blind protocols.
`from
`Patients sequentially discharged from the Unit
`I974 to 1996 were included in the analysis if they com-
`pleted one or tnore double-blind monotherapy protocols
`and associated research procedures and wished to remain
`on the Unit to begin a more clinically based treatment
`phase of hospitalization. This was. again. often conducted
`on a blind basis utilizing alternative and add—on medica-
`tion in an attempt to furthertreat and acutely stabilize their
`refractory affective illness. There was no standard clinical
`algorithm for the study group; each patient‘s case was
`evaluated separately taking into account
`initial double-
`blind, protocol-driven monotherapy. drug trial responsive-
`ness, past drug trials prior to NIMH. and clinical to1erabi1-
`ity. The vast majority of patients had experienced multiple
`unsuccessful clinical trials prior to their NIMH admission.
`Patients gave informed consent for a placebo period of
`evaluation and for each of the protocol medications under
`clinical research investigation. This first included a major
`monotherapy research focus on piribedil" and pitnozide,"
`and then.
`sequentially. carbamazepine."”" valproate.”
`thyrotropin-releasing hormone (TRH), nimodipinef" la-
`motrigine.” and gabapentin.” Patients almost always con-
`tinued taking double—blind medications throughout
`the
`hospitalization: i.e., neither they nor the nursing staff were
`aware of when they were on active medication or the se-
`quence of new monotherapies and then “add-on" medica-
`tion trials including conventional antidepressants, benze-
`diazepines. neuroleptics. and thyroid hormones. Only in
`the last year of the study (1995) were patients aware of
`when they were in a given 6-week phase (1. 2. or 3} com-
`paring lamotrigine. gabaperttin. and placebo on a random-
`ized crossover basis.”
`
`Double—blind ratings consisted of twice-daily nurses"
`ratings by consensus using the 15-point Bunney-Hamburg
`Rating Scale for depression. mania. anger. anxiety, and
`psychosis" and a self-rating of mood utilizing a I00-mm
`visual analog scale. These daily longitudinal measures
`were depicted graphically for comparison with prior course
`of i llness, as assessed by the retrospective life chart method
`(NIMH-LCM}.‘”‘ The NIMH-LCM allows for systematic
`quantification of a number of course-of-illness variables
`including age at time of first symptoms. duration ofillness,
`and past hospitalizations. Not all of the I78 patients had a
`
`10
`
`J Clin Psychiatry 61:], January 20(l(l
`
`Alkermes Ex. 1
`
`2 of 7
`
`Alkermes, Ex. 1029
`
`

`
`reflected in age at onset
`retrospective life chart as
`(N = 160) and lifetime weeks of depression (N = 138) cor-
`relations to discharge date.
`The demographic profile of the 178 patients included
`131 with bipolar disorder (76, bipolar I; 50. bipolar II:
`5. schizoaffective bipolar type) and 4? with recurrent
`unipolar depression (5 schizoaffective depressed type):
`108 female and 70 male patients were included. The
`mean i SD patient age at discharge was 40 i 12.8 years:
`women were older
`(42.1 i 12.3
`years)
`than men
`(36.9 i 12.9 years, pc .008). There was no correlation
`between age and discharge date (N m 178. r= 0.04.
`p < .64). suggesting that age at discharge remained rela-
`tively constant over the 22-year period. The mean i SD
`duration of prior illness was 17.3 i 11.2 years (N = 160).
`The NIMH-LCM retrospective clinical demographics
`examined by gender revealed a longer duration of illness
`for women (mean i SD = l9.8 i 10.9 years, N = 99)
`than for men (13.3ir 10.5 years. N =6l; p< .0002), a
`greater number of hospitalizations for depression for
`women (mean i SD = 4.5 i 5.83. N = 91) than for men
`(2.5 i 3.53. N = 55; p < .02). and a greater number of1ife-
`time weeks of depression for women than for men (Mann-
`Whitney U mean rank = 518 for women versus 41.3 for
`men. N : 103; U = 820.5. p < .01). When age. duration of
`illness. and lifetime weeks depressed were controlled for.
`gender difference remained significant (p < .007. p < .05.
`respectively). No significant differences in age at dis-
`charge (p = .89) or duration of illness {p = .'l) by bipolar
`versus unipolar subtype were found.
`The overall rating of improvement at discharge was
`made by the Clinical Global Impressions scale (CGI) as
`modified for bipolar illness (CG1-BP).‘"" which allows for
`rating of degree of clinical improvement in depression.
`mania, and overall illness. Moreover, it addresses many of
`the specific criticisms leveled at the CGI relating to the
`types of ratings. technical and scaling problems. defini-
`tion of time domain of the rating. and confounding of
`clinical response with tolerability and side effects. The
`main measure was degree ofoverall clinical improvement
`at discharge. as assessed from the patients’ most appropri-
`ate worst phase of illness, which almost invariably was
`during their period of baseline evaluation while receiving
`placebo. Degree of
`improvement was classified as
`marked (essentially complete remission). moderate (dis-
`tinct clinically important improvement. but some symp-
`toms
`remain). mild (slight but
`insufficient
`to affect
`patient‘s basic clinical status or
`functioning). or no
`change or similar degrees of worsening. as described in
`detail elsewhere.”
`
`Degree of clinical global response achieved at dis-
`charge was subsequently analyzed as it related to the ma-
`jor demographic and course-of-illness variables available
`from the NIMH-LCM. Statistical analysis was conducted
`using SPSS software (version 8.0; Chicago, 111.). Pearson
`
`J Clin Psychiatry 61:1. January 2000
`
`Polypharmacotherapy for Refractory Mood Disorders
`
`Figure 1. Increasing Polypharmacotherapy in More Recent
`National Institute of Mental Health {NIMH) Discharges
`
`I Bipolar Patient
`I Unlpo|arPa1ient
`I = 0.45
`p ¢ .0001
`
`NumberofMedications
`
`ll'|'l'|IIrI|IIII|lII
`19?6
`1981
`1986
`Discharge Date
`
`1991
`
`r correlations between discharge date and other NIMH—
`LCM variables were calculated. A stepwise multiple re-
`gression analysis was performed on these variables using
`number of medications at discharge as the dependent vari-
`able. Unipolar and bipolar subgroups were analyzed sepa-
`rately. but when no major differences were observed. they
`were combined for the sake of brevity of presentation.
`Means are reported including ir standard deviation. Group
`differences were compared using the Student t test except
`where extreme outliers required the use of the Mann-
`Whitney U test.
`
`RESULTS
`
`The overall response rate as measured by CGI score at
`the time of hospital discharge was 78% (35% marked im-
`provement. 43% moderate improvement). Of the 21%
`who were nonresponders. 16% were mildly improved, 4%
`showed no change. and 1% were mildly to moderately
`worse. The analysis of CGI versus date of discharge
`yielded a weak positive correlation (r: 0.20, p -1.007).
`showing that the patients more recently discharged from
`the NIMH were. if anything, slightly more improved than
`those studied earlier.
`
`There was a highly significant positive relationship be-
`tween increased number of discharge medications and the
`more recent discharge date (r = 0.45. p < .000}: N = 1718:
`Figure 1). There was no correlation between the degree
`of polypharmacotherapy and age at discharge (r =—0.03.
`p = .66). Length of hospital stay correlated with discharge
`year (r: 0.432. p < .0001) and the number of discharge
`medications (r=0.34. p < .0001):
`i.e.. more recent pa-
`tients had longer hospitalizations. most likely related to
`the greater number of blinded monotherapy and add—on
`trials available and offered to patients who remained un-
`improved in their clinical treatment phase of their hospi-
`
`11
`
`Alkermes Ex. 1
`
`3 of 7
`
`Alkermes, Ex. 1029
`
`

`
`Frye et al.
`
`Table l. Adjunctive Medication to Primary Mood Stabilizer at NIMH Discharge
`
`Carbamazcpinc
`(N = 49)
`
`Unipolar Bipolar
`(N = II)
`(N :38)
`
`Divalprocx Sodium
`(N=l2)
`Unipolar Bipolar
`{N=0)
`tN=12)
`
`Adjunctive
`Medication, N Ulla)
`Any adjunctive
`medication
`Antidepressant
`Ncuroleptic
`Benzodiazepine
`Calcium channel
`0
`1 (9)
`l (2)
`0
`blocker
`4 (1 ll
`I (9)
`2 (4)
`3 (33)
`Thyroid
`“A total of 10 patients were discharged on treatment with a calcium channel blocker. only 3 of them as an adjunctive medication.
`
`Total
`(N=l23)
`Unipolar Bipolar
`(N=2l) (N = 102]
`
`|2(57)
`5124}
`1(5)
`0
`
`1(5)
`4(l9)
`
`49(48)
`l8(l8)
`l0(|0l
`3(3)
`
`2(2)
`l3(I3l
`
`Calcium
`Channel Blocker
`(N='f)"
`Unipolar Bipolar
`(N=|)
`(N=6]
`
`2(33)
`2(33J
`
`00
`
`H100)
`D
`0
`0
`
`0
`0
`
`0
`0
`
`l2(|00)
`4(33J
`I (8)
`0
`
`1(8)
`T(58)
`
`00 0
`
`0
`
`0
`0
`
`IS (55)
`2 (I8)
`0
`0
`
`23 (61)
`6 (I6)
`5 ( I3)
`2(5)
`
`Lithium
`(N : S5)
`Unipolar Bipolar
`(N = 9)
`[N = 46)
`
`5 (56)
`3 (33)
`1 (ll)
`0
`
`12 (26)
`6 (13)
`4 (9)
`I (2)
`
`talization following the protocol-driven research phase.
`However, the partial correlation between discharge date
`and number of medications, controlling for length of
`hospital stay, was Still significant (r=0.36, df= 175,
`p < .00! ). The significance remained when controlling for
`rapid-cycling status (r = 0.32. (if: 159. p < .001). More-
`over, for statistical confirmation, a stepwise multiple re-
`gression analysis was performed evaluating the continu-
`ous variables such as age at discharge, age at illness onset,
`past hospitalizations for depression, length of NIMH hos-
`pitalization, and discharge date with number of discharge
`medications as the dependent variable. The only variable
`showing significance was discharge date (R2=0.182,
`t= 4.60, p < .0001).
`the mean number of
`By arbitrarily defined epochs,
`discharge medications
`for 1974-1979 was
`|.S;
`for
`1980-1984, 1.5; for l985—1989, 2.5; and for 1990-1995.
`
`3.0. The percentages of patients discharged on treatment
`with 3 or more medications in these same epochs were
`3.3%. 9.3%, 34.9%, and 43.8%, respectively. The degree
`of clinical global improvement on the CGI-BP was not
`correlated with the number of discharge medications
`fr : 0.09. p < .26; N = US).
`Table 1 summarizes the types of adjunctive discharge
`medication to 4 major mood stabilization treatment
`groups sequentially utilized (lithium. carbamazepine, di-
`valproex, and calcium channel blockers). Over the entire
`study period, for those patients who were discharged on
`treatment with a mood stabilizer (N: 123), adjunctive
`medications included conventional (or unimodal) antide-
`pressants (183%),
`thyroid supplementation (13.8%),
`neuroleptics (8.9%), benzodiazepines (2.4%), and cal~
`cium channel blockers (2.4%). In comparison with bi-
`polar patients discharged on treatment with fewer than 2
`medications, bipolar patients who were discharged on
`treatment with 2 or more medications were more likely to
`be rapid cyclers (Fisher exact test, p = .04). There was no
`difference in monotherapy versus polytherapy (i.e., 22
`medications) by gender, age at discharge, or age at illness
`onset. Remarkably.
`the unimodal antidepressants and
`
`12
`
`Figure 2. Earlier Onset of Symptoms in More Recent NIMH
`Cohorts
`
`I Bipolar Patient
`o Unipolar Patient
`
`' = "9-39
`rt -= -0001
`
`70"
`an -
`
`U1‘.3
`
`3-‘~0
`
`(.0
`
`
`
`AgeatFirstSymptoms
`
`19?1
`
`19?'6
`
`1935
`1981
`Discharge Date
`
`1991
`
`neuroleptics, while used as necessary when other agents
`were not effective, did not constitute a major portion
`of the discharge medications for this group of refractory
`patients.
`A number of NIMH-LCM retrospective demographic
`variables that might be related to the increasing use of
`polypharmacy were examined. When the age at onset of
`first mood symptoms was assessed, a significant decrease
`over time (r: -0.30, p < .0001: N = 160) was noted; i.e.,
`the patients more recently discharged from the NIMH re-
`ported earlier symptom onset than patients who were dis-
`charged earlier (Figure 2). Secondly, over the 22-year pe-
`riod.
`there was a concomitant pattern of increasing
`duration of lifetime weeks of depression experienced
`prior to NIMH hospitalization as a function of discharge
`date (r: 0.28, p -1.001; N = 138).
`There was also an increase in the percentage of rapid
`cyclers over the study period. In the 19703. rapid cyclers
`constituted 30% ofthe population; in the 19805, 56%; and
`in the 19905, 70% (xi: 14.66. p< .001). The rapid cy-
`clers, in comparison with non—rapid cyclers. had a longer
`
`J Clin Psychiatry 61:1, January 2000
`
`Alkermes Ex.
`
`4 of 7
`
`Alkermes, Ex. 1029
`
`

`
`duration of illness (t:2.86. df= ll6, p: .005), more
`past hospitalizations for depression (I = 2.05. df= 92.
`p = .04). and a trend for a greater number of medications
`at discharge {t = L74. df = 1 I9, p = .08).
`
`DISCUSSION
`
`Several assets and liabilities are apparent in the inter-
`pretation of this study. One of many liabilities of this study
`was that it was conducted in a research setting and im-
`provement was based only on status at discharge: confir-
`mation of more substantial and sustained clinical efficacy
`requires longer-term follow-up. which is in progress. Sec-
`ondly. there was no precise clinical algorithm under which
`all patients were treated. This option was precluded be-
`cause of the evolution in research focus and potential
`therapeutic agents evaluated over the study period. How-
`ever, after primary research evaluations and monotherapy
`protocols were completed, the general pattern was to tar-
`get current symptomatology in sequential. blinded mono-
`therapy and then use add-on clinical trials in an attempt to
`maximize mood stability on an individualized basis. This
`would be attempted using all prior information {i.e., retro-
`spective life chart) and the patient’s carefully observed
`course of illness at the NIMH. Although viewed as a limi-
`tation for development of a large-scale algorithm, the gen-
`eral use of sequential add-on clinical trials does, to some
`extent, parallel clinical practice, although in a blinded
`fashion. Finally, the potential implications that this unique
`treatment-refractory.
`increasingly rapid-cycling cohort
`has for the general population of patients in a practice set-
`ting must be cautiously and conservatively considered.
`One of the study assets was that virtually all of the
`medication trials were conducted on a double-blind basis.
`
`Secondly, clinical response to an initially blind protocol
`medication was often reconfirmed with a phase of pla-
`cebo substitution and rechallenge with the active agent.
`Thirdly. extensive life chart data were available on each
`patient, so that the likelihood of a placebo response or a
`response attributable to the natural course of illness could
`be factored into the clinical and research evaluations in
`
`further attempting to determine clinical improvement at
`discharge not likely related to spontaneous illness varia-
`tion. Finally,
`the primary research goal of the initial
`phases of study allowed for a more extended continuation
`of the blind evaluations that would not be possible in most
`clinical settings.
`Despite the liabilities noted above, several preliminary
`conclusions about the increasing need for combination
`treatment at discharge nevertheless can be drawn. The
`relatively low percentage in bipolar and unipolar patients
`of the use of adjunctive antidepressants (bipolar, 18%: uni-
`polar, 24%) and neuroleptics (bipolar. 10%: unipolar. 5%)
`in discharge regimens, despite a highly favorable overall
`improvement rate of 78%, was surprising. This is at vari-
`
`J Clin Psychiatry 61:], January 2000
`
`Polypharmacotherapy for Refractory Mood Disorders
`
`ance with most traditional clinical treatment units in which
`
`patients with acute mania or rapid cycling. under pressure
`of short-term hospitalizations. are almost uniformly ex-
`posed to and treated with neuroleptics. A recent review
`noted 40% to 72% of bipolar patients were currently
`treated with an antipsychotic and 90% to l00% had his-
`tory of neuroleptic exposure.” Secondly, as reviewed by
`Frye et al.,5' typical neuroleptics have significant liability
`for lack of mood stabilization, acute extrapyramidal symp-
`toms. and tardive dyskinesia in bipolar patients. In the
`course of exposing fulminantly manic patients to alterna-
`tive investigatory and now more routinely used agents
`such as carbamazepine and valproate, we uncovered this
`general lack of necessity for neuroleptic use even in this
`highly treatment-refractory rapid-cycling population.
`At the opposite pole, the potential liability of unimodal
`antidepressants to precipitate acute manic episodes or
`induce cycle acceleration in bipolar patients has been
`noted by many investigators.'l2‘5‘ Again, the vast majority
`of this unusually treatment-refractory population. over-
`represented with rapid cyclers compared with most com-
`munity settings, were able to be discharged without the
`use of conventional antidepressants. When conventional
`antidepressants were used, this was almost always in the
`context of one or more mood stabilizers.
`
`sequential pharmacotherapy and add-on ap-
`The
`proaches were utilized under the general rubric of using
`new agents with potentially different mechanisms of ac-
`tion, as well as specific targeting of remaining symptoms
`and illness patterns in an attempt to achieve a more robust
`or complete therapeutic effect, as discussed elsewhere.”
`It is our impression that these at times complex psycho-
`pharmacologic regimens were well tolerated because of
`the use of the principle of titrating to reach greatest eff-
`cacy with fewest side effects (rather than targeting spe-
`cific dose or blood level windows). These data thus do not
`
`directly address important issues regarding the potential
`for added toxicity, teratogenicity, or noncompliance with
`combination treatments.5‘5'5“
`
`Several possibilities could account for the observed
`need for increased multimodal medication regimens used
`at hospital discharge. This could be driven by (1) more
`clinical
`treatments available: (2) more extensive treat-
`
`ment of patients in the community prior to referral to the
`clinical research programs of the NIMH, such that cohorts
`of the more treatment—refractory patients were referred:
`(3) increased severity of illness due to a changing referral
`bias for earlier-onset rapid cyclers; andfor (4) an increas-
`ing severity or refractoriness of illness in the general
`population. such that the need for polypharmacotherapy
`was reflective of a similar trend in the community at
`iarge. The latter possibility cannot be dismissed altogether
`in light of the evidence for a cohort effect for unipolar and
`bipolar illnesssml attributable to a variety of potential
`causes, including genetic anticipation.“
`
`I3
`
`Alkermes Ex. 1
`
`5 of 7
`
`Alkermes, Ex. 1029
`
`

`
`Frye et al.
`
`What trends in the characteristics of this patient popu-
`lation are consistent with one or more of these possibili-
`ties? Over the study period, patients were admitted with a
`progressively earlier age at illness onset and an increased
`incidence of rapid cycling. Taken together, these data sug-
`gest that a generally more ill and treatment—rcfractory
`group based on course-of-illness characteristics were ad-
`mitted to the NIMH over the study period. Perhaps data
`on number of unsuccessful medication trials prior to
`NIMH referral over the study period would be most tell-
`ing about past treatment refractoriness. These data are not
`currently available in a systematic fashion, but it is our
`impression that bipolar patients referred to the NIMH
`were generally lithium refractory in the decade of the
`19705, lithium and carbamazepine refractory in the dec-
`ade of the 19803, and. in the 1990s, lithium. carbamaze-
`
`pine. and valproate refractory. This might suggest that pa-
`tients in recent cohorts were more extensively treated in
`the community prior to their referral to a tertiary clinical
`research unit such as the NIMH. Whatever the basis for
`
`the referral of the more ill patients. as inferred from their
`prior course-of-illness variables, there was a highly sig-
`nificant relationship of increased numbers of medications
`utilized in the more recently discharged patients (r = 0.45,
`p < .0001; N = 178}. This occurred while maintaining or
`slightly enhancing the overall degree of improvement
`achieved at discharge over the study period.
`
`It is particularly ‘disheartening to note that, aside from
`lithium, there are no FDA-approved agents for long-terrn
`prophylaxis of bipolar illness. Furthermore. there have
`been no recent attempts at approval of “add-on" drug
`regimens for the large group of refractory bipolar patients,
`whereas this has been the mode of approval for the last 4
`anticonvulsants for refractory epilepsy patients. More-
`over. few acute or long-term clinical trials in bipolar ill-
`ness have been funded by the NIMH in the past decade”;
`thus, bipolar patients not responsive to lithium and other
`commonly used therapies are treated prophylaetically,
`without the benefit and guidance of a systematic clinical
`trials literature.
`There are also no controlled studies of the relative mer-
`
`its of aggressive early-intervention polypharmacotherapy
`as opposed to the late salvage polypharmacotherapy de-
`scribed here. This is in marked contrast to polypharmaco—
`therapy in reducing human immunodeficiency viral load“
`or the clinical practice of combination chemotherapy for
`malignancy. Polypharmacotherapy may be an underuti-
`lized strategy for achieving maximal mood stability given
`the potential clinical and neurobiological consequences of
`an inadequately treated illness: i.e.. increased severity, cy-
`cling. and refractorinesss‘
`Although this retrospective study has many limitations
`(i.e., retrospective review,
`lack of precise algorithm or
`prospective follow-up data, and a treatment-refractory
`population screened for willingness to participate 'in
`
`14
`
`it does
`trials research}.
`neurobiological and clinical
`impart the great need for further studies in recurrent at"-
`fective illness to clarify the relationship of comorbidities
`and course-of-illness characteristics to the subsequent de-
`gree of polypharmacotherapy and long-term efficacy. In
`managing refractory mood disorders with complex poly-
`pharrnacotherapies, tolerability of agents needs to be vig-
`orously monitored to ensure safety and tolerability. espe-
`cially since complex regimens have been associated with
`noncompliance.”
`Given the increasing number of agents available in the
`bipolar and unipolar pharmacopoeia, controlled study of
`combination therapy (both “add—on“ and aggressive “at-
`onset" polypharmacotherapy) could only benefit the devel-
`opment of optimal and empirically based algorithms for
`achieving maximal mood stabilization in the large popu-
`lation of patients with difficu|t—lo—treat affective illness.
`
`Drug names.‘ carbamazepine (Tegrclol and others). divalprocx Mtdiurn
`(Depalcote). gahapentin (Neurontin),
`lamotriginc tLamieta|]. nimo-
`dipine (Nimotop), pimozidc lOrup).
`
`REFERENCES
`
`'
`
`. Bean RB, Osler Sirw. Aphorisms: From His Bedside Teaching and Writ-
`ings. Springfield. Ill: Charles C Thomas Publisher: |95l
`. Goodwin FK_ Jamison KR. M:tnic—Depressive lllness. New Yorlt, NY:
`Oxford University Press; 1990
`. Post RM, Ketter TA. Dcnicofi"K. et al. The place of anticonvulsant therapy
`in bipolar illness. Psychopharmacology {Bern |996;l 28,-l |S—l2’~)
`. Vestergaard P. Treatment and prevention of mania: :1 S£.':lI'I(llI1tI\'l:J.l1 per-
`spective. Ncuropsychopharmacology l992‘.'I:'.E49—2S9
`. Bowden CL. and the Depakole Mania Study Group. Ellicacy or dival-
`procx vs lithium and placebo in the treatment of mania. JAMA 199-i;2'i'I:
`9l8—92-1
`. Hirnmelhoch JM. Garfinkel ME. Mixed mania: diagnosis and treatment.
`Psychopharmacol Buil l9ll6;22:fi13—620
`. Dunner DL, Fieve RR. Clinical factors in lithium carbonate prophylaxis
`lailurc. Arch Gen Psychiatry l974:30:229-233
`. Faedda GL. Baldessarini RI. Tohen M, et al. Episode sequence in bipolar
`disorder and response to lithium treatment. Am J Psychiatry |99l:l-13:
`l1’37—| 239
`. O'Connell RA. Mayo IA, Fiutow L. et al. Outcome of bipolar disorder on
`long term treatment with lithium. Br] Psychiatry |99l:|59:l23—|29
`. Brady KT, Sonne SC. The relationship between substance abuse and hi-
`polur disorder. J Clin Psychiatry l995;5t‘i(suppl 3):l9-24
`. Tohen M. Waternaux CM. Tsuang MT. ct al. Four year follow-up of
`twenty—lour first episode titanic patients] Affect Disord I990: l9:T9—86
`. Sporn J, Sachs G. The anticonvulsant lamotrigine in treatment resistant
`manic depressive illness] Clin Psychopharrnacol I997: I T: I 85489
`_ Young LT. .1001: R. Gabttpentirt in bipolar depression: 21 case series. Biol
`Psychiatry l997:42:8Sl—853
`. Calabrese JR. Bowden CL. Mcl-Zlroy SL, et ul. Spectrum of activity of la-
`motriginc in treatment-refractory bipolar