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The Need for Long-term Treatment Options in Depression Fourth most disabling condition worldwide 1 ; most disabling condition for females (US) Increased.

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Presentation on theme: "The Need for Long-term Treatment Options in Depression Fourth most disabling condition worldwide 1 ; most disabling condition for females (US) Increased."— Presentation transcript:

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2 The Need for Long-term Treatment Options in Depression Fourth most disabling condition worldwide 1 ; most disabling condition for females (US) Increased morbidity of comorbid general medical conditions 2 and increased rate of suicide as percent of total mortality 3 Loss of productivity in workplace 2 Patients with depression use substantially more healthcare services than do patients without depression 4-6 Depression is life shortening – Increased risk of CV events, stroke, etc. 1. World Health Organization Web Site. Accessed July 7, 2005. 2. Greden JF. J Clin Psychiatry. 2001;62(suppl 22):5-9. 3. Fawcett J. Int Clin Psychopharmacol. 1993;8:217-220. 4. Rowan PJ, et al. Psychol Med. 2002;32:903-908. 5. Druss BG, et al. Am J Psychiatry. 2000;157:1274-1278. 6. Simon GE. Biol Psychiatry. 2003;54:208-215.

3 Why is Treatment of Depression so Important? MDD UK Pop. Chang CK, et al. PLoS One. 2011;6:e19590. Annual mortality risk (%) by age groups and diagnoses of mental illness, compared to England and Wales population in 2008. Life expectancy was reduced by 10.6 years for males and 7.2 years in females with MDD compared with UK population.

4 Chapter 1: Lack of Appropriate Treatment Response: Impact, and Neurobiology

5 STAR-D Remission Rates Are Generally Low Across All 4 Levels 1 Trivedi MH et al. Am J Psychiatry. 2006;163(1):28-40; 2 Trivedi MH et al. N Engl J Med. 2006;354(12):1243-1252; 3 Rush AJ et al. N Engl J Med. 2006;354(12):1231-1242; 4 Nierenberg AA et al. Am J Psychiatry. 2006;163(9):1519-1530; 5 Fava M et al. Am J Psychiatry. 2006;163(7):1161-1172; 6 McGrath PJ et al. Am J Psychiatry. 2006;163(9):1531-1541. % Remission Remission Definition: HAMD-17 ≤7 Level 1 1 11.9 weeks Level 2 2,3 8-10 weeks Level 3 4,5 ≤14 weeks Level 4 6 ≤14 weeks Low Treatment Resistance High Mono, single medication regimen; Augm, combination medication treatment.

6 STAR-D Reveals Its Secrets – The Dangers of Residual Symptoms & Lack of Remission Nierenberg AA et al. Psychol Med. 2010;40(1):41–50 Sleep disturbance Sad mood Appetite/weight Concentration Outlook Suicidal ideation Involvement Energy/fatigue Psychomotor Increasing number of symptom domains leads to increased risk of relapse (x 2 [5]=17.7155, P=0.0033) Overall 40% relapse rate 0 domains 1 domain 2 domains 3 domains 4 domains 5 domains 1.00 0.75 0.50 0.25 0.00 0102030405060 QIDS-IVR Relapse Time (Weeks) Cumulative Probability of Relapse

7 Potential Causes of Poor Response to Antidepressant Treatment Misdiagnosis Inadequate treatment, under-treatment, or starting treatment too late 1 Failure to achieve initial remission 2 Non-adherence Failure to address concurrent disorders 1 – Occult substance abuse – Occult general medical conditions (GMCs) – Concurrent Axis I or II disorders 1. Thase ME, Rush JA. J Clin Psychiatry. 1997;58(suppl 13):23-29. 2. Judd LL, et al. J Affect Disord.1998;50:97-108.

8 Number of Events Occurring During the 4-year Follow-up Period Delay of Treatment May Influence the Future Course of MDD Altamura et al. Int J Clin Pract 2007;61(10):1697-700. DUI=Duration of untreated illness, interval between the onset of the first episode and the first antidepressant treatment; MDD=Major depressive disorder. *p=0.027 RecurrencesHospitalizationsSuicide Attempts 0 2.5 2.0 1.5 1.0 0.5 DUI >12 Months (n=23) DUI ≤12 Months (n=45) 2.17* 1.24 0.65 0.31 0.20 0.39

9 Is antidepressant resistance a precursor to Bipolar Disorder? 30 – DTT 25 – 20 – 15 – ITT 10 – ETT-1 ETT-2 5– 0– 2000 2001 2002 2003 2004 2005 2006 2007 Participants with medication-resistant history (difficult-to-treat group (DTT)) without any antidepressant use (easy-to-treat group 1 (ETT-1)) or those without any change in antidepressant (easy-to-treat group 2 (ETT-2)). Participants who changed antidepressant just once, after an adequate antidepressant trial (intermediate level of difficulty to treat (ITT)). Rates of diagnosis change from MDD to bipolar disorder Li et al, 2011, Br J Psychiatry, in press

10 Patients With MDD Who Did Not Respond to Antidepressants Had Higher Inflammatory Cytokine Levels p=0.01 p=0.004 24 healthy controls and 28 patients with depression (HAMD 17 >20) after 6 weeks of SSRI treatment and 16 euthymic patients (previously resistant to SSRIs) currently successfully treated with an SNRI or an addition of lithium to SSRI treatment. HAM-D=Hamilton depression score; MDD=Major depressive disorder; SNRI=Serotonin–norepinephrine reuptake inhibitor; SSRI=Selective serotonin reuptake inhibitor; TNF=Tumor necrosis factor. O’Brien SM, et al. J Psychiatr Res. 2007;41:326–331. Controls Depressed Euthymic TNF-  IL-6 TNF-  (pg/ml) IL-6 (pg/ml)

11 Remission May Protect the Brain From Long-Term Depression-Related Changes In this prospective, longitudinal study, 38 participants with MDD and 30 controls were followed for 3 years. At the start and end of this period all participants had brain morphometry assessed by MRI. Patients with MDD who went into remission showed significantly less volume reduction in brain areas of direct relevance to the path- ophysiology of MDD when compared to patients with MDD who did not achieve remission. Frodl TS et al. Arch Gen Psychiatry 2008;65(10):1156-1165.

12 Chapter 2: Inflammation and Depression: Cause, Consequence or Collaborator ?

13 Stress and inflammation in MDD Raison et al, Arch Gen Psychiatry. 2010;67(12):1211-1224

14 Inflammatory Markers Predict the Future Development of Depression Pasco et al. Brit J Psychiatry 2010, 197:372-377. In a cohort of 644 initially non-depressed females, 48 developed de novo MDD over an approximate 10 year follow up. Survival plot (Kaplan-Meier) showing the probability of remaining free of de novo major depressive disorder for women stratified into tertiles of hsCRP. The concentration of hsCRP in each tertile is: low, 2.97 mg.l.

15 *Correlations of IL-6 level with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correction IL-6=Interleukin-6; MDD=Major depressive disorder; VAS=Visual analogue scale. Inflammatory Cytokine Levels May Be Associated With Symptom Severity in MDD Patients Alesci et al. J Clin Endocrinol Metab 2005;90(5):2522-30. Comparison of 9 MDD patients with 9 matched healthy controls

16 Elevation of Inflammatory Cytokines in CSF May Alter 5-HT and DA Metabolism Inflammatory cytokines and monoamine metabolites were compared in 63 suicide attempters and 47 healthy controls. MADRS scores correlated significantly with CSF IL-6 levels. IL-6 and TNF-alpha correlated with CSF 5-HIAA (5-hydroxyindoleacetic acid) and HVA (homovanillic acid).Higher cytokine levels were associated with increased suicidality. Lindqvist D, et al. Biol Psychiatry. 2009;66:287-292.

17 Glia–Neuron Interaction May Influence Neurotrophic Factors Miller et al. Biol Psychiatry 2009;65(9):732-41.

18 Relationship between Depression & Inflammatory Cytokines and Neurotrophic Factors Positive correlation between depression and IL-6 Negative correlation between depression and brain-derived neurotrophic factor Yoshimura R, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(4):722–726.

19 Chapter 3: Obesity and Depression: A Path to Consternation?

20 Relationship Between Obesity, Metabolic Syndrome and Depression Association between the metabolic syndrome (MetS) and depression in each body massindex (BMI) category.Graph displays the odds ratio (OR) for depression after adjustment for age, gender, prior cardiovascular disease, employment status, marital status, smoking status, dietary score, and physical activity. Obesity was defined as a BMI 30 and overweight status as a BMI between 25 and 30 kg/m 2 Skilton et al, 2007, Biol Psychiatry, 62(11): 1251-7. Odds Ratio - Depression

21 Adiposity, Inflammation and Depression High caloric intake in the diet leads to increased accumulations of lipids in adipocytes. Increased lipid content results in an increased release of MCP-1 (CCL2), a chemoattractant that increases the infiltration of macrophages into adipose tissue. Both adipocytes and macrophages release inflammatory mediators such as IL-6 and TNFa into the peripheral circulation. Shelton and Miller, Progress in Neurobiology 91 (2010) 275–299

22 MDD, Adiposity and Inflammatory Markers Miller GE et al. Am J of Cardiol. 2002;90(12):1279-83 50 MDD patients compared with 50 healthy matched controls

23 Kloiber et al. Biol Psychiatry. 2007, 62(4): 321-6 Body Mass Index Impacts Antidepressant Response Response to antidepressant treatment according to weight status. Mean Hamilton Depression test (HAM-D) rating scores and SEMs for 5 weeks after hospitalization (left) in normal-body mass index (BMI) and high-BMI patients and (right) in normal-BMI, overweight, and obese patients 29 27 25 23 21 19 17 15 13 BMI ≤25 BMI >25 admissionweek 1week 2week 3week 4week 5 HAM-D score admissionweek 1week 2week 3week 4week 5 29 27 25 23 21 19 17 15 13 31 BMI ≤25 25< BMI ≤30 BMI >30

24 Chapter 4: Fascinating Folate: 1.Genetic Regulation of Folate Metabolism 2.Two Sides of the Coin : L-methylfolate and Homocysteine 3.The Role of L-methylfolate in Tri-Monoamine Synthesis

25 Folate Essentials: Folate is a B-vitamin that cannot be synthesized de novo by the body; it must be derived from diet or augmentation Dietary folate found in leafy green vegetables, legumes, beans, liver, citrus fruits and yeast Folic acid is a synthetic molecule more highly absorbed (85-95%) than is dietary folate (dihydrofolate) Multiple biochemical conversions required for dietary folate (or folic acid) to become metabolically active Miller, A.L. Alt Med Rev 2008;13:216-26

26 Williams FF et al. Pharmacokinetic Study on the Utilization of 5-methyltetrahydrofolate and Folic Acid in Patients with Coronary Artery Disease. Br J Pharmacol. 2004;141(5):825-30. DHF Reductase Dihydrofolate Tetrahydrofolate 10-formyl-THF 5,10 Methyenyl THF 5,10 Methylene THF 5-MTHF5-MTHF MTHFD1 Folate Metabolism BBB MTHFR 5-MTHF5-MTHF Synthetic Folic Acid

27 Morris DW et al. J Altern Complement Med. 2008;14(3):277-285; Miller AL. Alt Med Rev. 2008;13(3):216-226; Stahl SM. J Clin Psychiatry. 2008;69(9):1352-1353; Farah A. CNS Spectr. 2009;14(1 Suppl 2):2-7. The Folate Cycle From 10,000 Feet MethionineHomocysteineCycle

28 cardiovascular, metabolic and psychiatric disturbance Homocysteine and NMDA Toxicity HOMOCYSTEINEHCS0 4 HMS0 3 SAH Glutamatergic NMDA agonism Glutamatergic NMDA agonism Reduced trophic support Reduced kyn acid Reduced NMDA antagonism Excitotoxic Cell death Haroon et al. Neuropsychopharmacol 2011; Epub; Oxenkrug. J Neural Trans 2011; Epub; B ottiglieri. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1103-12

29 Interface of inflammation and neurotransmitter synthesis in MDD Tetrahydrobiopterin (BH4) is a critical cofactor for the rate-limiting enzymes involved in the synthesis of the monoamine neurotransmitters, including (1) the synthesis of tyrosine (tyr) from phenylalanine (phe) by PAH; (2) the synthesis of L- 3,4-dihydroxyphenylalanine (L-DOPA) from tyrosine (tyr) by tyrosine hydroxylase (TH) leading to the production of dopamine and norepinephrine; and (3) the synthesis of 5-hydoxy-L-tryptophan (5-HTP) from tryptophan (tryp). BH4 is degraded to BH2, which can be regenerated to BH4 through pathways supported by folic acid, L-methylfolate, and SAMe. BH4 is relatively unstable and in the context of inflammation and oxidative stress can undergo non-enzymatic oxidation leading to the irreversible degradation of BH4 to XPH2. Haroon et al,2011,Neuropsychopharmacology, in press

30 L-Methylfolate is a Required Cofactor for Monoamine Synthesis 1 1.Adapted from: Bottiglieri T. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2005;29:1103-12. 2.Stahl SM. L-Methylfolate: A Vitamin for Your Monoamines. J Clin Psychiatry. 2008. 69;9:1352-53. 3. Borjigin J. et al, Circa Circa dian regulation of pineal gland rhythmicity. Mol Cell Endocrinol, 2011, in press Robust levels of CNS L-methylfolate may be necessary to maximize monoamine synthesis. 2 MTHFRMTHFR TryptophanhydroxylaseTryptophanhydroxylase L-methylfolate TyrosinehydoxylaseTyrosinehydoxylase BLOOD CNS TryptophanTryptophan TyrosineTyrosine BH 4 NorepinephrineNorepinephrine DopamineDopamine MelatoninMelatonin SerotoninSerotonin

31 Up to 70% of MDD Patients Have a Genetic Mutation Reducing Ability to Convert Folic Acid to L-methylfolate 1.Kelly CB et al. J Psychopharmacol. 2004;18(4):567-71. 2.Bottiglieri T et al. J Neurol Neurosurg Psychiatry. 2000;69:228-32. 3.Surtees R, Heales S, & Bowron. Clinical Science. 1994;86:697-702. Patients with the C677T MTHFR polymorphism have low CNS L-methylfolate. 1 Patients with the C677T MTHFR polymorphism have low CNS L-methylfolate. 1 Low CNS L-methylfolate is associated with low production of serotonin, norepinephrine and dopamine. 2,3 Low CNS L-methylfolate is associated with low production of serotonin, norepinephrine and dopamine. 2,3 C/TPolymorphism56% C/CPolymorphism30% T/T Polymorphism14% C/C C/T T/T

32 Risk Factors for Low CNS L-methylfolate 1. Bottiglieri T. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2005;29:1103-12.; 2. Stahl SM.J Clin Psychiatry. 2008;69(9):1352-53.; 3. Kelly B J et al. Psychopharmacol. 2004;18(4):567-71.; 4. Amilburu A et al. Inhibition of intestinal absorption of 5-methyltetrahydrofolate by fluoxetine. J Physiol Biochem. 2201;57(2):71-80; 5. Sobczyriska-Malefora A et al. Erythrocyte folate and 5-methyltetrahydrofolate levels decline during 6 months of oral anticoagulation with warfarin. Blood Coagul Fibrinolysis. 2009; Jun;20(4):297-302.; 6. Kelly CB et al. J Psychopharmacol. 2004;18(4):567-71; 7. Bottiglieri T et al. J Neurol Neurosurg Psychiatry. 2000;69:228-32.; 8. Surtees R, Heales S, & Bowron. Clinical Science. 1994;86:697-702. Anticonvulsants such as lamotrigine, carbamezapine, phenobarbital and valproate, methotrexate, sulphasalazine, oral contraceptives, metformin, niacin and fenofibrates, fluoxetine, warfarin Drugs Diabetes, atrophic gastritis, Crohn’s, colitis, bypass surgery, renal failure and hypothyroidism Disease Excess alcohol, smoking and poor nutrition Lifestyle CNS L-methylfolate levels markedly decrease in individuals over 70 years of age Aging

33 Chapter 5: Folate: Clinical Studies and Their Usefulnes in Clinical Practice

34 Study Inclusion Criteria Study Subjects Adults meeting DSM-IV criteria for MDD, current QIDS-SR ≥12 at screen and baseline visit Has not failed more than 2 antidepressant trials of adequate dose and adequate duration in current MDE (adequate duration = at least 8 weeks) Treated with SSRI during current episode for ≥8 weeks with stable SSRI dose in therapeutic range X 4 weeks 75 depressed patients with inadequate response to SSRIs were enrolled in a 60-day trial which was divided into two, 30-day periods (Phases 1 and 2).

35 SSRI + L-methylfolate 15mg SSRI + L-methylfolate 15mg Efficacy Analysis SPCD Trial Design Phase 1 30 days Phase 2 30 days Group X is included in Phase 2 for the purpose of blinding but not in the study results. Groups 1 and 2 were pooled for L-methylfolate analysis and groups 3-5 were pooled for the placebo analysis. SSRI + Placebo Randomize Non Responders Non Responders SSRI + Placebo 134 52X SSRI + L-methylfolate 15mg

36 Efficacy Results of Study II HDRS-17 Response Rates – 30 Days * *p=0.04 (pooled) % of Patients with 50% Reduction HDRS-17 L-Methylfolate Placebo

37 Safety Results and Overall Discontinuation n = 1/42n = 2/54 % of Patient Discontinuation N/S L-methylfolate patient was removed from the trial due to mood elevation. Patient’s medical history included bipolar disorder which was not detected at baseline. No Difference in Discontinuation Due to Adverse Events

38 HDRS-28 Treatment Effect by MTHFR C677T Genotype CC CT TT Phase I N = 39 18 6 Phase II N = 20 8 4

39 Efficacy Results and Obesity HDRS-17 Mean Change – 30 Days

40 Efficacy Results and Obesity CGI Mean Change – 30 Days

41 Summary: L-methylfolate 15mg/day as adjunctive treatment to antidepressant therapy resulted in superior treatment outcome in 30 days (efficacy) compared to continued antidepressant therapy plus placebo in: – both co-primary outcome measures achieving statistical significance in: response rates (50% ↓HDRS-17, p=0.04) degree of improvement (Reduction in HDRS-17, p=0.05) – as well as in most secondary measures, including change in scores QIDS-SR (p=0.04) Clinical Global Impression Severity scale (CGI-S, p=0.01) Obese patients (BMI > 30; HDRS-17, p = 0.02; CGI-S, p = 0.001) Genetic variations of folate metabolism Clinical management of MDD may be optimized with adjuvant L-methylfolate 15mg.


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