Decreased Brain-Derived Neurotrophic Factor (BDNF ...

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Brain-derived neurotrophic factor (BDNF) is part of the family of neurotrophic factors and is widely expressed in the human brain. BDNF is involved in.

Decreased Brain-Derived Neurotrophic Factor (BDNF) in Older Adults with Bipolar Disorder: Meaning and Utility? Breno S. Diniz, M.D., Ph.D.

rain-derived neurotrophic factor (BDNF) is part of the family of neurotrophic factors and is widely expressed in the human brain. BDNF is involved in many neuronal physiological functions, including synaptic plasticity and remodeling, axonal guidance, induction of long-term potentiation, modulation of gene expression, and resilience to neuronal insults.1 Given its relevance to the maintenance of neuronal functioning, several studies have now investigated its role in the physiopathology of mood disorders. There is consistent evidence that BDNF levels are reduced in patients with major depressive disorder, both in younger and older adults. 2,3 In older adults with late-life depression, lower cerebrospinal fluid and peripheral levels of BDNF are further associated with mild cognitive impairment, independent of the presence of Alzheimer disease pathology.4 Despite some mixed results, bipolar disorder patients, during euthymia, manic, or depressive episodes, also show significant reductions in peripheral BDNF levels when compared with age-matched healthy controls.5 The study from Soares and collaborators6 adds relevant information and expands our understanding of the role of BDNF in late-life mood disorders. The investigators found that euthymic older adults with bipolar disorder, in particular those with bipolar disorder type 1, have significantly lower levels of BDNF compared with healthy, age- and sex-matched controls. Interestingly, BDNF levels of BD type 2 patients

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were not significantly different from controls. This study is the first to focus on BDNF changes in late-life bipolar disorder and to shed light on the relevance of neurotrophic support in its pathophysiology. Despite the importance and originality of the data presented by Soares and collaborators, there remain many unanswered questions about the role and significance of measuring peripheral BDNF levels in our patients. These issues can be posed in three broad questions: 1) Do BDNF measures have diagnostic value for latelife psychiatric disorders? 2) Can the BDNF system be a therapeutic target or be helpful to monitor the effect of treatment? 3) What do “low BDNF levels” represent? The answers to these questions can put the results from Soares and collaborators in a broader perspective to guide clinical decision-making and future research on the topic.

DO BDNF MEASURES HAVE DIAGNOSTIC VALUE FOR LATE-LIFE PSYCHIATRIC DISORDERS? The short answer is no. The measurement of peripheral BDNF levels has low sensitivity and specificity for the diagnosis of BD in older adults. First, BDNF level reduction is nonspecific and can be found in other

Received March 9, 2016; accepted March 9, 2016. From the Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX. e-mail: [email protected] Conflict of interest: The author has no conflict of interest related to this work. © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jagp.2016.03.003

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Diniz psychiatric and neurologic disorders. For example, adults and older patients with unipolar major depressive episode, with acute bipolar depression, acute mania, and Alzheimer disease also present low BDNF levels compared with healthy controls. Second, BDNF levels have high variability, with substantial overlap in values between patients and controls. Finally, there is neither a standardized laboratory protocol for its analysis nor population-based norms for BDNF levels in young and older adults. These factors preclude the use of BDNF as a diagnostic marker for psychiatric disorders.

CAN THE BDNF LEVELS BE HELPFUL TO MONITOR THE EFFECT OF TREATMENT? The short answer is maybe. Many studies have shown that antidepressants (e.g., selective serotonin reuptake inhibitors) and mood stabilizers (e.g., lithium and valproic acid) can increase the levels of BDNF in patients with mood disorders.7 Higher levels of BDNF are usually accompanied by improvement in depressive or manic symptoms. BDNF levels also provide prognostic information in predicting faster cognitive decline in late-life depression and progression from mild cognitive impairment to Alzheimer disease in older adults. Nonetheless, such findings are limited by studies with a small number of participants, or post-hoc analysis of clinical trials that were not designed or powered to evaluate the prognostic value of BDNF as a marker of antidepressant or anti-manic treatment.

WHAT DO “LOW BDNF LEVELS” REPRESENT? Because BDNF is ubiquitous in the maintenance of normal neuronal functioning and resilience against brain insults, the observation that BDNF is reduced in distinct psychiatric disorders is not unexpected. Within this perspective, the BDNF levels can be viewed as a nonspecific marker of brain health, instead of a marker of specific disease processes. That is, low BDNF levels in psychiatric disorders would indicate that a patient has more severe pathophysiological process or is more vulnerable to neuronal insults. The concept of markers of a system / organ health is common in other areas of medicine. For example, internal medicine physicians measure serum creatinine level to determine renal function. But creatinine level is nonspecific to underlying pathophysiological process and can be altered in different conditions (e.g., high blood pressure, diabetes, or renal infection). The study from Soares and collaborators expands our understanding of the physiopathology of bipolar disorder in older adults and about the role of BDNF in distinct psychiatric disorders across the lifespan. Although BDNF is not a suitable marker for diagnosis purposes, it can be useful for monitoring treatment outcomes or even as a general marker of brain health. We need well-designed and adequately powered studies to evaluate its usefulness for these goals, however. Finally, other significant obstacles need to be overcome before its widespread use—in particular, the need for standardized laboratory protocols and population norms for measuring BDNF levels.

References 1. Teixeira AL, Barbosa IG, Diniz BS, et al: Circulating levels of brainderived neurotrophic factor: correlation with mood, cognition and motor function. Biomark Med 2010; 4:871–887 2. Diniz BS, Reynolds CF 3rd, Begley A, et al: Brain-derived neurotrophic factor levels in late-life depression and comorbid mild cognitive impairment: a longitudinal study. J Psychiatr Res 2014; 49:96–101 3. Brunoni AR, Lopes M, Fregni F: A systematic review and metaanalysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 2008; 11:1169–1180 4. Diniz BS, Teixeira AL, Machado-Vieira R, et al: Reduced cerebrospinal fluid levels of brain-derived neurotrophic factor is associated

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with cognitive impairment in late-life major depression. J Gerontol B Psychol Sci Soc Sci 2014; 69:845–851 5. Fernandes BS, Molendijk ML, Köhler CA, et al: Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. BMC Med 2015; 13: 289 6. Soares AT, Andreazza AC, Rej S, et al: Decreased Brain-Derived Neurotrophic Factor (BDNF) in older adults with bipolar disorder. Am J Geriatr Psychiatry 2016; doi:10.1016/j.jagp.2016.02.052 7. Polyakova M, Stuke K, Schuemberg K, et al: BDNF as a biomarker for successful treatment of mood disorders: a systematic and quantitative meta-analysis. J Affect Disord 2015; 174:432–440

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