Schizophrenia and Bipolar Disorder

Part 3: Recent Advances in the Treatment of Bipolar Disorder

First published in Psychiatry Weekly, March 3, 2008 

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.

Accreditation Statement

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council 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.

Credit Designation

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.

Faculty Disclosure Policy Statement

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices.

This activity has been peer reviewed and approved by Eric Hollander, MD, Professor of Psychiatry and Chair at Mount Sinai School of Medicine. Review Date: February 4, 2008

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 disorder.

Bipolar treatment research is advancing steadily. Genome research is becoming of increasing importance, as well as the exploration of brain size and structure, and neurotrophins.

Learning Objectives

• Explain the most significant aids and hindrances to successful treatment of bipolar disorder
• Explore the benefits and limitations of pharmacologic treatment
• Summarize current and upcoming treatment research

Target Audience

This activity will benefit psychiatrists, hospital staff physicians, and office-based “attending” physicians from the community.

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Eli Lilly and Company.

Faculty Disclosure

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, and Pfizer.

Peer Reviewer

Eric Hollander, MD, reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

To Receive Credit for this Activity

Read this poster, reflect on the information presented, and then complete the CME posttest found in the accompanying brochure or online (mbl.cmeoutreach.com). To obtain credit you should score 70% or better. The estimated time to complete this activity is 1 hour.

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 therapy.⁷

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 Options

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 disorders.¹⁰

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 profile.

Future Bipolar Disorder Treatments and Research: Mood Stabilizers

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 schizophrenia.¹⁷

Conclusion

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 psychosocial interventions.

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

References

1. Huxley NA, Parikh SV, Baldessarini RJ. Effectiveness of psychosocial treatments in bipolar disorder: state of the evidence. Harv Rev Psychiatry. 2000;8(3):126-140.

2. Fountoulakis KN, Vieta E, Siamouli M, et al. Treatment of bipolar disorder: a complex treatment for a multi-facet disorder. Ann Gen Psychiatry. 2007;6(1):27.

3. Sachs GS, Thase ME. Bipolar disorder therapeutics: maintenance treatment. Biol Psychiatry. 2000;48(6):573-581.

4. Perlis R. Review: adding second generation antipsychotics to mood stabilizers reduces acute mania symptoms. Evid Based Ment Health. 2007;10:111.

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 w.nami.org/Template.cfm? Section=By_Illness&Template=/TaggedPage/TaggedPa geDisplay.cfm&TPLID=54&ContentID=23037. 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. 2007;64(4):419-426.

8. Depression Bipolar Support Alliance. Available at: www.dbsalliance.org. Accessed on January 18, 2008.

9. Justo L, Soares B, Calil H. Family interventions for bipolar disorder. Cochrane Database Syst Rev. 2007;(4):CD005167.

10. Amann B, Grunze H, Vieta E, Trimble M. Antiepileptic drugs and mood stability. Clin EEG Neurosci. 2007;38(2):116-123.

11. Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the systematic treatment enhancement program for bipolar disorder (STEP-BD). Am J Psychiatry. 2006;163(2):217-224.

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 Med. 2005;353(12):1209-1223.

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. 2007;7(1):22-26.

17. Buckley PF, Mahadik S, Pillai A, Terry A Jr. Neurotrophins and schizophrenia. Schizophr Res. 2007;94(1-3):1-11.

To take the free, online CME posttest, go to cmeoutreach