Schizophrenia and Bipolar
Part 3: Recent Advances in the
Treatment of Bipolar Disorder
Peter F. Buckley, MD
Professor and Chairman, Department of Psychiatry, Medical
College of Georgia
First published in Psychiatry Weekly, March
This is the final installment of a three-part series
covering recent advances in diagnosis and treatment of
schizophrenia and bipolar disorder. The first installment covered the
etiology and diagnosis of both disorders, and the second feature focused on
the development of new treatment strategies for
schizophrenia and the importance of acute clinical
investigation of their outcomes.
activity has been planned and implemented in accordance
with the Essentials and Standards of the Accreditation
for Continuing Medical Education (ACCME) through the joint
sponsorship of the Mount
Sinai School of Medicine and MBL Communications, Inc. The
Mount Sinai School of
Medicine is accredited by the ACCME to provide continuing
medical education for physicians.
The Mount Sinai School of Medicine designates this
educational activity for a maximum of 1 AMA PRA
Category 1 Credit(s)™.
Physicians should only claim credit commensurate with the
extent of their participation in the activity.
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unapproved drugs or devices.
This activity has been peer reviewed and approved by
Eric Hollander, MD, Professor of Psychiatry and Chair at
School of Medicine. Review Date: February 4,
Statement of Need
Although medications are still foundational for
treatment of bipolar disorder, psychosocial, and other
counseling options, are very important to augment and
enhance the positive effects of medications. Strong family
and community support is critical for patients undergoing
treatment for bipolar disorder.
Many drugs are approved for the treatment, or
maintenance, of mood disorders. Lithium, for example, is
one of the oldest, and most frequently prescribed, mood-
stabilizing agent, although a common pathway or mechanism
of mood stabilizing drugs is not known. Other classes of
drugs, such as anticonvulsants, are undergoing investigation
to determine their efficacy as mood stabilizing agents. The
widespread practice of prescribing medications off-label for
mood disorders makes it critically important for clinicians to
be cognizant of what is—and is not—approved for use in
Bipolar treatment research is advancing steadily.
Genome research is becoming of increasing importance, as
well as the exploration of brain size and structure, and
- Explain the most significant aids and
hindrances to successful treatment of bipolar disorder
- Explore the benefits and limitations of
- Summarize current and upcoming
This activity will benefit psychiatrists, hospital staff
physicians, and office-based “attending”
from the community.
Acknowledgement of Commercial
This activity is supported by an educational grant from
Eli Lilly and Company.
Peter Buckley, MD, is a consultant
to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen,
Pfizer, Solvay, and Wyeth; receives grant/research support
from AstraZeneca, the National Institute of Mental Health,
Pfizer, Solvay, and Wyeth; and receives
honorarium/expenses from Bristol-Myers Squibb, Janssen,
Eric Hollander, MD, reports no
affiliation with or financial interest in any organization that
a conflict of interest.
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Release Date: March 3, 2008
Termination Date: March 31, 2010
Components of Bipolar Disorder Treatment
For bipolar disorder, a mainstay of treatment includes
use of medications in conjunction with psychosocial
interventions, which is similar to treatment approaches for
schizophrenia.1 With a stable mood,
psychosocial and other counseling options can assist patients
in mediating stressors that may contribute toward relapse,
reduce hospitalizations, and improve general functioning.
Without intervention, the likelihood that medication alone will
buffer against relapse is low, as is the likelihood that patients
will continue to take medication as prescribed for as long as
is necessary. A comprehensive approach works best.
Patients with bipolar disorder often abuse drugs—most
commonly, alcohol and marijuana, followed by cocaine and
other opiates. A relationship may exist in which reward
circuits in the brain may cause a higher propensity for
patients with mental illness to engage in drug abuse. The
effects of drug abuse for bipolar disorder patients include
more frequent and prolonged affective episodes, decreased
compliance with treatment, a lower quality of life, and
increased suicidal behavior.
The most commonly used medication for the treatment
of bipolar disorder is lithium, which is one of the oldest and
most frequently-used mood stabilizing drugs available.
Lithium has shown efficacy in the treatment of bipolar
disorder symptoms throughout the course of the illness and
may be particularly effective in preventing
suicide.2 A variety of anticonvulsants and anti
epilepsy medications, such as valproic acid and
carbamazepine, have also shown variable degrees of
efficacy in mood stabilization.3
Increasingly, clinicians have begun to use second-
generation antipsychotics, such as aripiprazole, olanzapine,
quetiapine, risperidone, and ziprasidone, for variable
degrees of mood stabilization.4,5 Many of
these drugs have been tested and are FDA-approved for
acute stabilization in the manic phases.6 Over
time, some of these medications have obtained indications
for and are being increasingly used in the maintenance
phase of the illness. However, it is also important to
recognize that many of these drugs do not have approval for
use in mood disorders, either in the acute or maintenance
phase of the illness. It is important that clinicians remain
aware of the approval status of these drugs, particularly as
off-label use of antipsychotics is strongly discouraged.
Some studies are examining medication/therapy
combination treatment of bipolar disorder, including a
variety of different treatment techniques. Among the
psychosocial and counseling options are general counseling
and support, focused CBT, and interpersonal
Although each of these therapy modalities have been
shown to be helpful in reducing relapse over time in patients
with bipolar disorder, researchers have not determined if
one option is better than another.7 What
researchers have concluded is that despite the type of
medication or counseling intervention, when medication is
used as the bedrock of treatment in order to achieve mood
stability in a patient and is combined with any psychological
therapy, the effect of the medication is boosted.
High levels of support are also extremely important for
patients with any mental illness including bipolar disorder.
Patient family, friends, and community are all key in helping
patients maintain a medication regimen, which, in turn,
better assures that the patient will improve. In addition, the
Depression Bipolar Support Alliance, which manages support
groups for patients with these disorders and creates
information literature on mental health, is an excellent
resource for patients.8 While researchers have
studied the effects of positive family and community
intervention for patients with mental illness, additional
studies are warranted to assess the types of interventions
that are most beneficial.9 Clinicians should
also work with patients with bipolar disorder on reentering
other areas of their lives also affected by their symptoms,
such as the work environment.
Pharmacology of Bipolar Disorder Treatment
The structure and function of various medications
continues to be an area of great interest and challenge for
researchers. There is no unified method of action for drugs
that treat mental health disorders, including bipolar disorder.
There is also not a single condition or mechanism that the
medications are counteracting or even a final common
pathway on which the medications are working.
For example, lithium is a very complex drug in that it
does not act directly on receptors and appears to have more
downstream effects on cells and metabolism.
Anticonvulsants may have selective effects on particular
neurotransmitters, particularly g-aminobutyric acid or
glutamate, but these drugs may also have effects in terms of
reducing excitability in epilepsy and altering second
messenger systems. If anticonvulsants, such as
carbamazepine, valproate, or lamotrigine, are used in
patients with mood disorders and, have similar treatment
effects for patients with mental health conditions, these
drugs may provide stabilization for patients with mood
Recognizing Medication Limitations
Clinicians often encounter patients who take medication
correctly but do not respond positively, and this result poses
a significant problem. Investigators at the National Institute
of Mental Health recently published results of two important
and large pragmatic trials: the Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD) and
CATIE.11,12 Researchers in the CATIE study
examined the use of antipsychotics in the treatment of
schizophrenia, while the STEP-BD study assessed patients
with bipolar disorder. Both studies showed that there are
limitations in current treatment in terms of effectiveness, the
ability of medication to treat target symptoms, and presence
of drug side effects.11 Because medications
are often not as effective as clinicians would like, many
patients are switched numerous times in order to find the
most effective treatment with the lowest side effect
Future Bipolar Disorder Treatments and Research:
Medications approved for the treatment of epilepsy may
be investigated by researchers for mood
stabilization.13 Newer antipsychotics are also
being investigated for mood stabilization properties both
alone and in combination with other mood stabilizers for an
additive effect. Add-on treatments have also been
investigated. An area that attracted much attention was
whether adding omega-3 fatty acids would boost response to
primary medication. This investigation was controversial and
did not pan out as originally promised.14
Although various add-on strategies have been
investigated (usually in small pilot studies), this is an area
where there is a lack of real evidence. Accordingly, clinicians
need to be extremely careful in off-label use of medications,
which is to be strongly discouraged and avoided. Moreover,
the promotion of medications for uses not formally approved
by the FDA is not acceptable. Thus, clinicians should remain
cognizant of what is, and even more importantly, what is not
approved for use in bipolar disorder.
Etiology and Pathophysiology Research
Genetics is now moving forward into the area of the
genome, in which researchers seek to find associations
between particular candidate genes. These genes may be
relevant for the metabolism of a neurotransmitter. In
addition, expression in patients with serious mental illness or
expression in relation to a particular aspect of illness are
also related to these genes. Beyond classical genetics,
association genetics works to tease out particular
abnormalities, and then examine protein expression.
Brain structure is another important area of research in
the understanding of bipolar disorder. Structural imaging of
patients with schizophrenia and bipolar disorder has
provided ample evidence that brain structure is altered in
patients with serious mental illness.15 These
findings are not robust enough to be found in the study of
one patient. However, this brain alteration is prevalent when
disorders are studied at a group level. Such changes in brain
structure may actually get worse over time, particularly in
patients who do not respond to medication.
There is also great interest in the role of neurotrophins
and neuroplasticity in bipolar disorder and in schizophrenia,
for example, brain derived neurotrophic factor (BDNF)
promotes cell development and synaptogenesis. Impaired
BDNF expression has been reported in mood disorders and
reduced BDNF has been associated with relapse of
depression.16 There is also evidence for
adnormalities of neurotrophins in
Although bipolar disorder and schizophrenia each
present with a varied and differing symptom profile, there
are some similarities in approaches to treatment for both
disorders. Treatment of schizophrenia and bipolar disorder
often include use of medications in conjunction with
Mood-stabilizing medications are typically used for
bipolar disorder treatment, while newer-generation
antipsychotics are often first-line treatment for
schizophrenia. Psychosocial therapies have been shown to
be effective when paired with appropriate medications for
both disorders. Ongoing research continues into mechanisms
of etiology and possible pathophysiology utilizing both
genetic and imaging techniques.
To take the free, online CME posttest, go to cmeoutreach
1. Huxley NA, Parikh SV, Baldessarini RJ.
Effectiveness of psychosocial treatments in bipolar disorder:
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2. Fountoulakis KN, Vieta E, Siamouli M, et al.
Treatment of bipolar disorder: a complex treatment for a
multi-facet disorder. Ann Gen Psychiatry.
3. Sachs GS, Thase ME. Bipolar disorder
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4. Perlis R. Review: adding second generation
antipsychotics to mood stabilizers reduces acute mania
symptoms. Evid Based Ment Health.
5. Surja AA, Tamas RL, El-Mallakh RS. Antipsychotic
medications in the treatment of bipolar disorder. Curr
Drug Targets. 2006;1217-1224.
6. National Alliance on Mental Illness. About Mental
Illness. Available at: ww
Accessed on December 18, 2007.
7. Miklowitz DJ, Otto MW, Frank E, et al.
Psychosocial treatments for bipolar depression: a 1-year
randomized trial from the Systematic Treatment
Enhancement Program. Arch Gen Psychiatry.
8. Depression Bipolar Support Alliance. Available at:
Accessed on January 18, 2008.
9. Justo L, Soares B, Calil H. Family interventions for
bipolar disorder. Cochrane Database Syst Rev.
10. Amann B, Grunze H, Vieta E, Trimble M.
Antiepileptic drugs and mood stability. Clin EEG
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of recurrence in bipolar disorder: primary outcomes from
the systematic treatment enhancement program for bipolar
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12. Lieberman JA, Stroup TS, McEvoy JP, et al, and
the Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE) Investigators. Effectiveness of antipsychotic drugs in
patients with chronic schizophrenia. N Engl J
13. Zaremba PD, Bialek M, Blaszczyk B, Cioczek P,
Czuczwar SJ. Non-epilepsy uses of antiepilepsy drugs.
Pharmacol Rep. 2006;58(1):1-12.
14. Chiu CC, Huang SY, Chen CC, Su KP. Omega-3
fatty acids are more beneficial in the depressive phase than
in the manic phase in patients with bipolar I disorder. J
Clin Psychiatry. 2005;66(12):1613-1614.
15. Yurgelun-Todd DA, Silveri MM, Gruber SA, Rohan
ML, Pimentel PJ. White matter abnormalities observed in
bipolar disorder: a diffusion tensor imaging study.
Bipolar Disord. 2007;9(5):504-512.
16. Shaltiel G, Chen G, Manji HK. Neurotrophic
signaling cascades in the pathophysiology and treatment of
bipolar disorder. Curr Opin Pharmacol.
17. Buckley PF, Mahadik S, Pillai A, Terry A Jr.
Neurotrophins and schizophrenia. Schizophr
To take the free, online CME posttest, go to cmeoutreach