Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue6.2000:
Treatment Advances in Bipolar Disorder—Making Up
for Lost Time
Much ground has been gained in recent years in improving
treatments for people with bipolar disorder. These exciting
developments are long overdue. As recently as 1993, only
one medication, lithium, was approved for the treatment of
this severe, recurrent illness. Psychotherapeutic strategies
had been either neglected or abandoned. Several factors
seem to have contributed to this protracted period of
therapeutic quiescence. First, lithium was presumed to be
an effective medication for most phases of bipolar disorder
for most patients. Clinical lore had long held that most
patients recovered fully from affective episodes and went
on to experience long periods of euthymia and good
functioning. Psychotherapeutic approaches were either
thought to be irrelevant in this biological illness or
appropriated willy-nilly from applications in other illnesses. Subsequent studies have shown that these beliefs
were seriously wrong. Only a minority of patients with
bipolar disorder experience the salutary effects of lithium
monotherapy (Maj 2000). Many patients have great difficulty returning to their previous level of functioning after
experiencing an affective episode, and recurrent episodes
can lead to permanent disability (Keck et al 1998). Bipolar
disorder was the sixth leading cause of disability worldwide in 1990 and, without further treatment advances, was
projected to remain so into this century (Murray and
Lopez 1996). The cost of this illness in human suffering is
profound and immeasurable (Coryell et al 1993). The
articles in this issue of Biological Psychiatry document
recent research efforts to gain ground in the struggle to
improve the lives of people with bipolar disorder.
The treatment of bipolar disorder is usually conceptualized as consisting of the acute treatment of affective
episodes (manic, mixed, and depressive) and prophylactic
treatment to prevent future episodes and eradicate interepisode or subsyndromal symptoms. That the role of medications in the treatment of all aspects of this illness is
crucial is beyond dispute. The role of specific forms of
psychotherapy, tailored to the unique needs of patients
with bipolar disorder, in the maintenance phase of treatment offers the promise of filling large gaps left by
straightforward pharmacotherapy.
The most significant advances in the pharmacologic
treatment of bipolar disorder have occurred in the
treatment of acute mania. This should not be surprising,
since mood-stabilizing medications have traditionally
been antimanic agents. In the last 6 years two medica© 2000 Society of Biological Psychiatry
tions, divalproex and olanzapine, have received approval in the United States for the treatment of acute
bipolar mania. Both medications also appear to fill a
treatment void in being equally effective in manic and
mixed episodes. Chlorpromazine, haloperidol, carbamazepine, risperidone, and ziprasidone have been efficacious in the treatment of acute bipolar mania in randomized, double-blind, controlled trials. Two major
groups of medications, the atypical antipsychotics
(quetiapine, aripiprazole, and iloperidone, in addition to
risperidone, olanzapine, and ziprasidone) and the new
antiepileptics (gabapentin, pregabalin, lamotrigine,
topiramate, tiagabine, oxcarbazepine, and zonisamide),
are being actively investigated as potential treatments
for bipolar disorder. The need for medications that act
quickly, are well tolerated, have efficacy in all components of the manic syndrome (mood, behavior, cognition, and psychosis), ameliorate mixed as well as manic
presentations, and can be parlayed into effective maintenance therapy remains substantial. Two recent studies
have shown that treatment with the combination of
risperidone (Sachs and Risperidone Study Group 1999)
or olanzapine (Tohen et al. 2000) and lithium or
divalproex is more effective than monotherapy with
lithium or divalproex in acute mania (with or without
psychosis). Although treatment of acute mania with an
antipsychotic and lithium or divalproex has been commonplace for years, these were the first studies to
actually demonstrate that such a strategy is more
effective than treatment with one agent alone.
The pharmacologic treatment of bipolar depression
remains vastly understudied. Two important placebocontrolled trials were concluded in the last several years
(Calabrese et al 1999; Nemeroff et al, in press);
however, many critical questions regarding the treatment of bipolar depression are unanswered. Although a
variety of antidepressants with novel mechanisms of
action and improved side effect profiles are available
(e.g., selective serotonin reuptake inhibitors, bupropion,
venlafaxine, nefazodone, mirtazapine) or in development (e.g., reboxetine, neurokinin 1 and corticotropinreleasing hormone antagonists), the vast majority of
these medications have not been systematically studied
in patients with bipolar depression. With the exception
of lamotrigine, the new antiepileptics and atypical
antipsychotics have not been studied in bipolar depres0006-3223/00/$20.00
PII S0006-3223(00)00990-2
Editorial
sion. This is a crucial area of study for these new
medications in order to determine whether they are bona
fide mood stabilizers. The optimal duration of antidepressant treatment (in conjunction with a mood stabilizer) balanced against the largely unknown probability
of switch induction in patients with bipolar I disorder is
also unclear from the available research. The pharmacologic treatment of bipolar II disorder has been the
most neglected. Remarkably, it is still not clear whether
treatment with a mood stabilizer (as opposed to antidepressant treatment alone) is necessary for many of these
patients.
Research regarding the prophylactic treatment of
bipolar disorder has been dormant for many years. In
addition, the efficacy of new psychotropic medications
as long-term mood stabilizers has been very difficult to
study in recent times; however, this is perhaps the most
important aspect of the pharmacologic treatment of this
recurrent illness (i.e., the development of well-tolerated
medications with staying power over the long haul).
Maintenance studies of lithium, divalproex, and carbamazepine indicate that these agents possess efficacy
in this phase of illness management, but that only a
minority of patients do well with treatment with any one
of these agents alone. Although combinations of mood
stabilizers and of antipsychotics and mood stabilizers
are commonly used in maintenance treatment, such
strategies have not yet been shown to be efficacious in
rigorous studies. Similarly, when a combination of an
antipsychotic and a mood stabilizer is used to treat acute
mania, there are no data to indicate when to taper and
discontinue the antipsychotic following resolution of
the acute episode. Although olanzapine received an
indication for the treatment of acute mania, its efficacy
as a maintenance treatment has not been established.
Some evidence suggests that, unlike typical antipsychotics, some of the atypical agents possess antidepressant properties, perhaps by virtue of their serotonin2
antagonist effects. If these antidepressant effects are
borne out in clinical trials, they may thus have bidirectional (antimanic and antidepressant) thymoleptic effects, in short, mood-stabilizing properties.
As Frank et al (2000) note in their article, “sustained
euthymia in bipolar disorder may remain an elusive goal
in the absence of sophisticated treatments that address
both the biological and psychological aspects of this
disorder.” In developing interpersonal and social
rhythm therapy (IPSRT), they have devised one of the
few psychotherapeutic strategies based on theoretical
and empirical findings regarding factors that influence
the course of bipolar disorder. This effort marks the first
time that a manual-based form of individual psychotherapy intended to address multiple aspects of bipolar
BIOL PSYCHIATRY
2000;48:430 – 432
431
disorder (prevention of manic, mixed, and depressive
episodes; enhancement of treatment compliance) has
been studied prospectively in a large, long-term randomized trial. Although the data presented are only
preliminary findings, they are intriguing. First, only
23% of patients who entered the preventative phase of
treatment entered on lithium alone, although lithium
monotherapy was the pharmacologic treatment goal.
Second, IPSRT helped patients achieve more stable
social rhythms. Third, an association between social
rhythm disruption and onset of manic episodes was
apparent. Finally, changes in treatment in general increased the risk of relapse, and the loss of IPSRT, in
particular, increased the risk of depressive relapse. Data
from the completion of this study should provide
important answers regarding the impact of this form of
psychotherapy on the course of bipolar disorder.
Miklowitz et al (2000) attempted to improve the
outcome of patients with bipolar I disorder using a
different approach that also combined the effects of
psychotherapy and pharmacotherapy. This randomized,
9-month, controlled trial compared manual-based family-focused psychoeducational treatment (FFT) with
treatment as usual in patients recovering from an acute
affective episode. This strategy is particularly targeted
at the immediate postillness aftercare period, a time of
heightened vulnerability to relapse and keen importance
in facilitating rehabilitation. The results of this study
suggest that FFT provided greater preventative benefit
than treatment as usual for depressive episodes. The
results also raised a number of interesting questions for
further study, including whether the prophylactic effects of FFT endure beyond the period of participation,
and whether these effects are as significant when
compared with a control form of psychotherapy
matched for amount and intensity of contact.
Overall, a number of unanswered fundamental questions regarding the treatment of patients with bipolar
disorder remain. Primarily the pharmaceutical industry
and private foundations have driven recent pharmacologic
treatment advances. Two major initiatives undertaken in
the late 1990s, the Stanley Foundation Bipolar Network
(Leverich et al, in press) and the NIMH Bipolar STEP
Network (Sachs et al 2000) should help make up for lost
time in improving treatments for people with bipolar
disorder.
Paul E. Keck, Jr
Biological Psychiatry Program
Department of Psychiatry
University of Cincinnati College of Medicine
231 Bethesda Avenue
P.O. Box 670559
Cincinnati OH 45267-0559
432
BIOL PSYCHIATRY
2000;48:430 – 432
References
Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E,
Rudd GD (1999): A double-blind placebo-controlled study of
lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry 60:79 – 88.
Coryell W, Scheftner W, Keller M, Endicott J, Maser J, Klerman
GL (1993): The enduring psychosocial consequences of
mania and depression. Am J Psychiatry 150:720 –727.
Frank E, Swartz HA, Kupfer DJ (2000): Interpersonal and social
rhythm therapy: Managing the chaos of bipolar disorder. Biol
Psychiatry 48:593– 604.
Keck PE Jr, McElroy SL, Strakowski SM, West SA, Sax KW,
Hawkins JM, et al. (1998): Twelve-month outcome of bipolar
patients following hospitalization for a manic or mixed
episode. Am J Psychiatry 155:646 – 652.
Leverich GS, Nolen W, Rush AJ, McElroy SL, Keck PE Jr,
Denicoff KD, et al (in press): The Stanley Foundation Bipolar
Treatment Outcome Network: I. Longitudinal methodology. J
Affect Disord.
Maj M (2000): The impact of lithium prophylaxis on the course
of bipolar disorder: A review of the research evidence.
Bipolar Disord 2:93–101.
Miklowitz DJ, Simoneau TL, George EL, Richards JA, Kalbag
A, Sachs-Ericsson N, Suddath R (2000): Family-focused
Editorial
treatment of bipolar disorder: 1-year effects of a psychoeducational program in conjunction with pharmacotherapy. Biol
Psychiatry 48:582–592.
Murray CJL, Lopez AD (1996): The Global Burden of Disease
Summary. Cambridge, MA: Harvard School of Public Health.
Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL,
Gergel IP (in press): A double-blind, placebo-controlled
comparison of imipramine and paroxetine in the treatment of
bipolar depression. Am J Psychiatry.
Sachs GS, Risperidone Study Group (1999, December):
Safety and efficacy of risperidone vs placebo as add-on
therapy to mood stabilizers in the treatment of manic phase
of bipolar disorder. Abstract presented at the 38th annual
meeting of the American College of Neuropsychopharmacology, Acapulco.
Sachs GS, Thase ME, Leahy L, Gaughan SR, Lavori P, Conley
J, et al (2000, May): The Systematic Treatment Enhancement
Program for Bipolar Disorder. Abstract presented at the
annual meeting of the American Psychiatric Association,
Chicago.
Tohen M, Jacobs TG, Meyers TM, Risser RC, Keeter EL, Breier
PD (2000, May): Efficacy of olanzapine combined with mood
stabilizers in the treatment of bipolar disorder. Abstract
presented at the annual meeting of the American Psychiatric
Association, Chicago.
for Lost Time
Much ground has been gained in recent years in improving
treatments for people with bipolar disorder. These exciting
developments are long overdue. As recently as 1993, only
one medication, lithium, was approved for the treatment of
this severe, recurrent illness. Psychotherapeutic strategies
had been either neglected or abandoned. Several factors
seem to have contributed to this protracted period of
therapeutic quiescence. First, lithium was presumed to be
an effective medication for most phases of bipolar disorder
for most patients. Clinical lore had long held that most
patients recovered fully from affective episodes and went
on to experience long periods of euthymia and good
functioning. Psychotherapeutic approaches were either
thought to be irrelevant in this biological illness or
appropriated willy-nilly from applications in other illnesses. Subsequent studies have shown that these beliefs
were seriously wrong. Only a minority of patients with
bipolar disorder experience the salutary effects of lithium
monotherapy (Maj 2000). Many patients have great difficulty returning to their previous level of functioning after
experiencing an affective episode, and recurrent episodes
can lead to permanent disability (Keck et al 1998). Bipolar
disorder was the sixth leading cause of disability worldwide in 1990 and, without further treatment advances, was
projected to remain so into this century (Murray and
Lopez 1996). The cost of this illness in human suffering is
profound and immeasurable (Coryell et al 1993). The
articles in this issue of Biological Psychiatry document
recent research efforts to gain ground in the struggle to
improve the lives of people with bipolar disorder.
The treatment of bipolar disorder is usually conceptualized as consisting of the acute treatment of affective
episodes (manic, mixed, and depressive) and prophylactic
treatment to prevent future episodes and eradicate interepisode or subsyndromal symptoms. That the role of medications in the treatment of all aspects of this illness is
crucial is beyond dispute. The role of specific forms of
psychotherapy, tailored to the unique needs of patients
with bipolar disorder, in the maintenance phase of treatment offers the promise of filling large gaps left by
straightforward pharmacotherapy.
The most significant advances in the pharmacologic
treatment of bipolar disorder have occurred in the
treatment of acute mania. This should not be surprising,
since mood-stabilizing medications have traditionally
been antimanic agents. In the last 6 years two medica© 2000 Society of Biological Psychiatry
tions, divalproex and olanzapine, have received approval in the United States for the treatment of acute
bipolar mania. Both medications also appear to fill a
treatment void in being equally effective in manic and
mixed episodes. Chlorpromazine, haloperidol, carbamazepine, risperidone, and ziprasidone have been efficacious in the treatment of acute bipolar mania in randomized, double-blind, controlled trials. Two major
groups of medications, the atypical antipsychotics
(quetiapine, aripiprazole, and iloperidone, in addition to
risperidone, olanzapine, and ziprasidone) and the new
antiepileptics (gabapentin, pregabalin, lamotrigine,
topiramate, tiagabine, oxcarbazepine, and zonisamide),
are being actively investigated as potential treatments
for bipolar disorder. The need for medications that act
quickly, are well tolerated, have efficacy in all components of the manic syndrome (mood, behavior, cognition, and psychosis), ameliorate mixed as well as manic
presentations, and can be parlayed into effective maintenance therapy remains substantial. Two recent studies
have shown that treatment with the combination of
risperidone (Sachs and Risperidone Study Group 1999)
or olanzapine (Tohen et al. 2000) and lithium or
divalproex is more effective than monotherapy with
lithium or divalproex in acute mania (with or without
psychosis). Although treatment of acute mania with an
antipsychotic and lithium or divalproex has been commonplace for years, these were the first studies to
actually demonstrate that such a strategy is more
effective than treatment with one agent alone.
The pharmacologic treatment of bipolar depression
remains vastly understudied. Two important placebocontrolled trials were concluded in the last several years
(Calabrese et al 1999; Nemeroff et al, in press);
however, many critical questions regarding the treatment of bipolar depression are unanswered. Although a
variety of antidepressants with novel mechanisms of
action and improved side effect profiles are available
(e.g., selective serotonin reuptake inhibitors, bupropion,
venlafaxine, nefazodone, mirtazapine) or in development (e.g., reboxetine, neurokinin 1 and corticotropinreleasing hormone antagonists), the vast majority of
these medications have not been systematically studied
in patients with bipolar depression. With the exception
of lamotrigine, the new antiepileptics and atypical
antipsychotics have not been studied in bipolar depres0006-3223/00/$20.00
PII S0006-3223(00)00990-2
Editorial
sion. This is a crucial area of study for these new
medications in order to determine whether they are bona
fide mood stabilizers. The optimal duration of antidepressant treatment (in conjunction with a mood stabilizer) balanced against the largely unknown probability
of switch induction in patients with bipolar I disorder is
also unclear from the available research. The pharmacologic treatment of bipolar II disorder has been the
most neglected. Remarkably, it is still not clear whether
treatment with a mood stabilizer (as opposed to antidepressant treatment alone) is necessary for many of these
patients.
Research regarding the prophylactic treatment of
bipolar disorder has been dormant for many years. In
addition, the efficacy of new psychotropic medications
as long-term mood stabilizers has been very difficult to
study in recent times; however, this is perhaps the most
important aspect of the pharmacologic treatment of this
recurrent illness (i.e., the development of well-tolerated
medications with staying power over the long haul).
Maintenance studies of lithium, divalproex, and carbamazepine indicate that these agents possess efficacy
in this phase of illness management, but that only a
minority of patients do well with treatment with any one
of these agents alone. Although combinations of mood
stabilizers and of antipsychotics and mood stabilizers
are commonly used in maintenance treatment, such
strategies have not yet been shown to be efficacious in
rigorous studies. Similarly, when a combination of an
antipsychotic and a mood stabilizer is used to treat acute
mania, there are no data to indicate when to taper and
discontinue the antipsychotic following resolution of
the acute episode. Although olanzapine received an
indication for the treatment of acute mania, its efficacy
as a maintenance treatment has not been established.
Some evidence suggests that, unlike typical antipsychotics, some of the atypical agents possess antidepressant properties, perhaps by virtue of their serotonin2
antagonist effects. If these antidepressant effects are
borne out in clinical trials, they may thus have bidirectional (antimanic and antidepressant) thymoleptic effects, in short, mood-stabilizing properties.
As Frank et al (2000) note in their article, “sustained
euthymia in bipolar disorder may remain an elusive goal
in the absence of sophisticated treatments that address
both the biological and psychological aspects of this
disorder.” In developing interpersonal and social
rhythm therapy (IPSRT), they have devised one of the
few psychotherapeutic strategies based on theoretical
and empirical findings regarding factors that influence
the course of bipolar disorder. This effort marks the first
time that a manual-based form of individual psychotherapy intended to address multiple aspects of bipolar
BIOL PSYCHIATRY
2000;48:430 – 432
431
disorder (prevention of manic, mixed, and depressive
episodes; enhancement of treatment compliance) has
been studied prospectively in a large, long-term randomized trial. Although the data presented are only
preliminary findings, they are intriguing. First, only
23% of patients who entered the preventative phase of
treatment entered on lithium alone, although lithium
monotherapy was the pharmacologic treatment goal.
Second, IPSRT helped patients achieve more stable
social rhythms. Third, an association between social
rhythm disruption and onset of manic episodes was
apparent. Finally, changes in treatment in general increased the risk of relapse, and the loss of IPSRT, in
particular, increased the risk of depressive relapse. Data
from the completion of this study should provide
important answers regarding the impact of this form of
psychotherapy on the course of bipolar disorder.
Miklowitz et al (2000) attempted to improve the
outcome of patients with bipolar I disorder using a
different approach that also combined the effects of
psychotherapy and pharmacotherapy. This randomized,
9-month, controlled trial compared manual-based family-focused psychoeducational treatment (FFT) with
treatment as usual in patients recovering from an acute
affective episode. This strategy is particularly targeted
at the immediate postillness aftercare period, a time of
heightened vulnerability to relapse and keen importance
in facilitating rehabilitation. The results of this study
suggest that FFT provided greater preventative benefit
than treatment as usual for depressive episodes. The
results also raised a number of interesting questions for
further study, including whether the prophylactic effects of FFT endure beyond the period of participation,
and whether these effects are as significant when
compared with a control form of psychotherapy
matched for amount and intensity of contact.
Overall, a number of unanswered fundamental questions regarding the treatment of patients with bipolar
disorder remain. Primarily the pharmaceutical industry
and private foundations have driven recent pharmacologic
treatment advances. Two major initiatives undertaken in
the late 1990s, the Stanley Foundation Bipolar Network
(Leverich et al, in press) and the NIMH Bipolar STEP
Network (Sachs et al 2000) should help make up for lost
time in improving treatments for people with bipolar
disorder.
Paul E. Keck, Jr
Biological Psychiatry Program
Department of Psychiatry
University of Cincinnati College of Medicine
231 Bethesda Avenue
P.O. Box 670559
Cincinnati OH 45267-0559
432
BIOL PSYCHIATRY
2000;48:430 – 432
References
Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E,
Rudd GD (1999): A double-blind placebo-controlled study of
lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry 60:79 – 88.
Coryell W, Scheftner W, Keller M, Endicott J, Maser J, Klerman
GL (1993): The enduring psychosocial consequences of
mania and depression. Am J Psychiatry 150:720 –727.
Frank E, Swartz HA, Kupfer DJ (2000): Interpersonal and social
rhythm therapy: Managing the chaos of bipolar disorder. Biol
Psychiatry 48:593– 604.
Keck PE Jr, McElroy SL, Strakowski SM, West SA, Sax KW,
Hawkins JM, et al. (1998): Twelve-month outcome of bipolar
patients following hospitalization for a manic or mixed
episode. Am J Psychiatry 155:646 – 652.
Leverich GS, Nolen W, Rush AJ, McElroy SL, Keck PE Jr,
Denicoff KD, et al (in press): The Stanley Foundation Bipolar
Treatment Outcome Network: I. Longitudinal methodology. J
Affect Disord.
Maj M (2000): The impact of lithium prophylaxis on the course
of bipolar disorder: A review of the research evidence.
Bipolar Disord 2:93–101.
Miklowitz DJ, Simoneau TL, George EL, Richards JA, Kalbag
A, Sachs-Ericsson N, Suddath R (2000): Family-focused
Editorial
treatment of bipolar disorder: 1-year effects of a psychoeducational program in conjunction with pharmacotherapy. Biol
Psychiatry 48:582–592.
Murray CJL, Lopez AD (1996): The Global Burden of Disease
Summary. Cambridge, MA: Harvard School of Public Health.
Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL,
Gergel IP (in press): A double-blind, placebo-controlled
comparison of imipramine and paroxetine in the treatment of
bipolar depression. Am J Psychiatry.
Sachs GS, Risperidone Study Group (1999, December):
Safety and efficacy of risperidone vs placebo as add-on
therapy to mood stabilizers in the treatment of manic phase
of bipolar disorder. Abstract presented at the 38th annual
meeting of the American College of Neuropsychopharmacology, Acapulco.
Sachs GS, Thase ME, Leahy L, Gaughan SR, Lavori P, Conley
J, et al (2000, May): The Systematic Treatment Enhancement
Program for Bipolar Disorder. Abstract presented at the
annual meeting of the American Psychiatric Association,
Chicago.
Tohen M, Jacobs TG, Meyers TM, Risser RC, Keeter EL, Breier
PD (2000, May): Efficacy of olanzapine combined with mood
stabilizers in the treatment of bipolar disorder. Abstract
presented at the annual meeting of the American Psychiatric
Association, Chicago.