Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients

2. Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients Amanda Henke 10/30/09

3. Bipolar Disorder Onset between ages typically 15-30 Childhood BD more common with advances in diagnosis - 1% of children estimated lifetime cost: (Begley et al., 2001) $11,720 for patients with a single manic episode $624,785 for patients with nonresponsive/ chronic episodes Often un-diagnosed for about 10 years, causing damage to life and brain (Ghaemi, 2001)

4. Manic Phase symptoms Elevated or irritable mood with 3-4 of the following: Decreased sleep Decreased appetite Grandiosity Distractibility Engage excessively in pleasurable, yet harmful activities Spending sprees Sexual promiscuity Foolish business ventures Flight of ideas Agitation

5. Depressive Phase Symptoms Sadness Hopelessness Suicidal thoughts or behavior Anxiety Guilt Sleep problems Appetite problems Fatigue Loss of interest in daily activities Problems concentrating Irritability Chronic pain without a known cause

6. Diagnosis Type depends on length of manic episode severity of manic episode Number of cycles Depression is 3x more common 1.2–1.5% of population diagnosed, yet estimated as many as 6% are bipolar Don’t seek treatment Condition mistaken for depression Symptoms don’t meet current diagnostic criteria

7. Types Bipolar I Disorder At least one manic episode lasting at least one week, with or without previous episodes of depression Severe episodes of mania or depression may result in psychosis Bipolar II disorder At least one episode of depression and one episode of hypomania much briefer (few days) elevated mood, irritability and some changes in functioning

8. Other Types Cyclothymia Mild form with mood swings, but with highs and lows not as severe for at least 2 years Rapid cycling Four or more mood swings within 12 months- mood shifts can occur within hours 10-20% of bipolar disorders Mixed state Symptoms of mania and depression occur simultaneously or in rapid sequence

9. Comorbid medical conditions Smoking and substance abuse Obesity and diabetes - often caused by therapy Sleep apnea and OCD can confound the presentation The suicide rate is 5–17 fold higher than in general population lifetime risk of 10% to 20%

10. Risk Factors Biological 80 to 90% of those who suffer from BP have relatives with some form of depression Val66Met SNP in BDNF gene Environment - Identical twin studies Periods of high stress Drug abuse Major life changes / significant loss Low self-esteem Childhood maltreatment

11. Medications Typical regiment mood stabilizers – stop mood swings, manic Anticonvulsants – stop mood swings, rapid cycling Antidepressants – semi-controversial, use in combination Atypical Antipsychotics – severe mania/ psychosis hypnotic benzodiazepines – anxiety agents used as monotherapy do not produce longterm responses, with low patient compliance rational polypharmacy - adding a drug for a specific symptom as it appears

12. Quick Review… Enlargement of the 3rd and lateral ventricles Reduced gray matter – orbital & medial PFC, ventral striatum, mesotemporal cortex Increased amygdala size, activity & dysfunction Reduced hippocampal volume during adolescence Cognitive impairment, related to the severity and duration of illness, and number manic episodes

13. BDNF Refresher! Brain-derived neurotrpic factor Functions: Neuronal development & survival Membrane potential Synaptic plasticity & strength Neuronal connectivity Dendritic arborization Controls 5-HT, DA and Glu systems Effects are region specific Result: Affect learning and memory (cognition) Alter information processing ? mood disorder

14. BDNF and Cognition High BDNF levels in cerebral cortex and hippocampus Regulate learning, memory and emotion Mice deficient in BDNF or TrkB - poor performance in Morris water maze Impairment is rescued with BDNF

15. Val66met SNP Single Nucleotide Polymorphism of valine for methionine at codon 66 disrupts proBDNF-sortilin interaction in Golgi (Chen et al., 2006) Reduces BDNF secretion Occurs in 20 to 30% in Caucasian populations Impaired cognitive performance (Rybakowski et al., 2003 ) Increased risk of rapid cycling (Muller et al., 2006) Better responders to lithium prophylaxis

16. BDNF & Stress Sorted & regulated in response to activity, not via a constitutive pathway Experience-dependent (i.e. stress) Numerous studies document stress decreases BDNF (Martinowich et al., 2007 review) Prenatal conditions decrease BDNF in hippocampus Maternal separation animal model – decreased BDNF History of trauma – lower BDNF (see above)

17. BDNF & Stress BDNF expression regulated by stress-responsive corticosteroids BDNF met/met polymorphism ? higher HPA activity Chronic stress ? alterations in hippocampus, amygdala, and PFC BDNF as a mediator of stress and mood disorders

18. BDNF and medications Studies have shown that after the administration of the following medications can increase BDNF levels: Antidepressants Mood stabilizers Atypical antipsychotics However, studies are mixed on whether BDNF signaling is the direct pharmacological target

19. Serum BDNF is decreased in bipolar disorder during depressive and manic episodes Cunha et al. 2006

20. Methods Patients recruited were diagnosed using SCID-I Only Bipolar I Disorder patients were used Symptoms assessed using: YMRS for mania HDRS for depression Considered euthymic if scored <7 on both scales Controls matched for: Age, Gender, Education Also, controls were: Non-smokers Not on medication No history of major psychiatric disorders, dementia, mental retardation, cancer or tumor in their 1st degree relatives

23. Testing BDNF levels BDNF measured in blood serum samples BDNF can cross BBB R=0.81 between serum and cortical levels (Karege et al., 2002) Non-CNS sources for BDNF= platelets, lymphocytes & vascular endothelial cells Sandwich-ELISA

24. Results BDNF lower in BP patients compared to healthy controls and euthymic patients: Manic (p=0.019) Depressed (p=0.027) BDNF levels ? mood stabilization?

25. Results BDNF serum level negatively correlated with score: YMRS (r=-0.37, p=0.005) HDRS (r=-0.30, p=0.033) Does BDNF level dictate mood state?

26. Conclusions BDNF serum is decreased in BD patients in manic and depressive phases Euthymic BD patients’ ~ control subjects’ BDNF level BDNF level could be related to mood? Limitations: Serum level BDNF Patients taking medication

27. Decreased BDNF in medicated and drug-free bipolar patients Oliveira et al. 2009

28. 2009 Paper Aim: to determine BDNF serum levels of drug-free BD patients are different than medicated BD patients or healthy controls Hypothesized: BP patients would have decreased BDNF serum levels BDNF changes would be more pronounced in drug-free BD patients than medicated patients

29. Methods No euthymic group Drug-free patients Did not take any psychotropic medications for 2 weeks Off for 5 weeks if taking: Prozac- long-acting SSRI to treat depression Depots – form of atypical antipsychotics given by injection, long-acting to promote compliance Controls Psychiatric assessment with SCID-I non-patient version

30. Results

31. Results

32. Results

33. Results

34. Conclusions BDNF serum levels are lower in patients in manic and depressive phase normalized when mood state is normalized BDNF – potential use as a marker for BD and neuronal dysfunction Proposed model for Bipolar Disorder: BD treatments that increase BDNF (PKC inhibitors or glu modulators) ? mood stabilizing & cognitive protective effect

35. Future Directions More patients Brain BDNF levels – TrkB ligand & PET scans?

36. Other Studies on BD & BDNF

37. ScienceScience

38. BDNF & Severity of Mania Machado-Vieira et al. (2007) used unmedicated bipolar patients during manic episode Plasma BDNF levels were negatively correlated with severity of mood symptoms Machado-Vieira R, Dierrich MO, Leke R et al. (2007). Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode. Biol Psychiatry 61 (2): 142-144. BDNF levels were negatively correlated with severity of mood symptoms.Machado-Vieira R, Dierrich MO, Leke R et al. (2007). Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode. Biol Psychiatry 61 (2): 142-144. BDNF levels were negatively correlated with severity of mood symptoms.

40. Bramham Messaoudi 2005Bramham Messaoudi 2005